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2. Smoking modifies pancreatic cancer risk loci on 2q21.3

Author

Mocci, E. Kundu, P. Wheeler, W. Arslan, A.A. Beane-Freeman, L.E. Bracci, P.M. Brennan, P. Canzian, F. Du, M. Gallinger, S. Giles, G.G. Goodman, P.J. Kooperberg, C. Le Marchand, L. Neale, R.E. Shu, X.-O. Visvanathan, K. White, E. Zheng, W. Albanes, D. Andreotti, G. Babic, A. Bamlet, W.R. Berndt, S.I. Blackford, A.L. Bueno-De-Mesquita, B. Buring, J.E. Campa, D. Chanock, S.J. Childs, E.J. Duell, E.J. Fuchs, C.S. Gaziano, J.M. Giovannucci, E.L. Goggins, M.G. Hartge, P. Hassan, M.M. Holly, E.A. Hoover, R.N. Hung, R.J. Kurtz, R.C. Lee, I.-M. Malats, N. Milne, R.L. Ng, K. Oberg, A.L. Panico, S. Peters, U. Porta, M. Rabe, K.G. Riboli, E. Rothman, N. Scelo, G. Sesso, H.D. Silverman, D.T. Stevens, V.L. Strobel, O. Thompson, I.M., Jr. Tjonneland, A. Trichopoulou, A. van Den Eeden, S.K. Wactawski-Wende, J. Wentzensen, N. Wilkens, L.R. Yu, H. Yuan, F. Zeleniuch-Jacquotte, A. Amundadottir, L.T. Li, D. Jacobs, E.J. Petersen, G.M. Wolpin, B.M. Risch, H.A. Kraft, P. Chatterjee, N. Klein, A.P. Stolzenberg-Solomon, R. and Mocci, E. Kundu, P. Wheeler, W. Arslan, A.A. Beane-Freeman, L.E. Bracci, P.M. Brennan, P. Canzian, F. Du, M. Gallinger, S. Giles, G.G. Goodman, P.J. Kooperberg, C. Le Marchand, L. Neale, R.E. Shu, X.-O. Visvanathan, K. White, E. Zheng, W. Albanes, D. Andreotti, G. Babic, A. Bamlet, W.R. Berndt, S.I. Blackford, A.L. Bueno-De-Mesquita, B. Buring, J.E. Campa, D. Chanock, S.J. Childs, E.J. Duell, E.J. Fuchs, C.S. Gaziano, J.M. Giovannucci, E.L. Goggins, M.G. Hartge, P. Hassan, M.M. Holly, E.A. Hoover, R.N. Hung, R.J. Kurtz, R.C. Lee, I.-M. Malats, N. Milne, R.L. Ng, K. Oberg, A.L. Panico, S. Peters, U. Porta, M. Rabe, K.G. Riboli, E. Rothman, N. Scelo, G. Sesso, H.D. Silverman, D.T. Stevens, V.L. Strobel, O. Thompson, I.M., Jr. Tjonneland, A. Trichopoulou, A. van Den Eeden, S.K. Wactawski-Wende, J. Wentzensen, N. Wilkens, L.R. Yu, H. Yuan, F. Zeleniuch-Jacquotte, A. Amundadottir, L.T. Li, D. Jacobs, E.J. Petersen, G.M. Wolpin, B.M. Risch, H.A. Kraft, P. Chatterjee, N. Klein, A.P. Stolzenberg-Solomon, R.

Abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, Pinteraction ¼ 3.08 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 ¼ 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. © 2021 American Association for Cancer Research.

Published
2021

3. Mendelian randomization analysis of n-6 polyunsaturated fatty acid levels and pancreatic cancer risk.

Author

Ghoneim D.H., Zhu J., Zheng W., Long J., Murff H.J., Ye F., Setiawan V.W., Wilkens L.R., Khankari N.K., Haycock P., Antwi S.O., Yang Y., Arslan A.A., Freeman L.E.B., Bracci P.M., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Marchand L.L., Neale R.E., Scelo G., Visvanathan K., White E., Albane D., Amiano P., Andreott G., Babic A., Bamlet W.R., Berndt S.I., Brais L.K., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Rabe K.G., Chanock S.J., Duggal P., Fuchs C.S., Gaziano J.M., Goggins M.G., Hackert T., Hassan M.M., Helzlsouer K.J., Holly E.A., Hoover R.N., Katske V., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Oberg A.L., Porta M., Rothman N., Sesso H.D., Silverman D.T., Ian T., Wactawski-Wende J., Wang X., Wentzensen N., Yu H., Zeleniuch-Jacquotte A., Yu K., Wolpin B.M., Jacobs E.J., Duell E.J., Risch H.A., Petersen G.M., Amundadottir L.T., Kraft P., Klein A.P., Stolzenberg-Solomon R.Z., Shu X.-O., Wu L., Ghoneim D.H., Zhu J., Zheng W., Long J., Murff H.J., Ye F., Setiawan V.W., Wilkens L.R., Khankari N.K., Haycock P., Antwi S.O., Yang Y., Arslan A.A., Freeman L.E.B., Bracci P.M., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Marchand L.L., Neale R.E., Scelo G., Visvanathan K., White E., Albane D., Amiano P., Andreott G., Babic A., Bamlet W.R., Berndt S.I., Brais L.K., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Rabe K.G., Chanock S.J., Duggal P., Fuchs C.S., Gaziano J.M., Goggins M.G., Hackert T., Hassan M.M., Helzlsouer K.J., Holly E.A., Hoover R.N., Katske V., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Oberg A.L., Porta M., Rothman N., Sesso H.D., Silverman D.T., Ian T., Wactawski-Wende J., Wang X., Wentzensen N., Yu H., Zeleniuch-Jacquotte A., Yu K., Wolpin B.M., Jacobs E.J., Duell E.J., Risch H.A., Petersen G.M., Amundadottir L.T., Kraft P., Klein A.P., Stolzenberg-Solomon R.Z., Shu X.-O., and Wu L.

Abstract

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Method(s): We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Result(s): Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: Linoleic acid odds ratio (OR)1.00, 95% confidence interval (CI) 0.98-1.02; arachidonic acid OR 1.00, 95% CI 0.99-1.01; and dihomo-gamma-linolenic acid OR 0.95, 95% CI 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusion(s): Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.Copyright © 2020 American Association for Cancer Research Inc.. All rights reserved.

Published
2021

4. Genome-wide genediabetes and geneobesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia.

Author

Campa D., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A., Bueno-De-Mesquita B., Buring J.E., Chanock S.J., Childs E., Duell E.J., Fuchs C., Michael Gaziano J., Goggins M., Hartge P., Hassam M.H., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Orlow I., Peters U., Porta M., Rabe K.G., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Thompson I.M., Tjonneland A., Trichopoulou A., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Amundadottir L.T., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Chatterjee N., Klein A.P., Li D., Kraft P., Wei P., Tang H., Jiang L., Stolzenberg-Solomon R.Z., Arslan A.A., Beane Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., Giles G.G., Campa D., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A., Bueno-De-Mesquita B., Buring J.E., Chanock S.J., Childs E., Duell E.J., Fuchs C., Michael Gaziano J., Goggins M., Hartge P., Hassam M.H., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Orlow I., Peters U., Porta M., Rabe K.G., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Thompson I.M., Tjonneland A., Trichopoulou A., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Amundadottir L.T., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Chatterjee N., Klein A.P., Li D., Kraft P., Wei P., Tang H., Jiang L., Stolzenberg-Solomon R.Z., Arslan A.A., Beane Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., and Giles G.G.

Abstract

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Method(s): We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index >=30 kg/m2) and diabetes (duration >=3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency >=0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Result(s): No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE 1/4 1.2 106, PJoint 1/4 4.2 107). Conclusion(s): This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may

Published
2021

5. Smoking modifies pancreatic cancer risk loci on 2q21.3.

Author

Mocci E., Kundu P., Wheeler W., Arslan A.A., Beane-Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A.L., Bueno-De-Mesquita B., Buring J.E., Campa D., Chanock S.J., Childs E.J., Duell E.J., Fuchs C.S., Gaziano J.M., Giovannucci E.L., Goggins M.G., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Panico S., Peters U., Porta M., Rabe K.G., Riboli E., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Stevens V.L., Strobel O., Thompson I.M., Tjonneland A., Trichopoulou A., van Den Eeden S.K., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Yuan F., Zeleniuch-Jacquotte A., Amundadottir L.T., Li D., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Kraft P., Chatterjee N., Klein A.P., Stolzenberg-Solomon R., Mocci E., Kundu P., Wheeler W., Arslan A.A., Beane-Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A.L., Bueno-De-Mesquita B., Buring J.E., Campa D., Chanock S.J., Childs E.J., Duell E.J., Fuchs C.S., Gaziano J.M., Giovannucci E.L., Goggins M.G., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Panico S., Peters U., Porta M., Rabe K.G., Riboli E., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Stevens V.L., Strobel O., Thompson I.M., Tjonneland A., Trichopoulou A., van Den Eeden S.K., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Yuan F., Zeleniuch-Jacquotte A., Amundadottir L.T., Li D., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Kraft P., Chatterjee N., Klein A.P., and Stolzenberg-Solomon R.

Abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, Pinteraction 1/4 3.08 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 1/4 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Copyright © 2021 American Association for Cancer Research.

Published
2021

6. Genome-wide association study data reveal genetic susceptibility to chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma risk.

Author

Wang X., Yuan F., Hung R.J., Walsh N., Zhang H., Platz E.A., Wheeler W., Song L., Arslan A.A., Beane Freeman L.E., Bracci P., Canzian F., Du M., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Shi J., Duell E.J., Amundadottir L.T., Li D., Petersen G.M., Wolpin B.M., Risch H.A., Yu K., Klein A.P., Stolzenberg-Solomon R., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Rosendahl J., Scelo G., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Amiano P., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Chanock S.J., Fuchs C.S., Michael Gaziano J., Goggins M.G., Hackert T., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Katzke V., Kirsten H., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Ng K., Oberg A.L., Porta M., Rabe K.G., Real F.X., Rothman N., Sesso H.D., Silverman D.T., Thompson I.M., Wactawski-Wende J., Wentzensen N., Wang X., Yuan F., Hung R.J., Walsh N., Zhang H., Platz E.A., Wheeler W., Song L., Arslan A.A., Beane Freeman L.E., Bracci P., Canzian F., Du M., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Shi J., Duell E.J., Amundadottir L.T., Li D., Petersen G.M., Wolpin B.M., Risch H.A., Yu K., Klein A.P., Stolzenberg-Solomon R., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Rosendahl J., Scelo G., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Amiano P., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Chanock S.J., Fuchs C.S., Michael Gaziano J., Goggins M.G., Hackert T., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Katzke V., Kirsten H., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Ng K., Oberg A.L., Porta M., Rabe K.G., Real F.X., Rothman N., Sesso H.D., Silverman D.T., Thompson I.M., Wactawski-Wende J., and Wentzensen N.

Abstract

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (+500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 x 10-6, respectively). After excluding the 20 PDAC susceptibility regions (+500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P 1/4 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P 1/4 0.22) and primary sclerosing cholangitis (P 1/4 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.Copyright © 2020 American Association for Cancer Research.

Published
2021

7. Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia

Author

Tang, H. Jiang, L. Stolzenberg-Solomon, R.Z. Arslan, A.A. Beane Freeman, L.E. Bracci, P.M. Brennan, P. Canzian, F. Du, M. Gallinger, S. Giles, G.G. Goodman, P.J. Kooperberg, C. Le Marchand, L. Neale, R.E. Shu, X.-O. Visvanathan, K. White, E. Zheng, W. Albanes, D. Andreotti, G. Babic, A. Bamlet, W.R. Berndt, S.I. Blackford, A. Bueno-De-Mesquita, B. Buring, J.E. Campa, D. Chanock, S.J. Childs, E. Duell, E.J. Fuchs, C. Michael Gaziano, J. Goggins, M. Hartge, P. Hassam, M.H. Holly, E.A. Hoover, R.N. Hung, R.J. Kurtz, R.C. Lee, I.-M. Malats, N. Milne, R.L. Ng, K. Oberg, A.L. Orlow, I. Peters, U. Porta, M. Rabe, K.G. Rothman, N. Scelo, G. Sesso, H.D. Silverman, D.T. Thompson, I.M. Tjønneland, A. Trichopoulou, A. Wactawski-Wende, J. Wentzensen, N. Wilkens, L.R. Yu, H. Zeleniuch-Jacquotte, A. Amundadottir, L.T. Jacobs, E.J. Petersen, G.M. Wolpin, B.M. Risch, H.A. Chatterjee, N. Klein, A.P. Li, D. Kraft, P. Wei, P.

Abstract

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE ¼ 1.2 106, PJoint ¼ 4.2 107). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer. © 2020 American Association for Cancer Research.

Published
2020

8. PF385 ANTICOAGULATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED WITH IBRUTINIB

Author

Archibald, W.J., primary, Ding, W., additional, Call, T.G., additional, Rabe, K.G., additional, Koehler, A.B., additional, Kay, N.E., additional, Kenderian, S.S., additional, Leis, J.F., additional, Kabat, B.F., additional, Schwager, S.M., additional, Fonder, A.L., additional, Slager, S.L., additional, Muchtar, E., additional, and Parikh, S.A., additional

Published
2019
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12. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, S.I., Skibola, C.F., Joseph, V., Camp, N.J., Nieters, A., Wang, Z., Cozen, W., Monnereau, A., Wang, S.S., Kelly, R.S., Lan, Q., Teras, L.R., Chatterjee, N., Chung, C.C., Yeager, M., Brooks-Wilson, A.R., Hartge, P., Purdue, M.P., Birmann, B.M., Armstrong, B.K., Cocco, P., Zhang, Y., Severi, G., Zeleniuch-Jacquotte, A., Lawrence, C., Burdette, L., Yuenger, J., Hutchinson, A., Jacobs, K.B., Call, T.G., Shanafelt, T.D., Novak, A.J., Kay, N.E., Liebow, M., Wang, A.H., Smedby, K.E., Adami, H.-O., Melbye, M., Glimelius, B., Chang, E.T., Glenn, M., Curtin, K., Cannon-Albright, L.A., Jones, B., Diver, W.R., Link, B.K., Weiner, G.J., Conde, L., Bracci, P.M., Riby, J., Holly, E.A., Smith, M.T., Jackson, R.D., Tinker, L.F., Benavente, Y., Becker, N., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Rabe, K.G., Achenbach, S.J., Vachon, C.M., Goldin, L.R., Strom, S.S., Lanasa, M.C., Spector, L.G., Leis, J.F., Cunningham, J.M., Weinberg, J.B., Morrison, V.A., Caporaso, N.E., Norman, A.D., Linet, M.S., De Roos, A.J., Morton, L.M., Severson, R.K., Riboli, E., Vineis, P., Kaaks, R., Trichopoulos, D., Masala, G., Weiderpass, E., Chirlaque, M.-D., Vermeulen, R.C.H., Travis, R.C., Giles, G.G., Albanes, D., Virtamo, J., Weinstein, S., Clavel, J., Zheng, T., Holford, T.R., Offit, K., Zelenetz, A., Klein, R.J., Spinelli, J.J., Bertrand, K.A., Laden, F., Giovannucci, E., Kraft, P., Kricker, A., Turner, J., Vajdic, C.M., Ennas, M.G., Ferri, G.M., Miligi, L., Liang, L., Sampson, J., Crouch, S., Park, J.-H., North, K.E., Cox, A., Snowden, J.A., Wright, J., Carracedo, A., Lopez-Otin, C., Bea, S., Salaverria, I., Martin-Garcia, D., Campo, E., Jr, F.J.F., de Sanjose, S., Hjalgrim, H., Cerhan, J.R., Chanock, S.J., Rothman, N., and Slager, S.L.

Abstract

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10−14), 18q21.33 (BCL2, P = 7.76 × 10−11), 11p15.5 (C11orf21, P = 2.15 × 10−10), 4q25 (LEF1, P = 4.24 × 10−10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10−9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10−8), 18q21.32 (PMAIP1, P = 2.51 × 10−8), 15q15.1 (BMF, P = 2.71 × 10−10) and 2p22.2 (QPCT, P = 1.68 × 10−8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10−18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10−8) and 5p15.33 (TERT, P = 1.92 × 10−7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.

Published
2013

16. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Roel Vermeulen, Robert J. Klein, Lindsay M. Morton, Lauren R. Teras, John A. Snowden, Angela Brooks-Wilson, Sonja I. Berndt, Pierluigi Cocco, Wendy Cozen, Rebecca D. Jackson, Lenka Foretova, Henrik Hjalgrim, Bruce K. Armstrong, Neil E. Caporaso, Mark P. Purdue, Itziar Salaverria, Anne J. Novak, Elizabeth A. Holly, Anneclaire J. De Roos, Kenneth Offit, Liming Liang, Paolo Vineis, Stephen J. Chanock, Anne Kricker, Sophia S. Wang, Vicki A. Morrison, George J. Weiner, Lesley F. Tinker, Nilanjan Chatterjee, Hans-Olov Adami, Ellen T. Chang, Mark Liebow, Mark C. Lanasa, Lisa A. Cannon-Albright, Andrew D. Zelenetz, Claire M. Vajdic, Sara J. Achenbach, James McKay, Gianluca Severi, Kari E. North, Edward Giovannucci, Rudolf Kaaks, Angela Cox, Karin E. Smedby, Susan L. Slager, Aaron D. Norman, Brian K. Link, Charles E. Lawrence, Amy Hutchinson, Jarmo Virtamo, Kari G. Rabe, Theodore R. Holford, Joshua N. Sampson, Lucia Conde, Timothy G. Call, Alice H. Wang, Julie M. Cunningham, Demetrius Albanes, Nikolaus Becker, Elio Riboli, Alain Monnereau, Francine Laden, Celine M. Vachon, Charles C. Chung, Ruth C. Travis, Brandt Jones, Brenda M. Birmann, Nathaniel Rothman, Yolanda Benavente, Kevin B. Jacobs, Tait D. Shanafelt, Rachel S. Kelly, Anthony Staines, Marc Maynadié, Lucia Miligi, Paul Brennan, Silvia de Sanjosé, Karen Curtin, Tongzhang Zheng, Sílvia Beà, Bengt Glimelius, Elias Campo, W. Ryan Diver, Jeffrey Yuenger, Qing Lan, Peter Kraft, Kimberly A. Bertrand, Laurie Burdette, Martha Glenn, Jenny Turner, J. Brice Weinberg, Ju-Hyun Park, Paolo Boffetta, Jacqueline Clavel, Joseph F. Fraumeni, Martyn T. Smith, Logan G. Spector, Lynn R. Goldin, Mads Melbye, Paige M. Bracci, David Martín-García, Sara S. Strom, Christine F. Skibola, Vijai Joseph, Nicola J. Camp, Dimitrios Trichopoulos, Richard K. Severson, Elisabete Weiderpass, James R. Cerhan, Maria Grazia Ennas, Carlos López-Otín, Yawei Zhang, Jose F. Leis, Angel Carracedo, Graham G. Giles, Patricia Hartge, María Dolores Chirlaque, Zhaoming Wang, Martha S. Linet, John J. Spinelli, Alexandra Nieters, Anne Zeleniuch-Jacquotte, Giovanni Maria Ferri, Stephanie J. Weinstein, Meredith Yeager, Giovanna Masala, Neil E. Kay, Jacques Riby, Simon Crouch, Josh Wright, Berndt, S.I., Skibola, C.F., Joseph, V., Camp, N.J., Nieters, A., Wang, Z., Cozen, W., Monnereau, A., Wang, S.S., Kelly, R.S., Lan, Q., Teras, L.R., Chatterjee, N., Chung, C.C., Yeager, M., Brooks-Wilson, A.R., Hartge, P., Purdue, M.P., Birmann, B.M., Armstrong, B.K., Cocco, P., Zhang, Y., Severi, G., Zeleniuch-Jacquotte, A., Lawrence, C., Burdette, L., Yuenger, J., Hutchinson, A., Jacobs, K.B., Call, T.G., Shanafelt, T.D., Novak, A.J., Kay, N.E., Liebow, M., Wang, A.H., Smedby, K.E., Adami, H.-O., Melbye, M., Glimelius, B., Chang, E.T., Glenn, M., Curtin, K., Cannon-Albright, L.A., Jones, B., Diver, W.R., Link, B.K., Weiner, G.J., Conde, L., Bracci, P.M., Riby, J., Holly, E.A., Smith, M.T., Jackson, R.D., Tinker, L.F., Benavente, Y., Becker, N., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Rabe, K.G., Achenbach, S.J., Vachon, C.M., Goldin, L.R., Strom, S.S., Lanasa, M.C., Spector, L.G., Leis, J.F., Cunningham, J.M., Weinberg, J.B., Morrison, V.A., Caporaso, N.E., Norman, A.D., Linet, M.S., De Roos, A.J., Morton, L.M., Severson, R.K., Riboli, E., Vineis, P., Kaaks, R., Trichopoulos, D., Masala, G., Weiderpass, E., Chirlaque, M.-D., Vermeulen, R.C.H., Travis, R.C., Giles, G.G., Albanes, D., Virtamo, J., Weinstein, S., Clavel, J., Zheng, T., Holford, T.R., Offit, K., Zelenetz, A., Klein, R.J., Spinelli, J.J., Bertrand, K.A., Laden, F., Giovannucci, E., Kraft, P., Kricker, A., Turner, J., Vajdic, C.M., Ennas, M.G., Ferri, G.M., Miligi, L., Liang, L., Sampson, J., Crouch, S., Park, J.-H., North, K.E., Cox, A., Snowden, J.A., Wright, J., Carracedo, A., Lopez-Otin, C., Bea, S., Salaverria, I., Martin-Garcia, D., Campo, E., Fraumeni Jr., J.F., De Sanjose, S., Hjalgrim, H., Cerhan, J.R., Chanock, S.J., Rothman, N., and Slager, S.L.

Subjects
Risk, Linkage disequilibrium, Chronic lymphocytic leukemia, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Leucèmia limfocítica crònica, Genome-wide association studies (GWAS), B-cell lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL), Genetic association, Recombination, Genetic, Genomics, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Genòmica, Leukemia, Genetic Loci, Case-Control Studies, Chromosomes, Human, Pair 2, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10-14), 18q21.33 (BCL2, P = 7.76 × 10-11), 11p15.5 (C11orf21, P = 2.15 × 10 -10), 4q25 (LEF1, P = 4.24 × 10-10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10-9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10-8), 18q21.32 (PMAIP1, P = 2.51 × 10 -8), 15q15.1 (BMF, P = 2.71 × 10-10) and 2p22.2 (QPCT, P = 1.68 × 10-8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10-18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10-8) and 5p15.33 (TERT, P = 1.92 × 10-7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism. © 2013 Nature America, Inc. All rights reserved.

Published
2013

17. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32

Author

Neil E. Kay, Jacques Riby, Bengt Glimelius, Scott Davis, Susan L. Slager, Maryjean Schenk, Hui Qi Low, Nathaniel Rothman, Yolanda Benavente, Nicola J. Camp, Logan G. Spector, Jianjun Liu, Laura Z. Rassenti, Sara S. Strom, Mark P. Purdue, Karin E. Smedby, Paul Brennan, Silvia de Sanjosé, Tongzhang Zheng, Qing Lan, Wendy Cozen, Julie M. Cunningham, Martha Glenn, Henrik Hjalgrim, Christine F. Skibola, Bruce K. Armstrong, Celine M. Vachon, Lenka Foretova, Sara J. Achenbach, Alexandra Nieters, Paolo Boffetta, Marc Maynadié, Lynn R. Goldin, Peter Boyle, Sophia S. Wang, Eran Halperin, Stephen J. Chanock, Patricia Hartge, Hans-Olov Adami, Kari G. Rabe, Sam Milliken, Katja Butterbach, Kevin M. Brown, Nikolaus Becker, Lindsay M. Morton, Pierluigi Cocco, Keith Humphreys, Yawei Zhang, Neil E. Caporaso, Claire M. Vajdic, Mark C. Lanasa, Anne Kricker, John J. Spinelli, Ellen T. Chang, Gerald E. Marti, Mads Melbye, Hatef Darabi, Anthony Staines, Lucia Conde, Jose F. Leis, Timothy G. Call, Martyn T. Smith, Curtis A. Hanson, Nicholas K. Akers, Elizabeth A. Holly, Luz Agana, J. Brice Weinberg, Shelia Hoar Zahm, Paige M. Bracci, James R. Cerhan, Angela Brooks-Wilson, Conde, L., Halperin, E., Akers, N.K., Brown, K.M., Smedby, K.E., Rothman, N., Nieters, A., Slager, S.L., Brooks-Wilson, A., Agana, L., Riby, J., Liu, J., Adami, H.-O., Darabi, H., Hjalgrim, H., Low, H.-Q., Humphreys, K., Melbye, M., Chang, E.T., Glimelius, B., Cozen, W., Davis, S., Hartge, P., Morton, L.M., Schenk, M., Wang, S.S., Armstrong, B., Kricker, A., Milliken, S., Purdue, M.P., Vajdic, C.M., Boyle, P., Lan, Q., Zahm, S.H., Zhang, Y., Zheng, T., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Butterbach, K., Cocco, P., Foretova, L., Maynadié, M., De Sanjosé, S., Staines, A., Spinelli, J.J., Achenbach, S.J., Call, T.G., Camp, N.J., Glenn, M., Caporaso, N.E., Cerhan, J.R., Cunningham, J.M., Goldin, L.R., Hanson, C.A., Kay, N.E., Lanasa, M.C., Leis, J.F., Marti, G.E., Rabe, K.G., Rassenti, L.Z., Spector, L.G., Strom, S.S., Vachon, C.M., Weinberg, J.B., Holly, E.A., Chanock, S., Smith, M.T., Bracci, P.M., and Skibola, C.F.

Subjects
Chronic lymphocytic leukemia, Follicular lymphoma, Locus (genetics), Genome-wide association study, Human leukocyte antigen, Biology, Article, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, follicular lymphoma, Risk Factors, hemic and lymphatic diseases, Genetics, medicine, Humans, Lymphoma, Follicular, 030304 developmental biology, 0303 health sciences, Lymphoma, Non-Hodgkin, Genetic Variation, 16. Peace & justice, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Lymphoma, Non-Hodgkin's lymphoma, Leukemia, 030220 oncology & carcinogenesis, Immunology, Disease Susceptibility, Genome-Wide Association Study
Abstract

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 × 10-29 and rs7755224, combined P = 2.00 × 10-19; r2 = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 × 10-9). © 2010 Nature America, Inc. All rights reserved.

Published
2010

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