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1. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

Author

Wang, Xiaoyu, Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A., Risch, H.A., Bernstein, L., Chow, W.H., Onstad, L., Shaheen, N.J., Lagergren, J., Hardie, L.J., Wu, A.H., Pharoah, P.D., Liu, G., Anderson, L.A., Iyer, P.G., Gammon, M.D., Caldas, C., Ye, W., Barr, H., Moayyedi, P., Harrison, R., Watson, R.G.P., Attwood, S., Chegwidden, L., Love, S.B., MacDonald, D., DeCaestecker, J., Prenen, H., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Reeh, M., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Tomlinson, I., Palles, C., Jankowski, J.A., Whiteman, D.C., MacGregor, S., Schumacher, J., Vaughan, T.L., Buas, M.F., Dai, J.Y., Wang, Xiaoyu, Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A., Risch, H.A., Bernstein, L., Chow, W.H., Onstad, L., Shaheen, N.J., Lagergren, J., Hardie, L.J., Wu, A.H., Pharoah, P.D., Liu, G., Anderson, L.A., Iyer, P.G., Gammon, M.D., Caldas, C., Ye, W., Barr, H., Moayyedi, P., Harrison, R., Watson, R.G.P., Attwood, S., Chegwidden, L., Love, S.B., MacDonald, D., DeCaestecker, J., Prenen, H., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Reeh, M., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Tomlinson, I., Palles, C., Jankowski, J.A., Whiteman, D.C., MacGregor, S., Schumacher, J., Vaughan, T.L., Buas, M.F., and Dai, J.Y.

Abstract

Item does not contain fulltext, BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Published
2022

2. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D.M., Palles, C., Ye, W., Gammon, M.D., Iyer, P.G., Anderson, L.A., Liu, G., Wu, A.H., Dai, J.Y., Chow, W.H., Risch, H.A., Lagergren, J., Shaheen, N.J., Bernstein, L., Corley, D.A., Prenen, H., DeCaestecker, J., MacDonald, D., Moayyedi, P., Barr, H., Love, S.B., Chegwidden, L., Attwood, S., Watson, P., Harrison, R., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Gockel, I., Vashist, Y., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Ambrosone, C.B., Moysich, K.B., MacGregor, S., Tomlinson, I., Whiteman, D.C., Jankowski, J., Schumacher, J., Vaughan, T.L., Madeleine, M.M., Hardie, L.J., Buas, M.F., Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D.M., Palles, C., Ye, W., Gammon, M.D., Iyer, P.G., Anderson, L.A., Liu, G., Wu, A.H., Dai, J.Y., Chow, W.H., Risch, H.A., Lagergren, J., Shaheen, N.J., Bernstein, L., Corley, D.A., Prenen, H., DeCaestecker, J., MacDonald, D., Moayyedi, P., Barr, H., Love, S.B., Chegwidden, L., Attwood, S., Watson, P., Harrison, R., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Gockel, I., Vashist, Y., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Ambrosone, C.B., Moysich, K.B., MacGregor, S., Tomlinson, I., Whiteman, D.C., Jankowski, J., Schumacher, J., Vaughan, T.L., Madeleine, M.M., Hardie, L.J., and Buas, M.F.

Abstract

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access), Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Published
2021

3. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author

Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q.T., Gharahkhani, P., Anderson, L.A., Wu, A.H., Ye, W., Bernstein, L., Borisov, O., Schröder, J., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Pharoah, P.D., Risch, H.A., May, A., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Izbicki, J.R., Hölscher, A.H., Schumacher, B., Vashist, Y., Neuhaus, H., Rösch, T., Knapp, M., Krawitz, P., Böhmer, A., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Corley, D.A., Gockel, I., Fitzgerald, R.C., Cook, M.B., Whiteman, D.C., Vaughan, T.L., Schumacher, J., Thrift, A.P., Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q.T., Gharahkhani, P., Anderson, L.A., Wu, A.H., Ye, W., Bernstein, L., Borisov, O., Schröder, J., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Pharoah, P.D., Risch, H.A., May, A., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Izbicki, J.R., Hölscher, A.H., Schumacher, B., Vashist, Y., Neuhaus, H., Rösch, T., Knapp, M., Krawitz, P., Böhmer, A., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Corley, D.A., Gockel, I., Fitzgerald, R.C., Cook, M.B., Whiteman, D.C., Vaughan, T.L., Schumacher, J., and Thrift, A.P.

Abstract

Contains fulltext : 229320.pdf (Publisher’s version ) (Closed access), BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P(BONF) = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P(BONF) = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Published
2020

6. No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study

Author

Dong, J., Gharahkhani, P., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Wu, A.H., Ye, W., Onstad, L., Anderson, L.A., Bernstein, L., Pharoah, P.D., Risch, H.A., Corley, D.A., Fitzgerald, R.C., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Vaughan, T.L., MacGregor, S., Love, S., Palles, C., Tomlinson, I., Gockel, I., May, A., Gerges, C., Anders, M., Bohmer, A.C., Becker, J., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Schmidt, C., Izbicki, J.R., Holscher, A.H., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismuller, J., Nothen, M.M., Moebus, S., Knapp, M., Peters, W.H.M., Neuhaus, H., Rosch, T., Ell, C., Jankowski, J., Schumacher, J., Neale, R.E., Whiteman, D.C., Thrift, A.P., Dong, J., Gharahkhani, P., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Wu, A.H., Ye, W., Onstad, L., Anderson, L.A., Bernstein, L., Pharoah, P.D., Risch, H.A., Corley, D.A., Fitzgerald, R.C., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Vaughan, T.L., MacGregor, S., Love, S., Palles, C., Tomlinson, I., Gockel, I., May, A., Gerges, C., Anders, M., Bohmer, A.C., Becker, J., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Schmidt, C., Izbicki, J.R., Holscher, A.H., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismuller, J., Nothen, M.M., Moebus, S., Knapp, M., Peters, W.H.M., Neuhaus, H., Rosch, T., Ell, C., Jankowski, J., Schumacher, J., Neale, R.E., Whiteman, D.C., and Thrift, A.P.

Abstract

Contains fulltext : 215282.pdf (publisher's version ) (Closed access), BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

Published
2019

7. Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization

Author

Thrift, A.P., Risch, H.A., Onstad, L., Shaheen, N.J., Casson, A.G., Bernstein, L., Corley, D.A., Levine, D.M., Chow, W-H., Reid, B.J., Romero, Y., Hardie, L.J., Liu, G., Wu, A.H., Bird, N.C., Gammon, M.D., Ye, W., Whiteman, D.C., and Vaughan, T.L.

Abstract

Background & Aims\ud \ud Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE).\ud Methods\ud \ud We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett's and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable.\ud Results\ud \ud Height was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62–0.79 for men and OR, 0.57; 95% CI 0.40–0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62–0.77 for men and OR, 0.61; 95% CI, 0.48–0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis.\ud Conclusions\ud \ud Height is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.

Published
2014

8. Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

Author

Palles, C. (Claire), Chegwidden, L. (Laura), Li, X. (Xinzhong), Findlay, J.M. (John M.), Farnham, G. (Garry), Castro Giner, F. (Francesc), Peppelenbosch, M.P. (Maikel), Kovac, M. (Michal), Adams, C.L. (Claire), Prenen, H. (Hans), Briggs, S. (Sarah), Harrison, R. (Rebecca), Sanders, S. (Scott), Macdonald, D.R.W. (David), Haigh, K. (Katharina), Tucker, A.T. (Art), Love, S. (Sharon), Nanji, M. (Manoj), Decaestecker, J. (John), Ferry, D.R. (David), Rathbone, B. (Barrie), Hapeshi, J. (Julie), Barr, H. (Hugh), Moayyedi, P. (Paul), Watson, P. (Peter), Zietek, B. (Barbara), Maroo, N. (Neera), Gay, L. (Laura), Underwood, T. (Tim), Boulter, L. (Lisa), McMurtry, H. (Hugh), Monk, A.B. (Alastair), Patel, P. (Poulam), Ragunath, K. (Krish), Al Dulaimi, D. (David), Murray, I. (Iain), Koss, C. (Clara), Veitch, A. (Andrew), Trudgill, N. (Nigel), Nwokolo, C. (Chuka), Rembacken, B., Atherfold, P. (Paul), Green, E.K. (Elaine K), Ang, Y. (Yeng), Kuipers, E.J. (Ernst), Chow, W. (Wu), Paterson, S. (Stuart), Kadri, S. (Sudarshan), Beales, I. (Ian), Grimley, C. (Charles), Mullins, P. (Paul), Beckett, C. (Conrad), Farrant, M. (Mark), Dixon, A. (Andrew), Kelly, S. (Sean), Johnson, M. (Matthew), Wajed, S. (Shahjehan), Dhar, A. (Archana), Sawyer, E.J. (Elinor), Roylance, R. (Rebecca), Onstad, L. (Lynn), Gammon, M.D. (Marilie), Corley, D.A. (Douglas), Shaheen, N. (Nazima), Bird, N.C. (Nigel), Hardie, B.G.S. (Bruce), Reid, B.J. (Brian), Ye, W. (Weimin), Liu, G. (Geoffrey), Romero, Y. (Yvonne), Bernstein, L. (Leslie), Wu, A.H. (Anna H.), Casson, A.G. (Alan), Fitzgerald, R.C. (Rebecca), Whiteman, D.C. (David C.), Risch, H. (Harvey), Levine, D.M. (David M.), Vaughan, T.L. (Thomas), Verhaar, A.P. (Auke), Van Den Brande, J. (Jan), Toxopeus, E.L.A. (Eelke), Spaander, M.C.W. (Manon), Wijnhoven, B.P.L. (Bas), Laan, L.J.W. (Luc) van der, Krishnadath, K.K. (Kausilia), Wijmenga, C. (Cisca), Trynka, G. (Gosia), McManus, R. (Ross), Reynolds, J.V. (John V.), O'Sullivan, J. (Jacintha), Macmathuna, P. (Padraic), McGarrigle, S.A. (Sarah A.), Kelleher, D. (Dermot), Vermeire, S. (Séverine), Cleynen, I. (Isabelle), Bisschops, R. (Raf), Tomlinson, I.P. (Ian), Jankowski, J.A. (Janusz Antoni), Palles, C. (Claire), Chegwidden, L. (Laura), Li, X. (Xinzhong), Findlay, J.M. (John M.), Farnham, G. (Garry), Castro Giner, F. (Francesc), Peppelenbosch, M.P. (Maikel), Kovac, M. (Michal), Adams, C.L. (Claire), Prenen, H. (Hans), Briggs, S. (Sarah), Harrison, R. (Rebecca), Sanders, S. (Scott), Macdonald, D.R.W. (David), Haigh, K. (Katharina), Tucker, A.T. (Art), Love, S. (Sharon), Nanji, M. (Manoj), Decaestecker, J. (John), Ferry, D.R. (David), Rathbone, B. (Barrie), Hapeshi, J. (Julie), Barr, H. (Hugh), Moayyedi, P. (Paul), Watson, P. (Peter), Zietek, B. (Barbara), Maroo, N. (Neera), Gay, L. (Laura), Underwood, T. (Tim), Boulter, L. (Lisa), McMurtry, H. (Hugh), Monk, A.B. (Alastair), Patel, P. (Poulam), Ragunath, K. (Krish), Al Dulaimi, D. (David), Murray, I. (Iain), Koss, C. (Clara), Veitch, A. (Andrew), Trudgill, N. (Nigel), Nwokolo, C. (Chuka), Rembacken, B., Atherfold, P. (Paul), Green, E.K. (Elaine K), Ang, Y. (Yeng), Kuipers, E.J. (Ernst), Chow, W. (Wu), Paterson, S. (Stuart), Kadri, S. (Sudarshan), Beales, I. (Ian), Grimley, C. (Charles), Mullins, P. (Paul), Beckett, C. (Conrad), Farrant, M. (Mark), Dixon, A. (Andrew), Kelly, S. (Sean), Johnson, M. (Matthew), Wajed, S. (Shahjehan), Dhar, A. (Archana), Sawyer, E.J. (Elinor), Roylance, R. (Rebecca), Onstad, L. (Lynn), Gammon, M.D. (Marilie), Corley, D.A. (Douglas), Shaheen, N. (Nazima), Bird, N.C. (Nigel), Hardie, B.G.S. (Bruce), Reid, B.J. (Brian), Ye, W. (Weimin), Liu, G. (Geoffrey), Romero, Y. (Yvonne), Bernstein, L. (Leslie), Wu, A.H. (Anna H.), Casson, A.G. (Alan), Fitzgerald, R.C. (Rebecca), Whiteman, D.C. (David C.), Risch, H. (Harvey), Levine, D.M. (David M.), Vaughan, T.L. (Thomas), Verhaar, A.P. (Auke), Van Den Brande, J. (Jan), Toxopeus, E.L.A. (Eelke), Spaander, M.C.W. (Manon), Wijnhoven, B.P.L. (Bas), Laan, L.J.W. (Luc) van der, Krishnadath, K.K. (Kausilia), Wijmenga, C. (Cisca), Trynka, G. (Gosia), McManus, R. (Ross), Reynolds, J.V. (John V.), O'Sullivan, J. (Jacintha), Macmathuna, P. (Padraic), McGarrigle, S.A. (Sarah A.), Kelleher, D. (Dermot), Vermeire, S. (Séverine), Cleynen, I. (Isabelle), Bisschops, R. (Raf), Tomlinson, I.P. (Ian), and Jankowski, J.A. (Janusz Antoni)

Abstract

Background & Aims Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10-11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10-9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10-9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Published
2015
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9. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Michailidou, K. (Kyriaki), Beesley, J. (Jonathan), Lindstrom, S. (Stephen), Canisius, S. (Sander), Dennis, J. (Joe), Lush, M. (Michael), Maranian, M. (Melanie), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Shah, M. (Mitul), Perkins, B. (Barbara), Czene, K. (Kamila), Eriksson, M. (Mikael), Darabi, H. (Hatef), Brand, J.S. (Judith S.), Bojesen, S.E. (Stig), Nordestgaard, B.G. (Børge), Flyger, H. (Henrik), Nielsen, S.F. (Sune), Rahman, N. (Nazneen), Turnbull, C. (Clare), Fletcher, O. (Olivia), Peto, J. (Julian), Gibson, L.J. (Lorna), Santos Silva, I. (Isabel) dos, Chang-Claude, J. (Jenny), Flesch-Janys, D. (Dieter), Rudolph, A. (Anja), Eilber, U. (Ursula), Behrens, T.W. (Timothy), Nevanlinna, H. (Heli), Muranen, T.A. (Taru), Aittomäki, K. (Kristiina), Blomqvist, C. (Carl), Khan, S. (Sofia), Aaltonen, K. (Kirsimari), Ahsan, H. (Habibul), Kibriya, M.G. (Muhammad), Whittemore, A.S. (Alice S.), John, E.M. (Esther M.), Malone, K.E. (Kathleen E.), Gammon, M.D. (Marilie), Santella, R.M. (Regina M.), Ursin, G. (Giske), Makalic, E. (Enes), Schmidt, D.F. (Daniel), Casey, G. (Graham), Hunter, D.J. (David J.), Gapstur, S.M. (Susan M.), Gaudet, M.M. (Mia), Diver, W.R. (Ryan), Haiman, C.A. (Christopher A.), Schumacher, F.R. (Fredrick), Henderson, B.E. (Brian), Le Marchand, L. (Loic), Berg, C.D. (Christine), Chanock, S.J. (Stephen), Figueroa, J.D. (Jonine), Hoover, R.N. (Robert N.), Lambrechts, D. (Diether), Neven, P. (Patrick), Wildiers, H. (Hans), Limbergen, E. (Erik) van, Schmidt, M.K. (Marjanka), Broeks, A. (Annegien), Verhoef, S., Cornelissen, S. (Sten), Couch, F.J. (Fergus), Olson, J.E. (Janet), Hallberg, B. (Boubou), Vachon, C. (Celine), Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Adank, M.A. (Muriel), Luijt, R.B. (Rob) van der, Li, J. (Jingmei), Liu, J. (Jianjun), Humphreys, M.K. (Manjeet), Kang, D. (Daehee), Choi, J.-Y. (Ji-Yeob), Park, S.K. (Sue K.), Yoo, K.Y., Matsuo, K. (Keitaro), Ito, H. (Hidemi), Iwata, H. (Hiroji), Tajima, K. (Kazuo), Guénel, P. (Pascal), Truong, T. (Thérèse), Mulot, C. (Claire), Sanchez, M. (Marie), Burwinkel, B. (Barbara), Marme, F. (Federick), Surowy, H. (Harald), Sohn, C. (Christof), Wu, A.H. (Anna H), Tseng, C.-C. (Chiu-chen), Van Den Berg, D. (David), Stram, D.O. (Daniel O.), González-Neira, A. (Anna), Benítez, J. (Javier), Zamora, M.P. (Pilar), Perez, J.I.A. (Jose Ignacio Arias), Shu, X.-O. (Xiao-Ou), Lu, W. (Wei), Gao, Y. (Ying), Cai, H. (Hui), Cox, A. (Angela), Cross, S.S. (Simon), Reed, M.W.R. (Malcolm), Andrulis, I.L. (Irene), Knight, J.A. (Julia), Glendon, G. (Gord), Mulligan, A.-M. (Anna-Marie), Sawyer, E.J. (Elinor), Tomlinson, I.P. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Lindblom, A. (Annika), Margolin, S. (Sara), Teo, S.H. (Soo Hwang), Yip, C.H. (Cheng Har), Taib, N.A.M. (Nur Aishah Mohd), Tan, G.-H. (Gie-Hooi), Hooning, M.J. (Maartje), Hollestelle, A. (Antoinette), Martens, J.W.M. (John), Collée, J.M. (Margriet), Blot, W.J. (William), Signorello, L.B. (Lisa B.), Cai, Q. (Qiuyin), Hopper, J. (John), Southey, M.C. (Melissa), Tsimiklis, H. (Helen), Apicella, C. (Carmel), Shen, C-Y. (Chen-Yang), Hsiung, C.-N. (Chia-Ni), Wu, P.-E. (Pei-Ei), Hou, M.-F. (Ming-Feng), Kristensen, V. (Vessela), Nord, S. (Silje), Alnæs, G.G. (Grethe), Giles, G.G. (Graham G.), Milne, R.L. (Roger), McLean, C.A. (Catriona Ann), Canzian, F. (Federico), Trichopoulos, D. (Dimitrios), Peeters, P.H.M., Lund, E. (Eiliv), Sund, R. (Reijo), Khaw, K.T., Gunter, M.J. (Marc J.), Palli, D. (Domenico), Mortensen, L.M. (Lotte Maxild), Dossus, L. (Laure), Huerta, J.-M. (Jose-Maria), Meindl, A. (Alfons), Schmutzler, R.K. (Rita), Sutter, C. (Christian), Yang, R. (Rongxi), Muir, K. (Kenneth), Lophatananon, A. (Artitaya), Stewart-Brown, S. (Sarah), Siriwanarangsan, P. (Pornthep), Hartman, J.M. (Joost), Miao, X., Chia, K.S. (Kee Seng), Chan, C.W. (Ching Wan), Fasching, P.A. (Peter), Hein, R. (Rebecca), Beckmann, M.W. (Matthias), Haeberle, L. (Lothar), Brenner, H. (Hermann), Dieffenbach, A.K. (Aida Karina), Arndt, V. (Volker), Stegmaier, C. (Christa), Ashworth, A. (Alan), Orr, N. (Nick), Schoemaker, M. (Minouk), Swerdlow, A.J. (Anthony ), Brinton, L.A. (Louise), García-Closas, M. (Montserrat), Zheng, W. (Wei), Halverson, S.L. (Sandra L.), Shrubsole, M. (Martha), Long, J. (Jirong), Goldberg, M.S. (Mark), Labrèche, F. (France), Dumont, M. (Martine), Winqvist, R. (Robert), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Brauch, H. (Hiltrud), Hamann, U. (Ute), Brüning, T. (Thomas), Radice, P. (Paolo), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Bernard, L. (Loris), Bogdanova, N.V. (Natalia), Dörk, T. (Thilo), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V-M. (Veli-Matti), Hartikainen, J.M. (J.), Devilee, P. (Peter), Tollenaar, R.A.E.M. (Rob), Seynaeve, C.M. (Caroline), Asperen, C.J. (Christi) van, Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Huzarski, T. (Tomasz), Sangrajrang, S. (Suleeporn), Gaborieau, V. (Valerie), Brennan, P. (Paul), McKay, J.D. (James), Slager, S. (Susan), Toland, A.E. (Amanda), Ambrosone, C.B. (Christine), Yannoukakos, D. (Drakoulis), Kabisch, M. (Maria), Torres, D. (Diana), Neuhausen, S.L. (Susan), Anton-Culver, H. (Hoda), Luccarini, C. (Craig), Baynes, C. (Caroline), Ahmed, S. (Shahana), Healey, S. (Sue), Tessier, D.C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Pita, G. (Guillermo), Alonso, M.R. (Rosario), Álvarez, N. (Nuria), Herrero, D. (Daniel), Simard, J. (Jacques), Pharoah, P.P.D.P. (Paul P.D.P.), Kraft, P. (Peter), Dunning, A.M. (Alison), Chenevix-Trench, G. (Georgia), Hall, P. (Per), Easton, D.F. (Douglas), Michailidou, K. (Kyriaki), Beesley, J. (Jonathan), Lindstrom, S. (Stephen), Canisius, S. (Sander), Dennis, J. (Joe), Lush, M. (Michael), Maranian, M. (Melanie), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Shah, M. (Mitul), Perkins, B. (Barbara), Czene, K. (Kamila), Eriksson, M. (Mikael), Darabi, H. (Hatef), Brand, J.S. (Judith S.), Bojesen, S.E. (Stig), Nordestgaard, B.G. (Børge), Flyger, H. (Henrik), Nielsen, S.F. (Sune), Rahman, N. (Nazneen), Turnbull, C. (Clare), Fletcher, O. (Olivia), Peto, J. (Julian), Gibson, L.J. (Lorna), Santos Silva, I. (Isabel) dos, Chang-Claude, J. (Jenny), Flesch-Janys, D. (Dieter), Rudolph, A. (Anja), Eilber, U. (Ursula), Behrens, T.W. (Timothy), Nevanlinna, H. (Heli), Muranen, T.A. (Taru), Aittomäki, K. (Kristiina), Blomqvist, C. (Carl), Khan, S. (Sofia), Aaltonen, K. (Kirsimari), Ahsan, H. (Habibul), Kibriya, M.G. (Muhammad), Whittemore, A.S. (Alice S.), John, E.M. (Esther M.), Malone, K.E. (Kathleen E.), Gammon, M.D. (Marilie), Santella, R.M. (Regina M.), Ursin, G. (Giske), Makalic, E. (Enes), Schmidt, D.F. (Daniel), Casey, G. (Graham), Hunter, D.J. (David J.), Gapstur, S.M. (Susan M.), Gaudet, M.M. (Mia), Diver, W.R. (Ryan), Haiman, C.A. (Christopher A.), Schumacher, F.R. (Fredrick), Henderson, B.E. (Brian), Le Marchand, L. (Loic), Berg, C.D. (Christine), Chanock, S.J. (Stephen), Figueroa, J.D. (Jonine), Hoover, R.N. (Robert N.), Lambrechts, D. (Diether), Neven, P. (Patrick), Wildiers, H. (Hans), Limbergen, E. (Erik) van, Schmidt, M.K. (Marjanka), Broeks, A. (Annegien), Verhoef, S., Cornelissen, S. (Sten), Couch, F.J. (Fergus), Olson, J.E. (Janet), Hallberg, B. (Boubou), Vachon, C. (Celine), Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Adank, M.A. (Muriel), Luijt, R.B. (Rob) van der, Li, J. (Jingmei), Liu, J. (Jianjun), Humphreys, M.K. (Manjeet), Kang, D. (Daehee), Choi, J.-Y. (Ji-Yeob), Park, S.K. (Sue K.), Yoo, K.Y., Matsuo, K. (Keitaro), Ito, H. (Hidemi), Iwata, H. (Hiroji), Tajima, K. (Kazuo), Guénel, P. (Pascal), Truong, T. (Thérèse), Mulot, C. (Claire), Sanchez, M. (Marie), Burwinkel, B. (Barbara), Marme, F. (Federick), Surowy, H. (Harald), Sohn, C. (Christof), Wu, A.H. (Anna H), Tseng, C.-C. (Chiu-chen), Van Den Berg, D. (David), Stram, D.O. (Daniel O.), González-Neira, A. (Anna), Benítez, J. (Javier), Zamora, M.P. (Pilar), Perez, J.I.A. (Jose Ignacio Arias), Shu, X.-O. (Xiao-Ou), Lu, W. (Wei), Gao, Y. (Ying), Cai, H. (Hui), Cox, A. (Angela), Cross, S.S. (Simon), Reed, M.W.R. (Malcolm), Andrulis, I.L. (Irene), Knight, J.A. (Julia), Glendon, G. (Gord), Mulligan, A.-M. (Anna-Marie), Sawyer, E.J. (Elinor), Tomlinson, I.P. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Lindblom, A. (Annika), Margolin, S. (Sara), Teo, S.H. (Soo Hwang), Yip, C.H. (Cheng Har), Taib, N.A.M. (Nur Aishah Mohd), Tan, G.-H. (Gie-Hooi), Hooning, M.J. (Maartje), Hollestelle, A. (Antoinette), Martens, J.W.M. (John), Collée, J.M. (Margriet), Blot, W.J. (William), Signorello, L.B. (Lisa B.), Cai, Q. (Qiuyin), Hopper, J. (John), Southey, M.C. (Melissa), Tsimiklis, H. (Helen), Apicella, C. (Carmel), Shen, C-Y. (Chen-Yang), Hsiung, C.-N. (Chia-Ni), Wu, P.-E. (Pei-Ei), Hou, M.-F. (Ming-Feng), Kristensen, V. (Vessela), Nord, S. (Silje), Alnæs, G.G. (Grethe), Giles, G.G. (Graham G.), Milne, R.L. (Roger), McLean, C.A. (Catriona Ann), Canzian, F. (Federico), Trichopoulos, D. (Dimitrios), Peeters, P.H.M., Lund, E. (Eiliv), Sund, R. (Reijo), Khaw, K.T., Gunter, M.J. (Marc J.), Palli, D. (Domenico), Mortensen, L.M. (Lotte Maxild), Dossus, L. (Laure), Huerta, J.-M. (Jose-Maria), Meindl, A. (Alfons), Schmutzler, R.K. (Rita), Sutter, C. (Christian), Yang, R. (Rongxi), Muir, K. (Kenneth), Lophatananon, A. (Artitaya), Stewart-Brown, S. (Sarah), Siriwanarangsan, P. (Pornthep), Hartman, J.M. (Joost), Miao, X., Chia, K.S. (Kee Seng), Chan, C.W. (Ching Wan), Fasching, P.A. (Peter), Hein, R. (Rebecca), Beckmann, M.W. (Matthias), Haeberle, L. (Lothar), Brenner, H. (Hermann), Dieffenbach, A.K. (Aida Karina), Arndt, V. (Volker), Stegmaier, C. (Christa), Ashworth, A. (Alan), Orr, N. (Nick), Schoemaker, M. (Minouk), Swerdlow, A.J. (Anthony ), Brinton, L.A. (Louise), García-Closas, M. (Montserrat), Zheng, W. (Wei), Halverson, S.L. (Sandra L.), Shrubsole, M. (Martha), Long, J. (Jirong), Goldberg, M.S. (Mark), Labrèche, F. (France), Dumont, M. (Martine), Winqvist, R. (Robert), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Brauch, H. (Hiltrud), Hamann, U. (Ute), Brüning, T. (Thomas), Radice, P. (Paolo), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Bernard, L. (Loris), Bogdanova, N.V. (Natalia), Dörk, T. (Thilo), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V-M. (Veli-Matti), Hartikainen, J.M. (J.), Devilee, P. (Peter), Tollenaar, R.A.E.M. (Rob), Seynaeve, C.M. (Caroline), Asperen, C.J. (Christi) van, Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Huzarski, T. (Tomasz), Sangrajrang, S. (Suleeporn), Gaborieau, V. (Valerie), Brennan, P. (Paul), McKay, J.D. (James), Slager, S. (Susan), Toland, A.E. (Amanda), Ambrosone, C.B. (Christine), Yannoukakos, D. (Drakoulis), Kabisch, M. (Maria), Torres, D. (Diana), Neuhausen, S.L. (Susan), Anton-Culver, H. (Hoda), Luccarini, C. (Craig), Baynes, C. (Caroline), Ahmed, S. (Shahana), Healey, S. (Sue), Tessier, D.C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Pita, G. (Guillermo), Alonso, M.R. (Rosario), Álvarez, N. (Nuria), Herrero, D. (Daniel), Simard, J. (Jacques), Pharoah, P.P.D.P. (Paul P.D.P.), Kraft, P. (Peter), Dunning, A.M. (Alison), Chenevix-Trench, G. (Georgia), Hall, P. (Per), and Easton, D.F. (Douglas)

Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10 â '8. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Published
2015
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10. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Author

Su, Z., Gay, L.J., Strange, A., Palles, C., Band, G., Whiteman, D.C., Lescai, F., Langford, C., Nanji, M., Edkins, S., van der Winkel, A., Levine, D., Sasieni, P., Bellenguez, C., Howarth, K., Freeman, C., Trudgill, N., Tucker, A.T., Pirinen, M., Peppelenbosch, M.P., van der Laan, L.J.W., Kuipers, E.J., Drenth, J.P.H., Peters, W.H., Reynolds, J.V., Kelleher, D.P., McManus, R., Grabsch, H., Prenen, H., Bisschops, R., Krishnadath, K., Siersema, P.D., van Baal, J.W.P.M., Middleton, M., Petty, R., Gillies, R., Burch, N., Bhandari, P., Paterson, S., Edwards, C., Penman, I., Vaidya, K., Ang, Y., Murray, I., Patel, P., Ye, W., Mullins, P., Wu, A.H., Bird, N.C., Dallal, H., Shaheen, N.J., Murray, L.J., Koss, K., Bernstein, L., Romero, Y., Hardie, L.J., Zhang, R., Winter, H., Corley, D.A., Panter, S., Risch, H.A., Reid, B.J., Sargeant, I., Gammon, M.D., Smart, H., Dhar, A., McMurtry, H., Ali, H., Liu, G., Casson, A.G., Chow, W.-H., Rutter, M., Tawil, A., Morris, D., Nwokolo, C., Isaacs, P., Rodgers, C., Ragunath, K., MacDonald, C., Haigh, C., Monk, D., Davies, G., Wajed, S., Johnston, D., Gibbons, M., Cullen, S., Church, N., Langley, R., Griffin, M., Alderson, D., Deloukas, P., Hunt, S.E., Gray, E., Dronov, S., Potter, S.C., Tashakkori-Ghanbaria, A., Anderson, M., Brooks, C., Blackwell, J.M., Bramon, E., Brown, M.A., Casas, J.P., Corvin, A., Duncanson, A., Markus, H.S., Mathew, C.G., Palmer, C.N.A., Plomin, R., Rautanen, A., Sawcer, S.J., Trembath, R.C., Viswanathan, A.C., Wood, N., Trynka, G., Wijmenga, C., Cazier, J.-B., Atherfold, P., Nicholson, A.M., Gellatly, N.L., Glancy, D., Cooper, S.C., Cunningham, D., Lind, T., Hapeshi, J., Ferry, D., Rathbone, B., Brown, J., Love, S., Attwood, S., MacGregor, S., Watson, P., Sanders, S., Ek, W., Harrison, R.F., Moayyedi, P., de Caestecker, J., Barr, H., Stupka, E., Vaughan, T.L., Peltonen, L., Spencer, C.C.A., Tomlinson, I., Donnelly, P., Jankowski, J.A.Z., Genetics, E.A., and Consor, W.T.C.C.

Subjects
digestive system diseases
Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Published
2012

11. High intakes of choline and betaine reduce breast cancer mortality in a population-based study

Author

Neugut, A.I., Zeisel, S.H., Xu, X., Chen, J., Teitelbaum, S.L., Bradshaw, P.T., Santella, R.M., Gammon, M.D., and Wetmur, J.G.

Abstract

Choline and betaine provide methyl groups for one-carbon metabolism. Humans obtain these nutrients from a wide range of foods. Betaine can also be synthesized endogenously from its precursor, choline. Although animal studies have implied a causal relationship between choline deficiency and carcinogenesis, the role of these two nutrients in human carcinogenesis and tumor progression is not well understood. We investigated the associations of dietary intakes of choline and betaine and breast cancer risk and mortality in the population-based Long Island Breast Cancer Study Project. Among the 1508 case-group women, 308 (20.2%) deaths occurred, among whom 164 (53.2%) died of breast cancer by December 31, 2005. There was an indication that a higher intake of free choline was associated with reduced risk of breast cancer (P trend=0.04). Higher intakes of betaine, phosphocholine, and free choline were associated with reduced all-cause as well as breast cancerspecific mortality in a dose-dependent fashion. We also explored associations of polymorphisms of three key choline- and betaine-metabolizing genes and breast cancer mortality. The betaine-homocysteine methyltransferase gene (BHMT) rs3733890 polymorphism was associated with reduced breast cancer-specific mortality (hazard ratio, 0.64; 95% confidence interval, 0.42-0.97). Our study supports the important roles of choline and betaine in breast carcinogenesis. It suggests that high intake of these nutrients may be a promising strategy to prevent the development of breast cancer and to reduce its mortality.

Published
2009
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15. The epidemiology of gastric cancer

Author

Terry, M.B., Gaudet, M.M., and Gammon, M.D.

Abstract

The epidemiology of gastric cancer is remarkable for both its dramatic decline in incidence over the past century and its continuing presence as the second leading cause of cancer deaths worldwide despite this decline. Factors including increased consumption of fruits and vegetables, and decreased intake of salty foods have largely been credited for the decline. Epidemiologic studies continue to provide data on other gastric cancer risk factors, including associations with Helicobacter pylori infection, as well as dietary factors, tobacco, and alcohol intake. In response to the opposing trends of decreasing distal gastric cancer and increasing gastric cardia adenocarcinoma, studies are beginning to identify gastric cancer risk factors separately by tumor subsite. Future epidemiologic studies that include information on site of origin as well as molecular markers promise to yield more homogeneous classification of case groups, which will enhance identification of underlying disease processes.

Published
2002
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17. Epidemiology of in situ and invasive breast cancer in women aged under 45

Author

Weiss, H.A., Brinton, L.A., Brogan, D., Coates, R.J., Gammon, M.D., Malone, D.E., Schoenberg, J.B., and Swanson, C.A.

Subjects
Breast cancer -- Demographic aspects, Health, Demographic aspects
Abstract

According to the authors' abstract of an article published in British Journal of Cancer, 'The incidence of in situ breast cancer in the USA has increased rapidly in recent years, [...]

Published
1996

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