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51. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

Author

Juran, B, Hirschfield, G, Invernizzi, P, Atkinson, E, Li, Y, Xie, G, Kosoy, R, Ransom, M, Sun, Y, Bianchi, I, Schlicht, E, Lleo, A, Coltescu, C, Bernuzzi, F, Podda, M, Lammert, C, Shigeta, R, Chan, L, Balschun, T, Marconi, M, Cusi, D, Heathcote, E, Mason, A, Myers, R, Milkiewicz, P, Odin, J, Luketic, V, Bacon, B, Bodenheimer, H, Liakina, V, Vincent, C, Levy, C, Franke, A, Gregersen, P, Bossa, F, Gershwin, M, Deandrade, M, Amos, C, Italian PBC Genetics Study, G, Lazaridis, K, Seldin, M, Siminovitch, K, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Crocè, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Fontana, R, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Malinverno, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Juran, BD, Hirschfield, GM, INVERNIZZI, PIETRO, Atkinson, EJ, Schlicht, EM, Bernuzzi, Francesca Veronica, Chan, LL, Heathcote, EJ, Mason, AL, Myers, RP, Odin, JA, Luketic, VA, Bacon, BR, Bodenheimer, HC Jr, Gregersen, PK, Gershwin, ME, deAndrade, M, Amos, CI, Italian PBC Genetics Study Group, Lazaridis, KN, Seldin, MF, Siminovitch, KA, Almasio, PL, Battezzati, PM, Crocè, LS, Niro, GA, STRAZZABOSCO, MARIO, Zuin, M., Juran, B, Hirschfield, G, Invernizzi, P, Atkinson, E, Li, Y, Xie, G, Kosoy, R, Ransom, M, Sun, Y, Bianchi, I, Schlicht, E, Lleo, A, Coltescu, C, Bernuzzi, F, Podda, M, Lammert, C, Shigeta, R, Chan, L, Balschun, T, Marconi, M, Cusi, D, Heathcote, E, Mason, A, Myers, R, Milkiewicz, P, Odin, J, Luketic, V, Bacon, B, Bodenheimer, H, Liakina, V, Vincent, C, Levy, C, Franke, A, Gregersen, P, Bossa, F, Gershwin, M, Deandrade, M, Amos, C, Italian PBC Genetics Study, G, Lazaridis, K, Seldin, M, Siminovitch, K, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Crocè, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Fontana, R, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Malinverno, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Juran, BD, Hirschfield, GM, INVERNIZZI, PIETRO, Atkinson, EJ, Schlicht, EM, Bernuzzi, Francesca Veronica, Chan, LL, Heathcote, EJ, Mason, AL, Myers, RP, Odin, JA, Luketic, VA, Bacon, BR, Bodenheimer, HC Jr, Gregersen, PK, Gershwin, ME, deAndrade, M, Amos, CI, Italian PBC Genetics Study Group, Lazaridis, KN, Seldin, MF, Siminovitch, KA, Almasio, PL, Battezzati, PM, Crocè, LS, Niro, GA, STRAZZABOSCO, MARIO, and Zuin, M.

Abstract

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

Published
2012

52. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis

Author

Invernizzi, P, Ransom, M, Raychaudhuri, S, Kosoy, R, Lleo, A, Shigeta, R, Franke, A, Bossa, F, Amos, C, Gregersen, P, Siminovitch, K, Cusi, D, de Bakker, P, Podda, M, Gershwin, M, Seldin, M, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Marra, F, Marzioni, M, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Moroni, L, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Prisco, C, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, INVERNIZZI, PIETRO, Amos, CI, Gregersen, PK, Siminovitch, KA, de Bakker, PI, Gershwin, ME, Seldin, MF, Almasio, PL, Bernuzzi, Francesca Veronica, Bragazzi, MC, Croce, LS, STRAZZABOSCO, MARIO, Zuin, M., Invernizzi, P, Ransom, M, Raychaudhuri, S, Kosoy, R, Lleo, A, Shigeta, R, Franke, A, Bossa, F, Amos, C, Gregersen, P, Siminovitch, K, Cusi, D, de Bakker, P, Podda, M, Gershwin, M, Seldin, M, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Marra, F, Marzioni, M, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Moroni, L, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Prisco, C, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, INVERNIZZI, PIETRO, Amos, CI, Gregersen, PK, Siminovitch, KA, de Bakker, PI, Gershwin, ME, Seldin, MF, Almasio, PL, Bernuzzi, Francesca Veronica, Bragazzi, MC, Croce, LS, STRAZZABOSCO, MARIO, and Zuin, M.

Abstract

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.

Published
2012

53. Genome-wide association study identifies three new melanoma susceptibility loci

Author

Barrett, JH, Iles, MM, Harland, M, Taylor, JC, Aitken, JF, Andresen, PA, Akslen, LA, Armstrong, BK, Avril, M-F, Azizi, E, Bakker, B, Bergman, W, Bianchi-Scarra, G, Bressac-de Paillerets, B, Calista, D, Cannon-Albright, LA, Corda, E, Cust, AE, Debniak, T, Duffy, D, Dunning, AM, Easton, DF, Friedman, E, Galan, P, Ghiorzo, P, Giles, GG, Hansson, J, Hocevar, M, Hoeiom, V, Hopper, JL, Ingvar, C, Janssen, B, Jenkins, MA, Joensson, G, Kefford, RF, Landi, G, Landi, MT, Lang, J, Lubinski, J, Mackie, R, Malvehy, J, Martin, NG, Molven, A, Montgomery, GW, van Nieuwpoort, FA, Novakovic, S, Olsson, H, Pastorino, L, Puig, S, Puig-Butille, JA, Randerson-Moor, J, Snowden, H, Tuominen, R, VanBelle, P, van der Stoep, N, Whiteman, DC, Zelenika, D, Han, J, Fang, S, Lee, JE, Wei, Q, Lathrop, GM, Gillanders, EM, Brown, KM, Goldstein, AM, Kanetsky, PA, Mann, GJ, MacGregor, S, Elder, DE, Amos, CI, Hayward, NK, Gruis, NA, Demenais, F, Bishop, JAN, Bishop, DT, Barrett, JH, Iles, MM, Harland, M, Taylor, JC, Aitken, JF, Andresen, PA, Akslen, LA, Armstrong, BK, Avril, M-F, Azizi, E, Bakker, B, Bergman, W, Bianchi-Scarra, G, Bressac-de Paillerets, B, Calista, D, Cannon-Albright, LA, Corda, E, Cust, AE, Debniak, T, Duffy, D, Dunning, AM, Easton, DF, Friedman, E, Galan, P, Ghiorzo, P, Giles, GG, Hansson, J, Hocevar, M, Hoeiom, V, Hopper, JL, Ingvar, C, Janssen, B, Jenkins, MA, Joensson, G, Kefford, RF, Landi, G, Landi, MT, Lang, J, Lubinski, J, Mackie, R, Malvehy, J, Martin, NG, Molven, A, Montgomery, GW, van Nieuwpoort, FA, Novakovic, S, Olsson, H, Pastorino, L, Puig, S, Puig-Butille, JA, Randerson-Moor, J, Snowden, H, Tuominen, R, VanBelle, P, van der Stoep, N, Whiteman, DC, Zelenika, D, Han, J, Fang, S, Lee, JE, Wei, Q, Lathrop, GM, Gillanders, EM, Brown, KM, Goldstein, AM, Kanetsky, PA, Mann, GJ, MacGregor, S, Elder, DE, Amos, CI, Hayward, NK, Gruis, NA, Demenais, F, Bishop, JAN, and Bishop, DT

Abstract

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Published
2011

54. Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

Author

MacGregor, S, Montgomery, GW, Liu, JZ, Zhao, ZZ, Henders, AK, Stark, M, Schmid, H, Holland, EA, Duffy, DL, Zhang, M, Painter, JN, Nyholt, DR, Maskiell, JA, Jetann, J, Ferguson, M, Cust, AE, Jenkins, MA, Whiteman, DC, Olsson, H, Puig, S, Bianchi-Scarra, G, Hansson, J, Demenais, F, Landi, MT, Debniak, T, Mackie, R, Azizi, E, Bressac-de Paillerets, B, Goldstein, AM, Kanetsky, PA, Gruis, NA, Elder, DE, Newton-Bishop, JA, Bishop, DT, Iles, MM, Helsing, P, Amos, CI, Wei, Q, Wang, L-E, Lee, JE, Qureshi, AA, Kefford, RF, Giles, GG, Armstrong, BK, Aitken, JF, Han, J, Hopper, JL, Trent, JM, Brown, KM, Martin, NG, Mann, GJ, Hayward, NK, MacGregor, S, Montgomery, GW, Liu, JZ, Zhao, ZZ, Henders, AK, Stark, M, Schmid, H, Holland, EA, Duffy, DL, Zhang, M, Painter, JN, Nyholt, DR, Maskiell, JA, Jetann, J, Ferguson, M, Cust, AE, Jenkins, MA, Whiteman, DC, Olsson, H, Puig, S, Bianchi-Scarra, G, Hansson, J, Demenais, F, Landi, MT, Debniak, T, Mackie, R, Azizi, E, Bressac-de Paillerets, B, Goldstein, AM, Kanetsky, PA, Gruis, NA, Elder, DE, Newton-Bishop, JA, Bishop, DT, Iles, MM, Helsing, P, Amos, CI, Wei, Q, Wang, L-E, Lee, JE, Qureshi, AA, Kefford, RF, Giles, GG, Armstrong, BK, Aitken, JF, Han, J, Hopper, JL, Trent, JM, Brown, KM, Martin, NG, Mann, GJ, and Hayward, NK

Abstract

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Published
2011

55. Evaluation of Association of HNF1B Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies

Author

Kronenberg, F, Elliott, KS, Zeggini, E, McCarthy, MI, Gudmundsson, J, Sulem, P, Stacey, SN, Thorlacius, S, Amundadottir, L, Groenberg, H, Xu, J, Gaborieau, V, Eeles, RA, Neal, DE, Donovan, JL, Hamdy, FC, Muir, K, Hwang, S-J, Spitz, MR, Zanke, B, Carvajal-Carmona, L, Brown, KM, Hayward, NK, Macgregor, S, Tomlinson, IPM, Lemire, M, Amos, CI, Murabito, JM, Isaacs, WB, Easton, DF, Brennan, P, Barkardottir, RB, Gudbjartsson, DF, Rafnar, T, Hunter, DJ, Chanock, SJ, Stefansson, K, Ioannidis, JPA, Kronenberg, F, Elliott, KS, Zeggini, E, McCarthy, MI, Gudmundsson, J, Sulem, P, Stacey, SN, Thorlacius, S, Amundadottir, L, Groenberg, H, Xu, J, Gaborieau, V, Eeles, RA, Neal, DE, Donovan, JL, Hamdy, FC, Muir, K, Hwang, S-J, Spitz, MR, Zanke, B, Carvajal-Carmona, L, Brown, KM, Hayward, NK, Macgregor, S, Tomlinson, IPM, Lemire, M, Amos, CI, Murabito, JM, Isaacs, WB, Easton, DF, Brennan, P, Barkardottir, RB, Gudbjartsson, DF, Rafnar, T, Hunter, DJ, Chanock, SJ, Stefansson, K, and Ioannidis, JPA

Abstract

BACKGROUND: Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only. METHODOLOGY/PRINCIPAL FINDINGS: In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10(-15) for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10(-15) for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association. CONCLUSIONS/SIGNIFICANCE: The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types.

Published
2010

56. Association between Acquired Uniparental Disomy and Homozygous Mutations and HER2/ER/PR Status in Breast Cancer

Author

Tuna, M, Smid, Marcel, Zhu, DK, Martens, John, Amos, CI, Tuna, M, Smid, Marcel, Zhu, DK, Martens, John, and Amos, CI

Abstract

Background: Genetic alterations in cellular signaling networks are a hallmark of cancer, however, effective methods to discover them are lacking. A novel form of abnormality called acquired uniparental disomy (aUPD) was recently found to pinpoint the region of mutated genes in various cancers, thereby identifying the region for next-generation sequencing. Methods/Principal Findings: We retrieved large genomic data sets from the Gene Expression Omnibus database to perform genome-wide analysis of aUPD in breast tumor samples and cell lines using approaches that can reliably detect aUPD. aUPD was identified in 52.29% of the tumor samples. The most frequent aUPD regions were located at chromosomes 2q, 3p, 5q, 9p, 9q, 10q, 11q, 13q, 14q and 17q. We evaluated the data for any correlation between the most frequent aUPD regions and HER2/neu, ER, and PR status, and found a statistically significant correlation between the recurrent regions of aUPD and triple negative (TN) breast cancers. aUPD at chromosome 17q (VEZF1, WNT3), 3p (SUMF1, GRM7), 9p (MTAP, NFIB) and 11q (CASP1, CASP4, CASP5) are predictors for TN. The frequency of aUPD was found to be significantly higher in TN breast cancer cases compared to HER2/neu-positive and/or ER or PR-positive cases. Furthermore, using previously published mutation data, we found TP53 homozygously mutated in cell lines having aUPD in that locus. Conclusions/Significance: We conclude that aUPD is a common and non-random molecular feature of breast cancer that is most prominent in triple negative cases. As aUPD regions are different among the main pathological subtypes, specific aUPD regions may aid the sub-classification of breast cancer. In addition, we provide statistical support using TP53 as an example that identifying aUPD regions can be an effective approach in finding aberrant genes. We thus conclude that a genome-wide scale analysis of aUPD regions for homozygous sequence alterations can provide valuable insights into breast tumor

Published
2010

57. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

Author

Liu, X, Invernizzi, P, Lu, Y, Kosoy, R, Bianchi, I, Podda, M, Xu, C, Xie, G, Macciardi, F, Selmi, C, Lupoli, S, Shigeta, R, Ransom, M, Lleo, A, Lee, A, Mason, A, Myers, R, Peltekian, K, Ghent, C, Bernuzzi, F, Zuin, M, Rosina, F, Borghesio, E, Floreani, A, Lazzari, R, Niro, G, Andriulli, A, Muratori, L, Muratori, P, Almasio, P, Andreone, P, Margotti, M, Brunetto, M, Coco, B, Alvaro, D, Bragazzi, M, Marra, F, Pisano, A, Rigamonti, C, Colombo, M, Marzioni, M, Benedetti, A, Fabris, L, Strazzabosco, M, Portincasa, P, Palmieri, V, Tiribelli, C, Croce, L, Bruno, S, Rossi, S, Vinci, M, Prisco, C, Mattalia, A, Toniutto, P, Picciotto, A, Galli, A, Ferrari, C, Colombo, S, Casella, G, Morini, L, Caporaso, N, Colli, A, Spinzi, G, Montanari, R, Gregersen, P, Heathcote, E, Hirschfield, G, Siminovitch, K, Amos, C, Gershwin, M, Seldin, M, INVERNIZZI, PIETRO, Lee, AT, Mason, AL, Myers, RP, Peltekian, KM, Ghent, CN, Bernuzzi, Francesca Veronica, Almasio, PL, Bragazzi, MC, STRAZZABOSCO, MARIO, Palmieri, VO, Gregersen, PK, Heathcote, EJ, Hirschfield, GM, Siminovitch, KA, Amos, CI, Gershwin, ME, Seldin, MF, Liu, X, Invernizzi, P, Lu, Y, Kosoy, R, Bianchi, I, Podda, M, Xu, C, Xie, G, Macciardi, F, Selmi, C, Lupoli, S, Shigeta, R, Ransom, M, Lleo, A, Lee, A, Mason, A, Myers, R, Peltekian, K, Ghent, C, Bernuzzi, F, Zuin, M, Rosina, F, Borghesio, E, Floreani, A, Lazzari, R, Niro, G, Andriulli, A, Muratori, L, Muratori, P, Almasio, P, Andreone, P, Margotti, M, Brunetto, M, Coco, B, Alvaro, D, Bragazzi, M, Marra, F, Pisano, A, Rigamonti, C, Colombo, M, Marzioni, M, Benedetti, A, Fabris, L, Strazzabosco, M, Portincasa, P, Palmieri, V, Tiribelli, C, Croce, L, Bruno, S, Rossi, S, Vinci, M, Prisco, C, Mattalia, A, Toniutto, P, Picciotto, A, Galli, A, Ferrari, C, Colombo, S, Casella, G, Morini, L, Caporaso, N, Colli, A, Spinzi, G, Montanari, R, Gregersen, P, Heathcote, E, Hirschfield, G, Siminovitch, K, Amos, C, Gershwin, M, Seldin, M, INVERNIZZI, PIETRO, Lee, AT, Mason, AL, Myers, RP, Peltekian, KM, Ghent, CN, Bernuzzi, Francesca Veronica, Almasio, PL, Bragazzi, MC, STRAZZABOSCO, MARIO, Palmieri, VO, Gregersen, PK, Heathcote, EJ, Hirschfield, GM, Siminovitch, KA, Amos, CI, Gershwin, ME, and Seldin, MF

Abstract

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

Published
2010

58. Evidence for a founder effect of the MPL-S505N mutation in eight Italian pedigrees with hereditary thrombocythemia

Author

Liu, K, Martini, Maurizio, Rocca, Bianca, Amos, Ci, Teofili, Luciana, Giona, F, Ding, J, Komatsu, H, Larocca, Luigi Maria, Skoda, Rc, Martini, Maurizio (ORCID:0000-0002-6260-6310), Rocca, Bianca (ORCID:0000-0001-8304-6423), Teofili, Luciana (ORCID:0000-0002-7214-1561), Larocca, Luigi Maria (ORCID:0000-0003-1739-4758), Liu, K, Martini, Maurizio, Rocca, Bianca, Amos, Ci, Teofili, Luciana, Giona, F, Ding, J, Komatsu, H, Larocca, Luigi Maria, Skoda, Rc, Martini, Maurizio (ORCID:0000-0002-6260-6310), Rocca, Bianca (ORCID:0000-0001-8304-6423), Teofili, Luciana (ORCID:0000-0002-7214-1561), and Larocca, Luigi Maria (ORCID:0000-0003-1739-4758)

Abstract

Hereditary thrombocythemia is a rare disease characterized by increased megakaryopoiesis and overproduction of platelets. Germ line mutations have been identified in the genes for thrombopoietin (THPO) and its receptor, MPL. A clustering of familial cases with the MPL-G1073A mutation that results in a serine to asparagine substitution (S505N) has been recently reported in Italy. Here we performed haplotype analysis in nine families (eight Italian and one Japanese) with hereditary thrombocythemia carrying the MPL-S505N mutation in the MPL gene.

Published
2009

59. BIRTH-ORDER, DELIVERY ROUTE, AND CONCORDANCE IN THE TRANSMISSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 FROM MOTHERS TO TWINS

Author

DULIEGE, AM, AMOS, CI, FELTON, S, BIGGAR, RJ, ZIEGLER, J, CRUIKSHANK, M, LEVY, J, MEATES, MA, GIBB, D, MAYAUX, MJ, TEGLAS, JP, LAURENT, C, BLANCHE, S, ROUZIOUX, C, HELLINGGIESE, G, MATTNER, U, HOEGER, PH, CONLON, T, GRIFFIN, E, DEMARIA, A, BENEDETTO, A, PRINCIPI, N, GIAQUINTO, C, GIANCOMELLI, A, MOK, J, CASABONA, J, FORTUNY, C, URIZ, S, PEREZ, JM, TUSETRUIZ, MC, LEON, P, ELORZA, JFY, CANOSA, C, BRANDLE, B, SEGER, R, NADAL, D, IRION, O, WYLER, CA, DAVIS, P, LALLEMANT, M, LALLEMANTLECOEUR, S, HITIMANA, DG, LEPAGE, P, VANDEPERRE, P, DABIS, F, MARUM, L, NDUGWA, C, TINDYEBWA, D, ACENG, E, MMIRO, F, SUTONGAS, T, OLNESS, K, LAPOINTE, N, RUBINSTEIN, A, BURGE, D, STECHENBERG, BW, COOPER, E, REGAN, AM, SHIPKOWITZ, S, WIZNIA, A, BRUNELL, PA, COURVILLE, T, RUTSTEIN, R, MCINTOSH, K, PETRU, A, OLEARY, M, CHURCH, J, TAYLOR, S, SQUIRES, J, MALLORY, M, YOGEV, R, RAKUSAN, T, PLUMLEY, S, SHELTON, MM, WILFERT, C, LANE, B, ABRAMS, EJ, RANA, S, CHANDAVASU, O, PUVABANDITSIN, S, CHOW, JH, SHAH, K, NACHMAN, S, ONEILL, R, SELWYN, P, SHOENBAUM, E, BARZILAI, A, WARFORD, R, AHERN, L, PAHWA, S, PNUGOTI, N, GARCIATRIAS, DE, BAKSHI, S, LANDESMAN, S, MENDEZ, H, MOROSO, G, MENDEZBAUTISTA, RD, FIKRIG, S, BELMAN, A, KLINE, MW, HANSON, C, EDELSON, P, HINDS, G, VANDYKE, R, CLARK, R, WARA, DW, MANIO, EB, JOHNSON, G, WELLS, L, JOHNSON, JP, ALGER, L, LUZURIAGA, K, MASTRUCCI, T, SUNKUTU, MR, RODRIGUEZ, Z, DOYLE, M, REUBEN, J, BRYSON, Y, DILLON, M, SIMPSON, BJ, ANDIMAN, W, URIBE, P, Klauke, B., and University of Groningen

Subjects
RISK, HIV-1 INFECTION, ANTIBODIES, WOMEN, INFANTS, CHILDREN, POLYMERASE CHAIN-REACTION, DIAGNOSIS, LABOR, SECRETIONS
Abstract

Background: We evaluated data from prospectively identified twins to understand better the mechanisms and covariates of mother-to-infant transmission of human immunodeficiency virus (HIV). Methods: Using data obtained from an international collaboration and multivariate quasilikelihood modeling, we assessed concordance, birth order, route of delivery, and other factors for HIV infection in 115 prospectively studied twin pairs born to HIV-infected women. Actuarial methods were used to evaluate overall survival and survival free of acquired immunodeficiency syndrome for HIV-infected twins. Results: Infection with HIV occurred in 35% of vaginally delivered firstborn (A) twins, 16% of cesarean-delivered A twins, 15% of vaginally delivered second-born (B) twins, and 8% of cesarean-delivered B twins. In a multivariate model, the adjusted odds ratios for HIV infection were 11.8 (confidence interval: 3.1 to 45.3) for concordance of infection with the co-twin, 2.8 (confidence interval: 1.6 to 5.0) for A versus B twins, and 2.7 (confidence interval: 1.1 to 6.6) for vaginally delivered versus cesarean-delivered twins. Among A twins, 52% (lower confidence limit: 6%) of the transmission risk was related to vaginal delivery, Comparing vaginally delivered A twins (infants most exposed to vaginal mucus and blood) to cesarean-delivered B twins (infants least exposed), 76% (lower confidence limit: 48%) of the transmission risk was related to vaginal exposure. Infected B twins had slightly reduced Quetelet indexes and more rapid development of illnesses related to acquired immunodeficiency syndrome. Conclusions: These results indicate that HIV infection of B twins occurs predominantly in utero, whereas infection of A twins (and, by implication, singletons) occurs predominantly intrapartum, We propose that intrapartum transmission is responsible for the majority of pediatric HIV infections and that reducing exposure to HIV in the birth canal may reduce transmission of the virus from mother to infant.

Published
1995

62. Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.

Author

Wu X, Ye Y, Rosell R, Amos CI, Stewart DJ, Hildebrandt MA, Roth JA, Minna JD, Gu J, Lin J, Buch SC, Nukui T, Ramirez Serrano JL, Taron M, Cassidy A, Lu C, Chang JY, Lippman SM, Hong WK, and Spitz MR

Abstract

Background: Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).Methods: To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.Results: SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).Conclusion: These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients. [ABSTRACT FROM AUTHOR]

Published
2011
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63. Nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk among African Americans: a case-control study.

Author

Amos CI, Gorlov IP, Dong Q, Wu X, Zhang H, Lu EY, Scheet P, Greisinger AJ, Mills GB, Spitz MR, Amos, Christopher I, Gorlov, Ivan P, Dong, Qiong, Wu, Xifeng, Zhang, Huifeng, Lu, Emily Y, Scheet, Paul, Greisinger, Anthony J, Mills, Gordon B, and Spitz, Margaret R

Abstract

Genome-wide association studies of white persons with lung cancer have identified a region of extensive linkage disequilibrium on chromosome 15q25.1 that appears to be associated with both risk for lung cancer and smoking dependence. Because studying African American persons, who exhibit lower levels of linkage disequilibrium in this region, may identify additional loci that are associated with lung cancer, we genotyped 34 single-nucleotide polymorphisms (SNPs) in this region (including LOC123688, PSMA4, CHRNA5, CHRNA3, and CHRNB4 genes) in 467 African American patients with lung cancer and 388 frequency-matched African American control subjects. Associations of SNPs in LOC123688 (rs10519203; odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.25 to 2.05, P = .00016), CHRNA5 (rs2036527; OR = 1.67, 95% CI = 1.26 to 2.21, P = .00031), and CHRNA3 (rs1051730; OR = 1.81, 95% CI = 1.26 to 2.59, P = .00137) genes with lung cancer risk reached Bonferroni-corrected levels of statistical significance (all statistical tests were two-sided). Joint logistic regression analysis showed that rs684513 (OR = 0.47, 95% CI = 0.31 to 0.71, P = .0003) in CHRNA5 and rs8034191 (OR = 1.76, 95% CI = 1.23 to 2.52, P = .002) in LOC123688 were also associated with risk. The functional A variant of rs1696698 in CHRNA5 had the strongest association with lung cancer (OR = 1.98, 95% CI = 1.25 to 3.11, P = .003). These SNPs were primarily associated with increased risk for lung adenocarcinoma histology and were only weakly associated with smoking phenotypes. Thus, among African American persons, multiple loci in the region of chromosome 15q25.1 appear to be strongly associated with lung cancer risk. [ABSTRACT FROM AUTHOR]

Published
2010
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65. The chromosome 7q region association with rheumatoid arthritis in females in a british population is not replicated in a North American case-control series.

Author

Korman BD, Seldin MF, Taylor KE, Le JM, Lee AT, Plenge RM, Amos CI, Criswell LA, Gregersen PK, Kastner DL, and Remmers EF

Abstract

OBJECTIVE: The single-nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population. METHODS: DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole-genome SNP data (772 cases and 1,213 controls). RESULTS: We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P = 0.0073), and rs11765576 showed association with RA in both the NARAC (P = 0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole-genome subset, neither SNP showed significant association with RA after correction for population stratification. CONCLUSION: While 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false-positive disease associations. [ABSTRACT FROM AUTHOR]

Published
2009
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66. Smoking-related genomic signatures in non-small cell lung cancer.

Author

Massion PP, Zou Y, Chen H, Jiang A, Coulson P, Amos CI, Wu X, Wistuba I, Wei Q, Shyr Y, Spitz MR, Massion, Pierre P, Zou, Yong, Chen, Heidi, Jiang, Aixiang, Coulson, Peter, Amos, Christopher I, Wu, Xifeng, Wistuba, Ignacio, and Wei, Qingyi

Abstract

Rationale: Tobacco smoking is responsible for 85% of all lung cancers. To further our understanding of the molecular pathogenesis of lung cancer, we determined whether smoking history leads to the emergence of specific genomic alterations found in non-small cell lung cancer (NSCLC).Objectives: To identify gene copy number alterations in NSCLCs associated with smoking history or DNA repair capacity.Methods: Seventy-five NSCLCs were selected for this study from patients with current, none, or past smoking history, including pack year information. Tissue sections were microdissected, and DNA was extracted, purified, and labeled by random priming before hybridization onto bacterial artificial chromosome (BAC) arrays. Normalized ratios were correlated with smoking history and DNA repair capacity was measured by an in vitro lymphocyte assay in the same patients.Measurements and Main Results: We identified smoking-related genomic signatures in NSCLCs that could be predicted with an overall 74% accuracy. Lung tumors arising from current-smokers had the greatest number of copy number alterations. The genomic regions most significantly associated with smoking were located within 60 regions and were functionally associated with genes controlling the M phase of the cell cycle, the segregation of chromosomes, and the methylation of DNA. Verification of the data is provided from data in the public domain and by quantitative real-time polymerase chain reaction. The associations between genomic abnormalities and DNA repair capacity did not reach statistical significance.Conclusions: These findings indicate that smoking history leaves a specific genomic signature in the DNA of lung tumors and suggest that these alterations may reflect new molecular pathways to cancer development. [ABSTRACT FROM AUTHOR]

Published
2008
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67. The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.

Author

Spitz MR, Amos CI, Dong Q, Lin J, Wu X, Spitz, Margaret R, Amos, Christopher I, Dong, Qiong, Lin, Jie, and Wu, Xifeng

Abstract

Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies, with no consensus as to the relative impact of the variants on the propensity to smoke vs a direct carcinogenic effect. To further explore our hypothesis that these variants are indeed associated with both cancer causation and nicotine dependence, we performed a more detailed analysis of the association of these putative risk genotypes with smoking phenotype, as well as in lifetime never smokers, and in other smoking-related cancers. We demonstrate a statistically significant association of the variants with both nicotine dependence, as well as lung cancer phenotypes, including earlier age at lung cancer onset. The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects, nor in other smoking-related cancers (bladder and renal). Thus, we conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk. [ABSTRACT FROM AUTHOR]

Published
2008
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72. Rheumatoid arthritis association with the FCRL3 -169C polymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population.

Author

Newman WG, Zhang Q, Liu X, Walker E, Ternan H, Owen J, Johnson B, Greer W, Mosher DP, Maksymowych WP, Bykerk VP, Keystone EC, Amos CI, and Siminovitch KA

Abstract

OBJECTIVE: Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls. METHODS: A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined. RESULTS: An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD. CONCLUSION: Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals. [ABSTRACT FROM AUTHOR]

Published
2006
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75. Support for previously identified alcoholism susceptibility Loci in a cohort selected for smoking behavior.

Author

Wilhelmsen KC, Swan GE, Cheng LS, Lessov-Schlaggar CN, Amos CI, Feiler HS, Hudmon KS, Ring HZ, Andrews JA, Tildesley E, Benowitz NL, and Hops H

Abstract

BACKGROUND: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior. METHODS: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality. RESULTS: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies. CONCLUSIONS: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition. [ABSTRACT FROM AUTHOR]

Published
2005
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76. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.

Author

Huizinga TWJ, Amos CI, van der Helm-van Mil AHM, Chen W, van Gaalen FA, Jawaheer D, Schreuder GMT, Wener M, Breedveld FC, Ahmad N, Lum RF, de Vries RRP, Gregersen PK, Toes REM, and Criswell LA

Abstract

OBJECTIVE: The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. METHODS: HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. RESULTS: For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. CONCLUSION: HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype. [ABSTRACT FROM AUTHOR]

Published
2005
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77. Relationship between plasma carotenoids and prostate cancer.

Author

Chang S, Erdman JW Jr., Clinton SK, Vadiveloo M, Strom SS, Yamamura Y, Duphorne CM, Spitz MR, Amos CI, Contois JH, Gu X, Babaian RJ, Scardino PT, and Hursting SD

Abstract

Carotenoids, particularly lycopene, are thought to decrease prostate cancer risk, but the relationship between plasma carotenoid concentrations and risk in various populations has not been well characterized. Comparing 118 non-Hispanic Caucasian men mainly from southeast Texas with nonmetastatic prostate cancer with 52 healthy men from the same area, we conducted a case-control analysis evaluating associations between risk and plasma levels of total carotenoids, beta-cryptoxanthin, alpha- and trans-beta-carotene, lutein and zeaxanthin, total lycopenes, trans-lycopene, total cis-lycopenes, and cis-lycopene isoforms 1, 2, 3, and 5. Risk for men with high plasma levels of alpha-carotene, trans-beta-carotene, beta-cryptoxanthin, and lutein and zeaxanthin was less than half that for those with lower levels. In contrast, we observed no significant associations for total lycopenes, all-trans-lycopene, and cis-lycopene isomer peaks 2, 3, and 5, although high levels of cis-lycopene isomer peak 1 were inversely associated with risk. Analysis of men with aggressive disease (Gleason scores of > or =7, n = 88) vs. less aggressive cases (Gleason scores of <7, n = 30) failed to reveal significant associations between carotenoid levels and the risk of diagnosis with aggressive disease. These findings suggest that, in these men, higher circulating levels of alpha-cryptoxanthin, alpha-carotene, trans-beta-carotene, and lutein and zeaxanthin may contribute to lower prostate cancer risk but not to disease progression. [ABSTRACT FROM AUTHOR]

Published
2005
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78. Deletion in poly(ADP-ribose)polymerase pseudogene and lung cancer risk.

Author

Wu, X, Hsu, TC, Cao, S, Lee, JJ, Amos, CI, and Spitz, MR

Abstract

The poly(ADP-ribose)polymerase (PADPRP) gene has been implicated in carcinogenesis through its role in DNA repair, replication and recombination. A two-allele polymorphism in the chromosome 13 PADPRP pseudogene has been studied in several racial groups. It has been suggested that the B allele, which results from a 193-bp deletion in the gene, predisposes to myeloma in Blacks. We assessed the association between chromosome 13 PADPRP pseudogene genotype, mutagen sensitivity (a marker reflecting host DNA repair capability), cigarette smoking, and lung cancer risk in a minority lung cancer case-control study. The chromosome 13 PADPRP pseudogene polymorphism was detected by polymerase chain reaction-based analysis. Mutagen sensitivity was measured by an in vitro assay that quantified bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures. We examined 121 cases (80 African-Americans and 41 Mexican-Americans) with previously untreated lung cancer and 171 matched controls. Our results suggested that the distribution of the PADPRP pseudogene genotype frequencies was significantly different among African-American and Mexican-American controls (P <0.001). The susceptibility genotype (i.e. at least one B allele) was found in 82.5% of African-American cases, 79.4% of African-American controls, 53.7% of Mexican-American cases, and 32.5% of Mexican-American controls. The odds ratios (OR) and 95% confidence intervals for the PADPRP susceptibility genotypes were 2.3 (95% CI = 0.7-8.0) and 3.2 (95% CI = 1.0-10.3) for African-Americans and Mexican-Americans respectively, after adjustment by age, sex, pack-years and mutagen sensitivity. Patients with the susceptibility genotype appeared to have more mutagen-induced breaks than did patients with the other genotype. Only adenocarcinoma was significantly associated with the PADPRP susceptibility genotype (OR = 3.8). Mutagen sensitivity ( 1 break/cell) was significantly associated with lung cancer risk for both ethnic groups with increased ORs of above three-fold. On stratified analysis, synergistic interactions were noted for the PADPRP susceptibility genotype, mutagen sensitivity and smoking status. In Mexican-Americans, the ORs for PADPRP susceptibility genotype, mutagen sensitivity and both risk factors combined were 1,3, 2.7 and 17.1 respectively. The combined OR for the PADPRP susceptibility genotype and smoking status was 15.6. Therefore, this polymorphism appears to be associated with lung cancer risk. However, it is likely that no single genotype is sufficiently predictive of risk and that a panel of susceptibility markers is needed to define the high-risk subgroup. [ABSTRACT FROM PUBLISHER]

Published
1998
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79. The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis.

Author

Brown, MA, Rudwaleit, M, Pile, KD, Kennedy, LG, Shatford, J, Amos, CI, Siminovitch, K, Rubin, L, Calin, A, and Wordsworth, BP

Abstract

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda  1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis. [ABSTRACT FROM PUBLISHER]

Published
1998
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81. Association analysis identifies 65 new breast cancer risk loci

Author

Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF

Subjects
ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

82. The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Amos, CI, Dennis, J, Wang, Z, Byun, J, Schumacher, FR, Gayther, SA, Casey, G, Hunter, DJ, Sellers, TA, Gruber, SB, Dunning, AM, Michailidou, K, Fachal, L, Doheny, K, Spurdle, AB, Li, Y, Xiao, X, Romm, J, Pugh, E, Coetzee, GA, Hazelett, DJ, Bojesen, SE, Caga-Anan, C, Haiman, CA, Kamal, A, Luccarini, C, Tessier, D, Vincent, D, Bacot, F, Van Den Berg, DJ, Nelson, S, Demetriades, S, Goldgar, DE, Couch, FJ, Forman, JL, Giles, GG, Conti, DV, Bickeböller, H, Risch, A, Waldenberger, M, Brüske-Hohlfeld, I, Hicks, BD, Ling, H, McGuffog, L, Lee, A, Kuchenbaecker, K, Soucy, P, Manz, J, Cunningham, JM, Butterbach, K, Kote-Jarai, Z, Kraft, P, FitzGerald, L, Lindström, S, Adams, M, McKay, JD, Phelan, CM, Benlloch, S, Kelemen, LE, Brennan, P, Riggan, M, O'Mara, TA, Shen, H, Shi, Y, Thompson, DJ, Goodman, MT, Nielsen, SF, Berchuck, A, Laboissiere, S, Schmit, SL, Shelford, T, Edlund, CK, Taylor, JA, Field, JK, Park, SK, Offit, K, Thomassen, M, Schmutzler, R, Ottini, L, Hung, RJ, Marchini, J, Amin Al Olama, A, Peters, U, Eeles, RA, Seldin, MF, Gillanders, E, Seminara, D, Antoniou, AC, Pharoah, PDP, Chenevix-Trench, G, Chanock, SJ, Simard, J, and Easton, DF

Subjects
Male, Genotype, Genetic Variation, Prognosis, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Neoplasms, Prevalence, Humans, Female, Genetic Predisposition to Disease, Selection, Genetic, Genome-Wide Association Study
Abstract

BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.

83. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Author

Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeböller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Ann Doherty, J, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, McKay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, and Caporaso, NE

Subjects
circadian rhythm, Male, Ovarian Neoplasms, Lung Neoplasms, Carcinogenesis, Prostatic Neoplasms, melatonin, Nerve Tissue Proteins, prostate cancer, Arylalkylamine N-Acetyltransferase, Polymorphism, Single Nucleotide, 3. Good health, Basic Helix-Loop-Helix Transcription Factors, cancer, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, Genetic Association Studies, Signal Transduction
Abstract

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

84. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, AOCS Study Group, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, Y-E, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, D'Aloisio, AA, Daly, MB, Damiola, F, Damirovna, SD, Dansonka-Mieszkowska, A, Dao, F, Davidson, R, DeFazio, A, Delnatte, C, Doheny, KF, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Dossus, L, Duran, M, Dürst, M, Dworniczak, B, Eccles, D, Edwards, T, Eeles, R, Eilber, U, Ejlertsen, B, Ekici, AB, Ellis, S, Elvira, M, EMBRACE Study, Eng, KH, Engel, C, Evans, DG, Fasching, PA, Ferguson, S, Ferrer, SF, Flanagan, JM, Fogarty, ZC, Fortner, RT, Fostira, F, Foulkes, WD, Fountzilas, G, Fridley, BL, Friebel, TM, Friedman, E, Frost, D, Ganz, PA, Garber, J, García, MJ, Garcia-Barberan, V, Gehrig, A, GEMO Study Collaborators, Gentry-Maharaj, A, Gerdes, A-M, Giles, GG, Glasspool, R, Glendon, G, Godwin, AK, Goldgar, DE, Goranova, T, Gore, M, Greene, MH, Gronwald, J, Gruber, S, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harrington, PA, Harris, HR, Hauke, J, HEBON Study, Hein, A, Henderson, A, Hildebrandt, MAT, Hillemanns, P, Hodgson, S, Høgdall, CK, Høgdall, E, Hogervorst, FBL, Holland, H, Hooning, MJ, Hosking, K, Huang, R-Y, Hulick, PJ, Hung, J, Hunter, DJ, Huntsman, DG, Huzarski, T, Imyanitov, EN, Isaacs, C, Iversen, ES, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jernetz, M, Jensen, A, Jensen, UB, John, EM, Johnatty, S, Jones, ME, Kannisto, P, Karlan, BY, Karnezis, A, Kast, K, KConFab Investigators, Kennedy, CJ, Khusnutdinova, E, Kiemeney, LA, Kiiski, JI, Kim, S-W, Kjaer, SK, Köbel, M, Kopperud, RK, Kruse, TA, Kupryjanczyk, J, Kwong, A, Laitman, Y, Lambrechts, D, Larrañaga, N, Larson, MC, Lazaro, C, Le, ND, Le Marchand, L, Lee, JW, Lele, SB, Leminen, A, Leroux, D, Lester, J, Lesueur, F, Levine, DA, Liang, D, Liebrich, C, Lilyquist, J, Lipworth, L, Lissowska, J, Lu, KH, Lubinński, J, Luccarini, C, Lundvall, L, Mai, PL, Mendoza-Fandiño, G, Manoukian, S, Massuger, LFAG, May, T, Mazoyer, S, McAlpine, JN, McGuire, V, McLaughlin, McNeish, I, Meijers-Heijboer, H, Meindl, A, Menon, U, Mensenkamp, AR, Merritt, MA, Milne, RL, Mitchell, G, Modugno, F, Moes-Sosnowska, J, Moffitt, M, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Nathanson, KL, Nedergaard, L, Ness, RB, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nussbaum, RL, Odunsi, K, Olah, E, Olopade, OI, Olsson, H, Olswold, C, O'Malley, DM, Ong, K-R, Onland-Moret, NC, OPAL Study Group, Orr, N, Orsulic, S, Osorio, A, Palli, D, Papi, L, Park-Simon, T-W, Paul, J, Pearce, CL, Pedersen, IS, Peeters, PHM, Peissel, B, Peixoto, A, Pejovic, T, Pelttari, LM, Permuth, JB, Peterlongo, P, Pezzani, L, Pfeiler, G, Phillips, K-A, Piedmonte, M, Pike, MC, Piskorz, AM, Poblete, Pocza, T, Poole, EM, Poppe, B, Porteous, ME, Prieur, F, Prokofyeva, D, Pugh, E, Pujana, MA, Pujol, P, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Rhiem, K, Rice, P, Richardson, A, Robson, M, Rodriguez, GC, Rodríguez-Antona, C, Romm, J, Rookus, MA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Salvesen, HB, Sandler, DP, Schoemaker, MJ, Senter, L, Setiawan, VW, Severi, G, Sharma, P, Shelford, T, Siddiqui, N, Side, LE, Sieh, W, Singer, CF, Sobol, H, Song, H, Southey, MC, Spurdle, AB, Stadler, Z, Steinemann, D, Stoppa-Lyonnet, D, Sucheston-Campbell, LE, Sukiennicki, G, Sutphen, R, Sutter, C, Swerdlow, AJ, Szabo, CI, Szafron, L, Tan, YY, Taylor, JA, Tea, M-K, Teixeira, MR, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, LCV, Thull, DL, Tihomirova, L, Tinker, AV, Tischkowitz, M, Tognazzo, S, Toland, AE, Tone, A, Trabert, B, Travis, RC, Trichopoulou, A, Tung, N, Tworoger, SS, Van Altena, AM, Van Den Berg, D, Van Der Hout, AH, Van Der Luijt, RB, Van Heetvelde, M, Van Nieuwenhuysen, E, Van Rensburg, EJ, Vanderstichele, A, Varon-Mateeva, R, Vega, A, Edwards, DV, Vergote, I, Vierkant, RA, Vijai, J, Vratimos, A, Walker, L, Walsh, C, Wand, D, Wang-Gohrke, S, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wijnen, JT, Wilkens, LR, Wolk, A, Woo, M, Wu, X, Wu, AH, Yang, H, Yannoukakos, D, Ziogas, A, Zorn, KK, Narod, SA, Easton, DF, Amos, CI, Schildkraut, JM, Ramus, SJ, Ottini, L, Goodman, MT, Park, SK, Kelemen, LE, Risch, HA, Thomassen, M, Offit, K, Simard, J, Schmutzler, RK, Hazelett, D, Monteiro, AN, Couch, FJ, Berchuck, A, Chenevix-Trench, G, Goode, EL, Sellers, TA, Gayther, SA, Antoniou, AC, and Pharoah, PDP

Subjects
ovarian cancer, endocrine system diseases, genome-wide association studies, epidemiology, female genital diseases and pregnancy complications, 3. Good health
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 $\textit{BRCA1}$ and $\textit{BRCA2}$ mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

88. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

Author

Massimo Zuin, Antonio Benedetti, Pierluigi Toniutto, Vincenzo Palmieri, Peter K. Gregersen, Cristina Rigamonti, Christopher I. Amos, Paolo Muratori, Barbara Coco, Francesca Bernuzzi, Piero Luigi Almasio, Renzo Montanari, Maurizia Rossana Brunetto, Fabio Macciardi, Andrea Galli, Pietro Andreone, Cameron N. Ghent, Yue Lu, Luca Fabris, Gideon M. Hirschfield, Marzia Margotti, Michael Ransom, Ilaria Bianchi, Agostino Colli, Carlo Selmi, Giancarlo Spinzi, Lory Saveria Crocè, S. Bruno, Gang Xie, Mario Strazzabosco, Claudio Tiribelli, Xiangdong Liu, Grazia Anna Niro, E. Jenny Heathcote, Russell Shigeta, Katherine A. Siminovitch, Elisabetta Borghesio, Nicola Caporaso, M. Eric Gershwin, Andrew Mason, Maria Vinci, Mauro Podda, Robert P. Myers, Fabio Marra, Cleofe Prisco, Lorenzo Morini, Roman Kosoy, Alberto Mattalia, Michael F. Seldin, Chun Xu, Maria Consiglia Bragazzi, Piero Portincasa, Roberta Lazzari, Giovanni Casella, Sonia Rossi, Marco Marzioni, Silvia Colombo, Domenico Alvaro, Luigi Muratori, Sara Lupoli, Carlo Ferrari, Annette Lee, Annarosa Floreani, Yan Lu, Floriano Rosina, Angelo Andriulli, Massimo Colombo, Antonio Picciotto, Kevork M. Peltekian, Ana Lleo, Alessandro Pisano, Pietro Invernizzi, Liu, X, Invernizzi, P, Lu, Y, Kosoy, R, Bianchi, I, Podda, M, Xu, C, Xie, G, Macciardi, F, Selmi, C, Lupoli, S, Shigeta, R, Ransom, M, Lleo, A, Lee, AT, Mason, AL, Myers, RP, Peltekian, KM, Ghent, CN, Bernuzzi, F, Zuin, M, Rosina, F, Borghesio, E, Floreani, A, Lazzari, R, Niro, G, Andriulli, A, Muratori, L, Muratori, P, Almasio, PL, Andreone, P, Margotti, M, Brunetto, M, Coco, B, Alvaro, D, Bragazzi, MC, Marra, F, Pisano, A, Rigamonti, C, Colombo, M, Marzioni, M, Benedetti, A, Fabris, L, Strazzabosco, M, Portincasa, P, Palmieri, VO, Tiribelli, C, Croce, L, Bruno, S, Rossi, S, Vinci, M, Prisco, C, Mattalia, A, Toniutto, P, Picciotto, A, Galli, A, Ferrari, C, Colombo, S, Casella, G, Morini, L, Caporaso, N, Colli, A, Spinzi, G, Montanari, R, Gregersen, PK, Heathcote, EJ, Hirschfield, GM, Siminovitch, KA, Amos, CI, Gershwin, ME, Seldin, MF, Lee, At, Mason, Al, Myers, Rp, Peltekian, Km, Ghent, Cn, Almasio, Pl, Bragazzi, Mc, Palmieri, Vo, Caporaso, Nicola, Gregersen, Pk, Heathcote, Ej, Hirschfield, Gm, Siminovitch, Ka, Amos, Ci, Gershwin, Me, Seldin, M. F., Lee, A, Mason, A, Myers, R, Peltekian, K, Ghent, C, Almasio, P, Bragazzi, M, Palmieri, V, Gregersen, P, Heathcote, E, Hirschfield, G, Siminovitch, K, Amos, C, Gershwin, M, Seldin, M, X., Liu, P., Invernizzi, Y., Lu, R., Kosoy, I., Bianchi, M., Podda, C., Xu, G., Xie, F., Macciardi, C., Selmi, S., Lupoli, R., Shigeta, M., Ransom, A., Lleo, A. T., Lee, A. L., Mason, R. P., Myer, K. M., Peltekian, C. N., Ghent, F., Bernuzzi, M., Zuin, F., Rosina, E., Borghesio, A., Floreani, R., Lazzari, G., Niro, A., Andriulli, L., Muratori, P., Muratori, P. L., Almasio, P., Andreone, M., Margotti, M., Brunetto, B., Coco, D., Alvaro, M. C., Bragazzi, F., Marra, A., Pisano, C., Rigamonti, M., Colombo, M., Marzioni, A., Benedetti, L., Fabri, M., Strazzabosco, P., Portincasa, V. O., Palmieri, Tiribelli, Claudio, Croce', Saveria, S., Bruno, S., Rossi, M., Vinci, C., Prisco, A., Mattalia, P., Toniutto, A., Picciotto, A., Galli, C., Ferrari, S., Colombo, G., Casella, L., Morini, N., Caporaso, A., Colli, G., Spinzi, R., Montanari, P. K., Gregersen, E. J., Heathcote, G. M., Hirschfield, K. A., Siminovitch, C. I., Amo, M. E., Gershwin, M. F., Seldin, Liu X, Invernizzi P, Lu Y, Kosoy R, Bianchi I, Podda M, Xu C, Xie G, Macciardi F, Selmi C, Lupoli S, Shigeta R, Ransom M, Lleo A, Lee AT, Mason AL, Myers RP, Peltekian KM, Ghent CN, Bernuzzi F, Zuin M, Rosina F, Borghesio E, Floreani A, Lazzari R, Niro G, Andriulli A, Muratori L, Muratori P, Almasio PL, Andreone P, Margotti M, Brunetto M, Coco B, Alvaro D, Bragazzi MC, Marra F, Pisano A, Rigamonti C, Colombo M, Marzioni M, Benedetti A, Fabris L, Strazzabosco M, Portincasa P, Palmieri VO, Tiribelli C, Croce L, Bruno S, Rossi S, Vinci M, Prisco C, Mattalia A, Toniutto P, Picciotto A, Galli A, Ferrari C, Colombo S, Casella G, Morini L, Caporaso N, Colli A, Spinzi G, Montanari R, Gregersen PK, Heathcote EJ, Hirschfield GM, Siminovitch KA, Amos CI, Gershwin ME, and Seldin MF.

Subjects
Liver Cirrhosis, Oncology, Canada, medicine.medical_specialty, Cirrhosis, European Continental Ancestry Group, LOCI, PRIMARY BILIARY CIRRHOSIS, GENOME WIDE ASSOCIATION, Genome-wide association study, Locus (genetics), genetics, Genome, Genome-Wide Association Study, Humans, Interferon Regulatory Factors, Liver Cirrhosi, Biology, Biliary, Meta-Analysis as Topic, Odds Ratio, White People, Article, Alleles, Canada, European Continental Ancestry Group, primary biliary cirrhosi, Primary biliary cirrhosis, Meta-Analysis as Topic, MED/12 - GASTROENTEROLOGIA, IL12A, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Allele, genome, genetics, Genome, Genome-Wide Association Study, Humans, Interferon Regulatory Factors, Liver Cirrhosis, Alleles, primary biliary cirrhosis, genome-wide meta-analyses, Liver Cirrhosis, Biliary, Biliary, Odds ratio, medicine.disease, Interferon Regulatory Factors, Cohort, Genome-Wide Association Study
Abstract

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

Published
2010

89. Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Author

Rothwell, S., Amos, C. I., Miller, F. W., Rider, L. G., Lundberg, I. E., Gregersen, P. K., Vencovsky, J., Mchugh, N., Limaye, V., Selva-O'Callaghan, A., Hanna, M. G., Machado, P. M., Pachman, L. M., Reed, A. M., Molberg, Ø., Benveniste, O., Mathiesen, P., Radstake, T., Doria, A., De Bleecker, J. L., De Paepe, B., Maurer, B., Ollier, W. E., Padyukov, L., O'Hanlon, T. P., Lee, A., Wedderburn, L. R., Chinoy, H., Lamb, J. A., Institut Català de la Salut, [Rothwell S] Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. [Amos CI] Baylor College of Medicine, Houston, Texas. [Miller FW, Rider LG] Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, NIH, Bethesda, Maryland. [Lundberg IE] Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. [Gregersen PK] The Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute, Manhasset, New York. [Selva-O'Callaghan A] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Rheumatology, Músculs - Malalties - Aspectes genètics, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Immunology, Malalties autoimmunitàries - Aspectes genètics, Immune System Diseases::Autoimmune Diseases [DISEASES], Other subheadings::Other subheadings::/genetics [Other subheadings], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], enfermedades del sistema inmune::enfermedades autoinmunes [ENFERMEDADES], Immunology and Allergy, Musculoskeletal Diseases::Muscular Diseases::Myositis [DISEASES], enfermedades musculoesqueléticas::enfermedades musculares::miositis [ENFERMEDADES], fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS]
Abstract

Idiopathic inflammatory myopathies; Genome Miopatías inflamatorias idiopáticas; Genoma Miopaties inflamatòries idiopàtiques; Genoma Objective The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. Methods We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. Results The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. Conclusion We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types. Supported by the Intramural Research Program, National Institute of Environmental Health Sciences, NIH. Dr. Lundberg's work was supported by grants from the Swedish Research Council and Stockholm Regional Council (ALF). Dr. Vencovsky's work was supported by the Czech Ministry of Health–Conceptual Development of Research Organization (award 00023728) (Institute of Rheumatology). Drs. Hanna and Machado's work were supported by the NIHR University College London Hospitals Biomedical Research Centre. Drs. De Bleecker and De Paepe's work were supported by the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). Dr. Wedderburn's work was supported by Versus Arthritis (awards 21593 and 21552), the Wellcome trust (award 085860), Myositis UK, the Cure JM Foundation, the Remission Charity, and the NIHR Biomedical research Centre at GOSH. Dr. Chinoy's work was supported by the Medical Research Council UK (award MR/N003322/1), Myositis UK, and the NIHR Manchester Biomedical Research Centre Funding Scheme. Dr. Lamb's work was supported by the Medical Research Council UK (award MR/N003322/1) and Myositis UK.

Published
2022

90. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. 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Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, 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Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, 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Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .

Subjects
Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Published
2021

91. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.

Author

Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PIW, Le JM, Lee H, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, and Criswell LA

Abstract

Background: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.Methods: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.Results: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.Conclusions: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses. [ABSTRACT FROM AUTHOR]

Published
2007

92. Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data

Author

Steven Gallinger, Robert R. McWilliams, Eric J. Duell, Mazda Jenab, Marie-Christine Boutron-Ruault, Elio Riboli, Donghui Li, Salvatore Panico, Hong Wei Tang, Petra H.M. Peeters, Rudolph Kaaks, Harvey A. Risch, Kay-Tee Khaw, H. Bas Bueno-de-Mesquita, Sara H. Olson, Dimitrios Trichopoulos, Gloria M. Petersen, Anne Tjønneland, Christopher I. Amos, Paige M. Bracci, Elizabeth A. Holly, Peng Wei, Malin Sund, Tang, H, Wei, P, Duell, Ej, Risch, Ha, Olson, Sh, Bueno de Mesquita, Hb, Gallinger, S, Holly, Ea, Petersen, G, Bracci, Pm, Mcwilliams, Rr, Jenab, M, Riboli, E, Tj?nneland, A, Boutron Ruault, Mc, Kaaks, R, Trichopoulos, D, Panico, Salvatore, Sund, M, Peeters, Ph, Khaw, Kt, Amos, Ci, and Li, D.

Subjects
Adult, Male, Risk, Cancer Research, Genome-wide association study, Single-nucleotide polymorphism, Original Manuscript, Biology, Polymorphism, Single Nucleotide, Polymorphism (computer science), Pancreatic cancer, Genotype, medicine, SNP, Humans, KEGG, Gene, Aged, Genetics, Aged, 80 and over, Smoking, General Medicine, Middle Aged, medicine.disease, Pancreatic Neoplasms, Case-Control Studies, Female, Gene-Environment Interaction, Genome-Wide Association Study, Signal Transduction
Abstract

Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene-smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling $$\left(P=2.12\times 1{0}^{-7}\right)$$ and α-adrenergic signaling $$\left(P=2.52\times 1{0}^{-5}\right)$$ genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.

Published
2014

93. Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: A GWAS data analysis

Author

Elio Riboli, Hong Wei Tang, Rudolf Kaaks, Gloria M. Petersen, Paige M. Bracci, Anne Tjønneland, Mazda Jenab, H. Bas Bueno-de-Mesquita, Petra H.M. Peeters, Elizabeth A. Holly, Donghui Li, Dimitrios Trichopoulos, Peng Wei, Kay-Tee Khaw, Harvey A. Risch, Malin Sund, Steven Gallinger, Salvatore Panico, Eric J. Duell, Sara H. Olson, Marie-Christine Boutron-Ruault, Robert R. McWilliams, Christopher I. Amos, Tang, H, Wei, P, Duell, Ej, Risch, Ha, Olson, Sh, Bueno de Mesquita, Hb, Gallinger, S, Holly, Ea, Petersen, Gm, Bracci, Pm, Mcwilliams, Rr, Jenab, M, Riboli, E, Tj?nneland, A, Boutron Ruault, Mc, Kaaks, R, Trichopoulos, D, Panico, Salvatore, Sund, M, Peeters, Ph, Khaw, Kt, Amos, Ci, and Li, D.

Subjects
Male, Genotype, Epidemiology, Genome-wide association study, Bioinformatics, Polymorphism, Single Nucleotide, Article, Diabetes Complications, Diabetes mellitus genetics, Risk Factors, Diabetes mellitus, Pancreatic cancer, medicine, Diabetes Mellitus, Humans, Obesity, Gene–environment interaction, Gene, Aged, Genetics, business.industry, Middle Aged, medicine.disease, Pancreatic Neoplasms, Oncology, Female, Gene-Environment Interaction, business, Genome-Wide Association Study
Abstract

Background: Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Methods: Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene–obesity and gene–diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA). Results: After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10−6) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10−4) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10−7) at a false discovery rate of 6%. Conclusions: Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. Impact: A gene–environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 23(1); 98–106. ©2013 AACR.

Published
2013

94. Alternative polyadenylation shapes the molecular and clinical features of lung adenocarcinoma.

Author

Gao Y, Shaw VR, and Amos CI

Abstract

Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation that affects mRNA stability, localization and translation efficiency. Previous pan-cancer studies have revealed that APA is frequently disrupted in cancer and is associated with patient outcomes. Yet, little is known about cancer type-specific APA alterations. Here, we integrated RNA-sequencing data from a Korean cohort (GEO: GSE40419) and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA alterations in lung adenocarcinomas (LUADs). Comparing expression levels of core genes involved in polyadenylation, we find that overall, the set of 28 of 31 genes are upregulated, with CSTF2 particularly upregulated. We observed broad and recurrent APA changes in LUAD growth-promoting genes. In addition, we find enrichment of APA events in genes associated with known LUAD pathways and an increased heterogeneity in polyadenylation (polyA) site usage of proliferation-associated genes. Upon further investigation, we report smoking-specific APA changes are also highly relevant to LUAD development. Overall, our in-depth analysis reveals APA as an important driver for the molecular and clinical features of lung adenocarcinoma., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2024
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95. Discovery of new myositis genetic associations through leveraging other immune-mediated diseases.

Author

Reales G, Amos CI, Benveniste O, Chinoy H, De Bleecker J, De Paepe B, Doria A, Gregersen PK, Lamb JA, Limaye V, Lundberg IE, Machado PM, Maurer B, Miller FW, Molberg Ø, Pachman LM, Padyukov L, Radstake TR, Reed AM, Rider LG, Rothwell S, Selva-O'Callaghan A, Vencovský J, Wedderburn LR, and Wallace C

Subjects
Humans, Polymorphism, Single Nucleotide, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Immune System Diseases genetics, Myositis genetics, Myositis immunology, Genome-Wide Association Study, Genetic Predisposition to Disease
Abstract

Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD., Competing Interests: Declaration of interests Dr. Wallace receives research funding from GSK and MSD and is a part-time employee of GSK. Neither company had any influence on this work or its publication. Dr. Radstake is an employee of Abbvie and may hold stock. Abbvie had no influence on the content of this work or its publication. Dr. Chinoy has received fees as a speaker for GSK and UCB; consulting for PTC Therapeutics; advisory board member for Astra Zeneca, Pfizer, Argenx, and Galapagos; and as a data and science monitoring board chair for Horizon Therapeutics. Dr. Maurer has grants from Novartis, consulting fees from Novartis, Boehringer Ingelheim, Jannsen-Cilag, and GSK; speaker fees from Boehringer-Ingelheim, GSK, Novartis, Otsuka, and MSD; congress support from Medtalk, Pfizer, Roche, Actelion, Mepha, and MSD; and has a patent mir-29 for the treatment of SSc (US8247389, EP2331143). Dr. Wedderburn has received speaker and consultancy fees from Pfizer paid to UCL, unrelated to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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96. Multiregional transcriptomic profiling provides improved prognostic insight in localized non-small cell lung cancer.

Author

Li C, Nguyen TT, Li JR, Song X, Fujimoto J, Little L, Gumb C, Chow CB, Wistuba II, Futreal AP, Zhang J, Hubert SM, Heymach JV, Wu J, Amos CI, Zhang J, and Cheng C

Abstract

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with survival) across different regions within a tumor were more prognostic than the average expression. Following that, we examined whether multiregional expression profiling can improve the performance of prognostic signatures. We investigated 11 gene signatures collected from previous publications and one signature developed in this study. For all of them, the prognostic prediction accuracy can be significantly improved by converting the regional expression of signature genes into sample-specific expression with a simple function-taking the maximal expression of hazardous genes and the minimal expression of protective genes. In the tumor microenvironment, we found a similar rule also seems applicable to immune ITH. We calculated the infiltration levels of major immune cell types in each region of a sample based on expression deconvolution. Prognostic analysis indicated that the region with the lowest infiltration level of protective or highest infiltration level of hazardous immune cells determined the prognosis of NSCLC patients. Our study highlighted the impact of RNA-ITH on the prognostication of NSCLC, which should be taken into consideration to optimize the design and application of expression-based prognostic biomarkers and models. Multiregional assays have the great potential to significantly improve their applications to prognostic stratification., (© 2024. The Author(s).)

Published
2024
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97. Multi-ancestry GWAS meta-analyses of lung cancer reveal susceptibility loci and elucidate smoking-independent genetic risk.

Author

Gorman BR, Ji SG, Francis M, Sendamarai AK, Shi Y, Devineni P, Saxena U, Partan E, DeVito AK, Byun J, Han Y, Xiao X, Sin DD, Timens W, Moser J, Muralidhar S, Ramoni R, Hung RJ, McKay JD, Bossé Y, Sun R, Amos CI, and Pyarajan S

Subjects
Aged, Female, Humans, Male, Middle Aged, Adenocarcinoma of Lung genetics, Carcinoma, Squamous Cell genetics, Case-Control Studies, Genetic Loci, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Risk Factors, White, Ethnicity genetics, Genetic Risk Score, Genetic Predisposition to Disease, Lung Neoplasms genetics, Lung Neoplasms mortality, Smoking genetics
Abstract

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits., (© 2024. The Author(s).)

Published
2024
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98. Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes.

Author

Long E, Yin J, Shin JH, Li Y, Li B, Kane A, Patel H, Sun X, Wang C, Luong T, Xia J, Han Y, Byun J, Zhang T, Zhao W, Landi MT, Rothman N, Lan Q, Chang YS, Yu F, Amos CI, Shi J, Lee JG, Kim EY, and Choi J

Subjects
Humans, Transcriptome, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Chromatin genetics, Chromatin metabolism, Male, Female, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid genetics, Multiomics, Lung Neoplasms genetics, Lung Neoplasms pathology, Genetic Predisposition to Disease, Genome-Wide Association Study, Single-Cell Analysis methods
Abstract

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Published
2024
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99. Multi-trait and multi-ancestry genetic analysis of comorbid lung diseases and traits improves genetic discovery and polygenic risk prediction.

Author

He Y, Lu W, Jee YH, Wang Y, Tsuo K, Qian DC, Diao JA, Huang H, Patel CJ, Byun J, Pasaniuc B, Atkinson EG, Amos CI, Moll M, Cho MH, and Martin AR

Abstract

While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction., Competing Interests: MHC has received grant support from GSK, consulting fees from Apogee and BMS, and speaking fees from Illumina. MM has received consulting fees from TheaHealth, 2ndMD, Axon Advisors, Verona Pharma, and Sanofi. ARM has received speaker fees from Novartis. All other authors declare no competing interests.

Published
2024
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100. The prognostic effect of infiltrating immune cells is shaped by proximal M2 macrophages in lung adenocarcinoma.

Author

Li JR, Shaw V, Lin Y, Wang X, Aminu M, Li Y, Wu J, Zhang J, Amos CI, and Cheng C

Subjects
Humans, Prognosis, B-Lymphocytes immunology, B-Lymphocytes pathology, B-Lymphocytes metabolism, Single-Cell Analysis methods, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung pathology, Adenocarcinoma of Lung mortality, Tumor Microenvironment immunology, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms mortality, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Macrophages immunology, Macrophages pathology, Macrophages metabolism
Abstract

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density and fractions. Consistent with previous reports, our results validate that proximity of T helper (Th) and B cells to cancer cells is associated with survival benefits. More importantly, we discover that the proximity of M2 macrophages to multiple immune cells is associated with poor prognosis. When Th/B cells are stratified into M2-distal and M2-proximal, the abundance of the former but not the latter category of Th/B cells is correlated with enhanced patient survival. Additionally, the abundance of M2-distal and M2-proximal cytotoxic T cells (Tc) is respectively associated with good and poor prognosis. Our results indicate that the prognostic effect of Th, Tc, and B cells in the tumor microenvironment is modulated by the nearby M2 macrophages. The proposed new method proposed can be readily applied to all single-cell spatial data for revealing functional impact of immune cell interactions., (© 2024. The Author(s).)

Published
2024
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