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

Author: Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R. G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, DeCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Reeh, Matthias, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., Dai, James Y., Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R. G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, DeCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Reeh, Matthias, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., and Dai, James Y.
Abstract: Background: Over 20 susceptibility single-nucleotide poly-morphisms (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, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., Buas, Matthew F., Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., and Buas, Matthew F.
Abstract: 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 metaanalysis. 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. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author: Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, other, and, Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, and other, and
Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.
Published: 2021

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

Author: Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., Buas, Matthew F., Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., and Buas, Matthew F.
Abstract: 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 metaanalysis. 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

5. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

6. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

7. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

8. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

9. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

10. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

11. Association between levels of sex hormones and risk of esophageal adenocarcinoma and Barrett’s esophagus

Author: Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, Lagergren, Jesper, Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P, Anderson, Lesley A, Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D, Risch, Harvey A, Shaheen, Nicholas J, Reid, Brian J, Wu, Anna H, Iyer, Prasad G, Liu, Geoffrey, Corley, Douglas A, Whiteman, David C, Caldas, Carlos, Pharoah, Paul, Hardie, Laura J, Fitzgerald, Rebecca C, Shen, Hongbing, Vaughan, Thomas L, and Lagergren, Jesper
Abstract: Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett’s esophagus (BE). Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01- 1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.
Published: 2020

12. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author: An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Whiteman, David C., MacGregor, Stuart, other, and, An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Whiteman, David C., MacGregor, Stuart, and other, and
Abstract: Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.
Published: 2019

13. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
Abstract: SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc
Published: 2017

14. Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author: Ek, Weronica E, Lagergren, Katarina, Cook, Michael, Wu, Anna H, Abnet, Christian C, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Corley, Douglas A, Hardie, Laura J, Fitzgerald, Rebecca C, Gammon, Marilie D, Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David C, Westberg, Lars, Lagergren, Jesper, Ek, Weronica E, Lagergren, Katarina, Cook, Michael, Wu, Anna H, Abnet, Christian C, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Corley, Douglas A, Hardie, Laura J, Fitzgerald, Rebecca C, Gammon, Marilie D, Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David C, Westberg, Lars, and Lagergren, Jesper
Abstract: The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.
Published: 2016
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15. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R. G. Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R. G. Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p< 5 x 10(-8)). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p= 4 .8 x 10(-1)), MSRA (rs17749155; p= 5.2 x 10(-1) x)
Published: 2016

16. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

17. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

18. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

19. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
Abstract: SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc
Published: 2016

20. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

21. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

22. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R. G. Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R. G. Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p< 5 x 10(-8)). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p= 4 .8 x 10(-1)), MSRA (rs17749155; p= 5.2 x 10(-1) x)
Published: 2016

23. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
Abstract: SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc
Published: 2016

24. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes
Abstract: Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

25. Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma : A Pooled Analysis from the BEACON Consortium.

Author: Lagergren, Katarina, Ek, Weronica E, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Wu, Anna H, Fitzgerald, Rebecca C, Pharoah, Paul, Caldas, Carlos, Romero, Yvonne, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David, Westberg, Lars, Nyren, Olof, Lagergren, Jesper, Lagergren, Katarina, Ek, Weronica E, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Wu, Anna H, Fitzgerald, Rebecca C, Pharoah, Paul, Caldas, Carlos, Romero, Yvonne, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David, Westberg, Lars, Nyren, Olof, and Lagergren, Jesper
Abstract: BACKGROUND: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. METHODS: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). RESULTS: Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. CONCLUSION: Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed., Shared first authorship
Published: 2015
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26. Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk.

Author: Lee, Eunjung, Stram, Daniel O, Ek, Weronica E, Onstad, Lynn E, MacGregor, Stuart, Gharahkhani, Puya, Ye, Weimin, Lagergren, Jesper, Shaheen, Nicholas J, Murray, Liam J, Hardie, Laura J, Gammon, Marilie D, Chow, Wong-Ho, Risch, Harvey A, Corley, Douglas A, Levine, David M, Whiteman, David C, Bernstein, Leslie, Bird, Nigel C, Vaughan, Thomas L, Wu, Anna H, Lee, Eunjung, Stram, Daniel O, Ek, Weronica E, Onstad, Lynn E, MacGregor, Stuart, Gharahkhani, Puya, Ye, Weimin, Lagergren, Jesper, Shaheen, Nicholas J, Murray, Liam J, Hardie, Laura J, Gammon, Marilie D, Chow, Wong-Ho, Risch, Harvey A, Corley, Douglas A, Levine, David M, Whiteman, David C, Bernstein, Leslie, Bird, Nigel C, Vaughan, Thomas L, and Wu, Anna H
Abstract: BACKGROUND: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. METHODS: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. RESULTS: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. CONCLUSIONS: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. IMPACT: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev; 24(11); 1801-3. ©2015 AACR.
Published: 2015
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27. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author: Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, Jankowski, Janusz, Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz
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

28. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author: Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, Jankowski, Janusz, Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz
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

29. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author: Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, Jankowski, Janusz, Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz
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

30. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author: Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, Jankowski, Janusz, Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz
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

31. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author: Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, Jankowski, Janusz, Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz
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

32. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author: Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, Jankowski, Janusz, Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz
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

33. Environmental, Dietary, Maternal, and Fetal Predictors of Bulky DNA Adducts in Cord Blood:A European Mother-Child Study (NewGeneris)

Author: Pedersen, Marie, Mendez, Michelle A, Schoket, Bernadette, Godschalk, Roger W, Espinosa, Ana, Landström, Anette, Villanueva, Cristina M, Merlo, Domenico F, Fthenou, Eleni, Gracia-Lavedan, Esther, van Schooten, Frederik-J, Hoek, Gerard, Brunborg, Gunnar, Meltzer, Helle M, Alexander, Jan, Nielsen, Jeanette Kolstrup Søgaard, Sunyer, Jordi, Wright, John, Kovács, Katalin, de Hoogh, Kees, Gutzkow, Kristine B, Hardie, Laura J, Chatzi, Leda, Knudsen, Lisbeth E., Anna, Lívia, Ketzel, Matthias, Haugen, Margaretha, Botsivali, Maria, Nieuwenhuijsen, Mark J, Cirach, Marta, Toledano, Mireille B, Smith, Rachel B, Fleming, Sarah, Agramunt, Silvia, Kyrtopoulos, Soterios A, Lukács, Viktória, Kleinjans, Jos C, Segerbäck, Dan, Kogevinas, Manolis, Pedersen, Marie, Mendez, Michelle A, Schoket, Bernadette, Godschalk, Roger W, Espinosa, Ana, Landström, Anette, Villanueva, Cristina M, Merlo, Domenico F, Fthenou, Eleni, Gracia-Lavedan, Esther, van Schooten, Frederik-J, Hoek, Gerard, Brunborg, Gunnar, Meltzer, Helle M, Alexander, Jan, Nielsen, Jeanette Kolstrup Søgaard, Sunyer, Jordi, Wright, John, Kovács, Katalin, de Hoogh, Kees, Gutzkow, Kristine B, Hardie, Laura J, Chatzi, Leda, Knudsen, Lisbeth E., Anna, Lívia, Ketzel, Matthias, Haugen, Margaretha, Botsivali, Maria, Nieuwenhuijsen, Mark J, Cirach, Marta, Toledano, Mireille B, Smith, Rachel B, Fleming, Sarah, Agramunt, Silvia, Kyrtopoulos, Soterios A, Lukács, Viktória, Kleinjans, Jos C, Segerbäck, Dan, and Kogevinas, Manolis
Abstract: BACKGROUND: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk.OBJECTIVE: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates.METHODS: Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006-2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population.RESULTS: Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England.CONCLUSION: These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates.
Published: 2015

34. Environmental, Dietary, Maternal, and Fetal Predictors of Bulky DNA Adducts in Cord Blood:A European Mother-Child Study (NewGeneris)

Author: Pedersen, Marie, Mendez, Michelle A, Schoket, Bernadette, Godschalk, Roger W, Espinosa, Ana, Landström, Anette, Villanueva, Cristina M, Merlo, Domenico F, Fthenou, Eleni, Gracia-Lavedan, Esther, van Schooten, Frederik-J, Hoek, Gerard, Brunborg, Gunnar, Meltzer, Helle M, Alexander, Jan, Nielsen, Jeanette Kolstrup Søgaard, Sunyer, Jordi, Wright, John, Kovács, Katalin, de Hoogh, Kees, Gutzkow, Kristine B, Hardie, Laura J, Chatzi, Leda, Knudsen, Lisbeth E., Anna, Lívia, Ketzel, Matthias, Haugen, Margaretha, Botsivali, Maria, Nieuwenhuijsen, Mark J, Cirach, Marta, Toledano, Mireille B, Smith, Rachel B, Fleming, Sarah, Agramunt, Silvia, Kyrtopoulos, Soterios A, Lukács, Viktória, Kleinjans, Jos C, Segerbäck, Dan, Kogevinas, Manolis, Pedersen, Marie, Mendez, Michelle A, Schoket, Bernadette, Godschalk, Roger W, Espinosa, Ana, Landström, Anette, Villanueva, Cristina M, Merlo, Domenico F, Fthenou, Eleni, Gracia-Lavedan, Esther, van Schooten, Frederik-J, Hoek, Gerard, Brunborg, Gunnar, Meltzer, Helle M, Alexander, Jan, Nielsen, Jeanette Kolstrup Søgaard, Sunyer, Jordi, Wright, John, Kovács, Katalin, de Hoogh, Kees, Gutzkow, Kristine B, Hardie, Laura J, Chatzi, Leda, Knudsen, Lisbeth E., Anna, Lívia, Ketzel, Matthias, Haugen, Margaretha, Botsivali, Maria, Nieuwenhuijsen, Mark J, Cirach, Marta, Toledano, Mireille B, Smith, Rachel B, Fleming, Sarah, Agramunt, Silvia, Kyrtopoulos, Soterios A, Lukács, Viktória, Kleinjans, Jos C, Segerbäck, Dan, and Kogevinas, Manolis
Abstract: BACKGROUND: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk.OBJECTIVE: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates.METHODS: Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006-2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population.RESULTS: Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England.CONCLUSION: These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates.
Published: 2015

35. Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus : a Mendelian randomization study.

Author: Thrift, Aaron P, Shaheen, Nicholas J, Gammon, Marilie D, Bernstein, Leslie, Reid, Brian J, Onstad, Lynn, Risch, Harvey A, Liu, Geoffrey, Bird, Nigel C, Wu, Anna H, Corley, Douglas A, Romero, Yvonne, Chanock, Stephen J, Chow, Wong-Ho, Casson, Alan G, Levine, David M, Zhang, Rui, Ek, Weronica E, MacGregor, Stuart, Ye, Weimin, Hardie, Laura J, Vaughan, Thomas L, Whiteman, David C, Thrift, Aaron P, Shaheen, Nicholas J, Gammon, Marilie D, Bernstein, Leslie, Reid, Brian J, Onstad, Lynn, Risch, Harvey A, Liu, Geoffrey, Bird, Nigel C, Wu, Anna H, Corley, Douglas A, Romero, Yvonne, Chanock, Stephen J, Chow, Wong-Ho, Casson, Alan G, Levine, David M, Zhang, Rui, Ek, Weronica E, MacGregor, Stuart, Ye, Weimin, Hardie, Laura J, Vaughan, Thomas L, and Whiteman, David C
Abstract: BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. METHODS: We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
Published: 2014
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36. Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression : The NewGeneris Cohort

Author: Merlo, Domenico Franco, Agramunt, Silvia, Anna, Livia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J., Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B., Fleming, Sarah, Fontana, Vincenzo, Foersti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W., Granum, Berit, Hardie, Laura J., Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E., Kogevinas, Manolis, Kovacs, Katalin, Kyrtopoulos, Soterios A., Lovik, Martinus, Nielsen, Jeanette K., Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J., vande Loock, Kim, von Stedingk, Hans, Wright, John, Kleinjans, Jos C., Kirsch-Volders, Micheline, van Delft, Joost H. M., Merlo, Domenico Franco, Agramunt, Silvia, Anna, Livia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J., Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B., Fleming, Sarah, Fontana, Vincenzo, Foersti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W., Granum, Berit, Hardie, Laura J., Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E., Kogevinas, Manolis, Kovacs, Katalin, Kyrtopoulos, Soterios A., Lovik, Martinus, Nielsen, Jeanette K., Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J., vande Loock, Kim, von Stedingk, Hans, Wright, John, Kleinjans, Jos C., Kirsch-Volders, Micheline, and van Delft, Joost H. M.
Abstract: Background: Leukemia incidence has increased in recent decades among European children, -suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M(1)dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M(1)dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX (R) (chemically activated luciferase expression for androgens) (8 genes), ER alpha CALUX (R) (for estrogens) (2 genes), and DR CALUX (R) (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity, AuthorCount:45
Published: 2014
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37. In Utero Exposure to Compounds with Dioxin-like Activity and Birth Outcomes

Author: Vafeiadi, Marina, Agramunt, Silvia, Pedersen, Marie, Besselink, Harrie, Chatzi, Leda, Fthenou, Eleni, Fleming, Sarah, Hardie, Laura J, Wright, John, Knudsen, Lisbeth E., Nielsen, Jeanette K S, Sunyer, Jordi, Carreras, Ramon, Brunborg, Gunnar, Gutzkow, Kristine B, Nygaard, Unni C, Løvik, Martinus, Kyrtopoulos, Soterios A, Segerbäck, Dan, Merlo, Domenico F, Kleinjans, Jos C, Vrijheid, Martine, Kogevinas, Manolis, Vafeiadi, Marina, Agramunt, Silvia, Pedersen, Marie, Besselink, Harrie, Chatzi, Leda, Fthenou, Eleni, Fleming, Sarah, Hardie, Laura J, Wright, John, Knudsen, Lisbeth E., Nielsen, Jeanette K S, Sunyer, Jordi, Carreras, Ramon, Brunborg, Gunnar, Gutzkow, Kristine B, Nygaard, Unni C, Løvik, Martinus, Kyrtopoulos, Soterios A, Segerbäck, Dan, Merlo, Domenico F, Kleinjans, Jos C, Vrijheid, Martine, and Kogevinas, Manolis
Abstract: BACKGROUND: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study.METHODS: We measured dioxin-like activity in maternal and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth weight, gestational age, and head circumference.RESULTS: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared with the lowest tertile. Gestational age was shorter by approximately half a week in the highest compared with the lowest (-0.4 weeks [95% CI = -0.8 to -0.1]). This association was stronger in boys than in girls, although the statistical evidence for interaction was weak (P = 0.22). Analysis based on CALUX-toxic equivalents expressed per milliliter of plasma showed similar trends. We found no association between dioxin-like activity in maternal plasma and birth outcomes.CONCLUSIONS: Results from this international general population study suggest an association between low-level prenatal dioxin-like activity and shorter gestational age, particularly in boys, with weaker associations for birth weight.
Published: 2014

38. Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression:the NewGeneris cohort

Author: Merlo, Domenico Franco, Agramunt, Silvia, Anna, Lívia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J, Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B, Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W, Granum, Berit, Hardie, Laura J, Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E, Kogevinas, Manolis, Kovács, Katalin, Kyrtopoulos, Soterios A, Løvik, Martinus, Nielsen, Jeanette K, Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J, Vande Loock, Kim, von Stedingk, Hans, Wright, Andrew John, Kleinjans, Jos C, Kirsch-Volders, Micheline, van Delft, Joost H M, Merlo, Domenico Franco, Agramunt, Silvia, Anna, Lívia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J, Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B, Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W, Granum, Berit, Hardie, Laura J, Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E, Kogevinas, Manolis, Kovács, Katalin, Kyrtopoulos, Soterios A, Løvik, Martinus, Nielsen, Jeanette K, Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J, Vande Loock, Kim, von Stedingk, Hans, Wright, Andrew John, Kleinjans, Jos C, Kirsch-Volders, Micheline, and van Delft, Joost H M
Abstract: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development.
Published: 2014

39. In Utero Exposure to Compounds with Dioxin-like Activity and Birth Outcomes

Author: Vafeiadi, Marina, Agramunt, Silvia, Pedersen, Marie, Besselink, Harrie, Chatzi, Leda, Fthenou, Eleni, Fleming, Sarah, Hardie, Laura J, Wright, John, Knudsen, Lisbeth E., Nielsen, Jeanette K S, Sunyer, Jordi, Carreras, Ramon, Brunborg, Gunnar, Gutzkow, Kristine B, Nygaard, Unni C, Løvik, Martinus, Kyrtopoulos, Soterios A, Segerbäck, Dan, Merlo, Domenico F, Kleinjans, Jos C, Vrijheid, Martine, Kogevinas, Manolis, Vafeiadi, Marina, Agramunt, Silvia, Pedersen, Marie, Besselink, Harrie, Chatzi, Leda, Fthenou, Eleni, Fleming, Sarah, Hardie, Laura J, Wright, John, Knudsen, Lisbeth E., Nielsen, Jeanette K S, Sunyer, Jordi, Carreras, Ramon, Brunborg, Gunnar, Gutzkow, Kristine B, Nygaard, Unni C, Løvik, Martinus, Kyrtopoulos, Soterios A, Segerbäck, Dan, Merlo, Domenico F, Kleinjans, Jos C, Vrijheid, Martine, and Kogevinas, Manolis
Abstract: BACKGROUND: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study.METHODS: We measured dioxin-like activity in maternal and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth weight, gestational age, and head circumference.RESULTS: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared with the lowest tertile. Gestational age was shorter by approximately half a week in the highest compared with the lowest (-0.4 weeks [95% CI = -0.8 to -0.1]). This association was stronger in boys than in girls, although the statistical evidence for interaction was weak (P = 0.22). Analysis based on CALUX-toxic equivalents expressed per milliliter of plasma showed similar trends. We found no association between dioxin-like activity in maternal plasma and birth outcomes.CONCLUSIONS: Results from this international general population study suggest an association between low-level prenatal dioxin-like activity and shorter gestational age, particularly in boys, with weaker associations for birth weight.
Published: 2014

40. Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort

Author: Merlo, Domenico Franco, Agramunt, Silvia, Anna, Livia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J., Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B., Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W., Granum, Berit, Hardie, Laura J., Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E., Kogevinas, Manolis, Kovacs, Katalin, Kyrtopoulos, Soterios A., Lovik, Martinus, Nielsen, Jeanette K., Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerback, Dan, Singh, Rajinder, Sunyer, Jordi, Tornqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J., vande Loock, Kim, von Stedingk, Hans, Wright, John, Kleinjans, Jos C., Kirsch-Volders, Micheline, van Delft, Joost H. M., Merlo, Domenico Franco, Agramunt, Silvia, Anna, Livia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J., Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B., Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W., Granum, Berit, Hardie, Laura J., Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E., Kogevinas, Manolis, Kovacs, Katalin, Kyrtopoulos, Soterios A., Lovik, Martinus, Nielsen, Jeanette K., Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerback, Dan, Singh, Rajinder, Sunyer, Jordi, Tornqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J., vande Loock, Kim, von Stedingk, Hans, Wright, John, Kleinjans, Jos C., Kirsch-Volders, Micheline, and van Delft, Joost H. M.
Abstract: Background: Leukemia incidence has increased in recent decades among European children, -suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M(1)dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M(1)dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX (R) (chemically activated luciferase expression for androgens) (8 genes), ER alpha CALUX (R) (for estrogens) (2 genes), and DR CALUX (R) (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity
Published: 2014

41. Maternal diet, prenatal exposure to dioxin-like compounds and birth outcomes in a European prospective mother–child study (NewGeneris)

Author: Papadopoulou, Eleni, Kogevinas, Manolis, Botsivali, Maria, Pedersen, Marie, Besselink, Harrie, Mendez, Michelle A, Fleming, Sarah, Hardie, Laura J, Knudsen, Lisbeth E, Wright, John, Agramunt, Silvia, Sunyer, Jordi, Granum, Berit, Gutzkow, Kristine B, Brunborg, Gunnar, Alexander, Jan, Meltzer, Helle Margrete, Brantsæter, Anne Lise, Sarri, Katerina, Chatzi, Leda, Merlo, Domenico F, Kleinjans, Jos C, Haugen, Margaretha, Papadopoulou, Eleni, Kogevinas, Manolis, Botsivali, Maria, Pedersen, Marie, Besselink, Harrie, Mendez, Michelle A, Fleming, Sarah, Hardie, Laura J, Knudsen, Lisbeth E, Wright, John, Agramunt, Silvia, Sunyer, Jordi, Granum, Berit, Gutzkow, Kristine B, Brunborg, Gunnar, Alexander, Jan, Meltzer, Helle Margrete, Brantsæter, Anne Lise, Sarri, Katerina, Chatzi, Leda, Merlo, Domenico F, Kleinjans, Jos C, and Haugen, Margaretha
Abstract: Maternal diet can result in exposure to environmental contaminants including dioxins which may influence foetal growth. We investigated the association between maternal diet and birth outcomes by defining a dioxin-rich diet. We used validated food frequency questionnaires to assess the diet of pregnant women from Greece, Spain, United Kingdom, Denmark and Norway and estimated plasma dioxin-like activity by the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX®) bioassay in 604 maternal blood samples collected at delivery. We applied reduced rank regression to identify a dioxin-rich dietary pattern based on dioxin-like activity (DR-CALUX®) levels in maternal plasma, and calculated a dioxin-diet score as an estimate of adherence to this dietary pattern. In the five country population, dioxin-diet score was characterised by high consumption of red and white meat, lean and fatty fish, low-fat dairy and low consumption of salty snacks and high-fat cheese, during pregnancy. The upper tertile of the dioxin-diet score was associated with a change in birth weight of -121g (95% confidence intervals: -232, -10g) compared to the lower tertile after adjustment for confounders. A small non-significant reduction in gestational age was also observed (-1.4days, 95% CI: -3.8, 1.0days). Our results suggest that maternal diet might contribute to the exposure of the foetus to dioxins and dioxin-like compounds and may be related to reduced birth weight. More studies are needed to develop updated dietary guidelines for women of reproductive age, aiming to the reduction of dietary exposure to persistent organic pollutants as dioxins and dioxin-like compounds.
Published: 2014

42. Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression:the NewGeneris cohort

Author: Merlo, Domenico Franco, Agramunt, Silvia, Anna, Lívia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J, Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B, Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W, Granum, Berit, Hardie, Laura J, Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E, Kogevinas, Manolis, Kovács, Katalin, Kyrtopoulos, Soterios A, Løvik, Martinus, Nielsen, Jeanette K, Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J, Vande Loock, Kim, von Stedingk, Hans, Wright, Andrew John, Kleinjans, Jos C, Kirsch-Volders, Micheline, van Delft, Joost H M, Merlo, Domenico Franco, Agramunt, Silvia, Anna, Lívia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J, Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B, Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W, Granum, Berit, Hardie, Laura J, Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E, Kogevinas, Manolis, Kovács, Katalin, Kyrtopoulos, Soterios A, Løvik, Martinus, Nielsen, Jeanette K, Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J, Vande Loock, Kim, von Stedingk, Hans, Wright, Andrew John, Kleinjans, Jos C, Kirsch-Volders, Micheline, and van Delft, Joost H M
Abstract: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development.
Published: 2014

43. Maternal diet, prenatal exposure to dioxin-like compounds and birth outcomes in a European prospective mother–child study (NewGeneris)

Author: Papadopoulou, Eleni, Kogevinas, Manolis, Botsivali, Maria, Pedersen, Marie, Besselink, Harrie, Mendez, Michelle A, Fleming, Sarah, Hardie, Laura J, Knudsen, Lisbeth E, Wright, John, Agramunt, Silvia, Sunyer, Jordi, Granum, Berit, Gutzkow, Kristine B, Brunborg, Gunnar, Alexander, Jan, Meltzer, Helle Margrete, Brantsæter, Anne Lise, Sarri, Katerina, Chatzi, Leda, Merlo, Domenico F, Kleinjans, Jos C, Haugen, Margaretha, Papadopoulou, Eleni, Kogevinas, Manolis, Botsivali, Maria, Pedersen, Marie, Besselink, Harrie, Mendez, Michelle A, Fleming, Sarah, Hardie, Laura J, Knudsen, Lisbeth E, Wright, John, Agramunt, Silvia, Sunyer, Jordi, Granum, Berit, Gutzkow, Kristine B, Brunborg, Gunnar, Alexander, Jan, Meltzer, Helle Margrete, Brantsæter, Anne Lise, Sarri, Katerina, Chatzi, Leda, Merlo, Domenico F, Kleinjans, Jos C, and Haugen, Margaretha
Abstract: Maternal diet can result in exposure to environmental contaminants including dioxins which may influence foetal growth. We investigated the association between maternal diet and birth outcomes by defining a dioxin-rich diet. We used validated food frequency questionnaires to assess the diet of pregnant women from Greece, Spain, United Kingdom, Denmark and Norway and estimated plasma dioxin-like activity by the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX®) bioassay in 604 maternal blood samples collected at delivery. We applied reduced rank regression to identify a dioxin-rich dietary pattern based on dioxin-like activity (DR-CALUX®) levels in maternal plasma, and calculated a dioxin-diet score as an estimate of adherence to this dietary pattern. In the five country population, dioxin-diet score was characterised by high consumption of red and white meat, lean and fatty fish, low-fat dairy and low consumption of salty snacks and high-fat cheese, during pregnancy. The upper tertile of the dioxin-diet score was associated with a change in birth weight of -121g (95% confidence intervals: -232, -10g) compared to the lower tertile after adjustment for confounders. A small non-significant reduction in gestational age was also observed (-1.4days, 95% CI: -3.8, 1.0days). Our results suggest that maternal diet might contribute to the exposure of the foetus to dioxins and dioxin-like compounds and may be related to reduced birth weight. More studies are needed to develop updated dietary guidelines for women of reproductive age, aiming to the reduction of dietary exposure to persistent organic pollutants as dioxins and dioxin-like compounds.
Published: 2014

44. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux

Author: Ek, Weronica E, Levine, David M, D'Amato, Mauro, Pedersen, Nancy L, Magnusson, Patrik K E, Bresso, Francesca, Onstad, Lynn E, Schmidt, Peter T, Törnblom, Hans, Nordenstedt, Helena, Romero, Yvonne, Chow, Wong-Ho, Murray, Liam J, Gammon, Marilie D, Liu, Geoffrey, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Ye, Weimin, Wu, Anna H, Zucchelli, Marco, Spector, Tim D, Hysi, Pirro, Vaughan, Thomas L, Whiteman, David C, MacGregor, Stuart, Ek, Weronica E, Levine, David M, D'Amato, Mauro, Pedersen, Nancy L, Magnusson, Patrik K E, Bresso, Francesca, Onstad, Lynn E, Schmidt, Peter T, Törnblom, Hans, Nordenstedt, Helena, Romero, Yvonne, Chow, Wong-Ho, Murray, Liam J, Gammon, Marilie D, Liu, Geoffrey, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Ye, Weimin, Wu, Anna H, Zucchelli, Marco, Spector, Tim D, Hysi, Pirro, Vaughan, Thomas L, Whiteman, David C, and MacGregor, Stuart
Abstract: BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used. RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
Published: 2013
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45. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Author: Levine, David M, Ek, Weronica E, Zhang, Rui, Liu, Xinxue, Onstad, Lynn, Sather, Cassandra, Lao-Sirieix, Pierre, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Murray, Liam J, Reid, Brian J, Chow, Wong-Ho, Risch, Harvey A, Nyrén, Olof, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Chanock, Stephen J, Harrington, Patricia, Caldas, Isabel, Debiram-Beecham, Irene, Caldas, Carlos, Hayward, Nicholas K, Pharoah, Paul D, Fitzgerald, Rebecca C, Macgregor, Stuart, Whiteman, David C, Vaughan, Thomas L, Levine, David M, Ek, Weronica E, Zhang, Rui, Liu, Xinxue, Onstad, Lynn, Sather, Cassandra, Lao-Sirieix, Pierre, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Murray, Liam J, Reid, Brian J, Chow, Wong-Ho, Risch, Harvey A, Nyrén, Olof, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Chanock, Stephen J, Harrington, Patricia, Caldas, Isabel, Debiram-Beecham, Irene, Caldas, Carlos, Hayward, Nicholas K, Pharoah, Paul D, Fitzgerald, Rebecca C, Macgregor, Stuart, Whiteman, David C, and Vaughan, Thomas L
Abstract: Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
Published: 2013
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46. Bulky DNA Adducts in Cord Blood, Maternal Fruit-and-Vegetable Consumption, and Birth Weight in a European Mother-Child Study (NewGeneris)

Author: Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W., Wright, John, von Stedingk, Hans, Törnqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K., Merlo, Domenico F., Mendez, Michelle A., Meltzer, Helle M., Lukacs, Viktoria, Landström, Anette, Kyrtopoulos, Soterios A., Kovacs, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J., Gutzkow, Kristine B., Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B., Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J., Botsivali, Maria, Arab, Khelifa, Anna, Livia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C., Segerbäck, Dan, Kogevinas, Manolis, Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W., Wright, John, von Stedingk, Hans, Törnqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K., Merlo, Domenico F., Mendez, Michelle A., Meltzer, Helle M., Lukacs, Viktoria, Landström, Anette, Kyrtopoulos, Soterios A., Kovacs, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J., Gutzkow, Kristine B., Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B., Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J., Botsivali, Maria, Arab, Khelifa, Anna, Livia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C., Segerbäck, Dan, and Kogevinas, Manolis
Abstract: Background: Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic-hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from -biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs. Objectives: We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy. Methods: Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006-2010. Adduct levels were measured by the 32P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires. Results: Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in 108 nucleotides; Spearman rank correlation coefficient = 0.66, p < 0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of -129 g (95% CI: -233, -25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (-248 g; 95% CI: -405, -92 g) compared with those with high intake (-58 g; 95% CI: -206, 90 g). Conclusions: Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective., AuthorCount:34
Published: 2013
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47. Bulky DNA Adducts in Cord Blood, Maternal Fruit-and-Vegetable Consumption, and Birth Weight in a European Mother-Child Study (NewGeneris)

Author: Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W, Wright, John, von Stedingk, Hans, Törnqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K, Merlo, Domenico F, Mendez, Michelle A, Meltzer, Helle M, Lukács, Viktória, Landström, Anette, Kyrtopoulos, Soterios A, Kovács, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J, Gützkow, Kristine B, Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B, Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J, Botsivali, Maria, Arab, Khelifa, Anna, Lívia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C, Segerbäck, Dan, Kogevinas, Manolis, Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W, Wright, John, von Stedingk, Hans, Törnqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K, Merlo, Domenico F, Mendez, Michelle A, Meltzer, Helle M, Lukács, Viktória, Landström, Anette, Kyrtopoulos, Soterios A, Kovács, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J, Gützkow, Kristine B, Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B, Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J, Botsivali, Maria, Arab, Khelifa, Anna, Lívia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C, Segerbäck, Dan, and Kogevinas, Manolis
Abstract: Background: Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs.Objectives: We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy.Methods: Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006-2010. Adduct levels were measured by the 32P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires.Results: Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in 108 nucleotides; Spearman rank correlation coefficient = 0.66, p <0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of -129 g (95% CI: -233, -25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (-248 g; 95% CI: -405, -92 g) compared with those with high intake (-58 g; 95% CI: -206, 90 g)Conclusions: Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective.Citation: Pedersen M, Schoket B, Godschalk RW, Wright J, von Stedingk H, Törnqvist M, Sunyer J, Nielsen JK, Merlo DF, Mendez MA, Meltzer HM, Lukács V, Landström A, Kyrtopoulos SA, Kovács K, Knudsen LE, Haugen M, Hardie LJ, Gützkow KB
Published: 2013

48. Bulky DNA Adducts in Cord Blood, Maternal Fruit-and-Vegetable Consumption, and Birth Weight in a European Mother-Child Study (NewGeneris)

Author: Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W, Wright, John, von Stedingk, Hans, Törnqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K, Merlo, Domenico F, Mendez, Michelle A, Meltzer, Helle M, Lukács, Viktória, Landström, Anette, Kyrtopoulos, Soterios A, Kovács, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J, Gützkow, Kristine B, Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B, Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J, Botsivali, Maria, Arab, Khelifa, Anna, Lívia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C, Segerbäck, Dan, Kogevinas, Manolis, Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W, Wright, John, von Stedingk, Hans, Törnqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K, Merlo, Domenico F, Mendez, Michelle A, Meltzer, Helle M, Lukács, Viktória, Landström, Anette, Kyrtopoulos, Soterios A, Kovács, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J, Gützkow, Kristine B, Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B, Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J, Botsivali, Maria, Arab, Khelifa, Anna, Lívia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C, Segerbäck, Dan, and Kogevinas, Manolis
Abstract: Background: Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs.Objectives: We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy.Methods: Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006-2010. Adduct levels were measured by the 32P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires.Results: Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in 108 nucleotides; Spearman rank correlation coefficient = 0.66, p <0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of -129 g (95% CI: -233, -25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (-248 g; 95% CI: -405, -92 g) compared with those with high intake (-58 g; 95% CI: -206, 90 g)Conclusions: Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective.Citation: Pedersen M, Schoket B, Godschalk RW, Wright J, von Stedingk H, Törnqvist M, Sunyer J, Nielsen JK, Merlo DF, Mendez MA, Meltzer HM, Lukács V, Landström A, Kyrtopoulos SA, Kovács K, Knudsen LE, Haugen M, Hardie LJ, Gützkow KB
Published: 2013

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

Author: Su, Zhan, Gay, Laura J, Strange, Amy, Palles, Claire, Band, Gavin, Whiteman, David C, Lescai, Francesco, Langford, Cordelia, Nanji, Manoj, Edkins, Sarah, van der Winkel, Anouk, Levine, David, Sasieni, Peter, Bellenguez, Céline, Howarth, Kimberley, Freeman, Colin, Trudgill, Nigel, Tucker, Art T, Pirinen, Matti, Peppelenbosch, Maikel P, van der Laan, Luc J W, Kuipers, Ernst J, Drenth, Joost P H, Peters, Wilbert H, Reynolds, John V, Kelleher, Dermot P, McManus, Ross, Grabsch, Heike, Prenen, Hans, Bisschops, Raf, Krishnadath, Kausila, Siersema, Peter D, van Baal, Jantine W P M, Middleton, Mark, Petty, Russell, Gillies, Richard, Burch, Nicola, Bhandari, Pradeep, Paterson, Stuart, Edwards, Cathryn, Penman, Ian, Vaidya, Kishor, Ang, Yeng, Murray, Iain, Patel, Praful, Ye, Weimin, Mullins, Paul, Wu, Anna H, Bird, Nigel C, Dallal, Helen, Shaheen, Nicholas J, Murray, Liam J, Koss, Konrad, Bernstein, Leslie, Romero, Yvonne, Hardie, Laura J, Zhang, Rui, Winter, Helen, Corley, Douglas A, Panter, Simon, Risch, Harvey A, Reid, Brian J, Sargeant, Ian, Gammon, Marilie D, Smart, Howard, Dhar, Anjan, McMurtry, Hugh, Ali, Haythem, Liu, Geoffrey, Casson, Alan G, Chow, Wong-Ho, Rutter, Matt, Tawil, Ashref, Morris, Danielle, Nwokolo, Chuka, Isaacs, Peter, Rodgers, Colin, Ragunath, Krish, MacDonald, Chris, Haigh, Chris, Monk, David, Davies, Gareth, Wajed, Saj, Johnston, David, Gibbons, Michael, Cullen, Sue, Church, Nicholas, Langley, Ruth, Griffin, Michael, Alderson, Derek, Deloukas, Panos, Hunt, Sarah E, Gray, Emma, Dronov, Serge, Potter, Simon C, Tashakkori-Ghanbaria, Avazeh, Anderson, Mark, Brooks, Claire, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas, Trynka, Gosia, Wijmenga, Cisca, Cazier, Jean-Baptiste, Atherfold, Paul, Nicholson, Anna M, Gellatly, Nichola L, Glancy, Deborah, Cooper, Sheldon C, Cunningham, David, Lind, Tore, Hapeshi, Julie, Ferry, David, Rathbone, Barrie, Brown, Julia, Love, Sharon, Attwood, Stephen, MacGregor, Stuart, Watson, Peter, Sanders, Scott, Ek, Weronica, Harrison, Rebecca F, Moayyedi, Paul, de Caestecker, John, Barr, Hugh, Stupka, Elia, Vaughan, Thomas L, Peltonen, Leena, Spencer, Chris C A, Tomlinson, Ian, Donnelly, Peter, Jankowski, Janusz A Z, Su, Zhan, Gay, Laura J, Strange, Amy, Palles, Claire, Band, Gavin, Whiteman, David C, Lescai, Francesco, Langford, Cordelia, Nanji, Manoj, Edkins, Sarah, van der Winkel, Anouk, Levine, David, Sasieni, Peter, Bellenguez, Céline, Howarth, Kimberley, Freeman, Colin, Trudgill, Nigel, Tucker, Art T, Pirinen, Matti, Peppelenbosch, Maikel P, van der Laan, Luc J W, Kuipers, Ernst J, Drenth, Joost P H, Peters, Wilbert H, Reynolds, John V, Kelleher, Dermot P, McManus, Ross, Grabsch, Heike, Prenen, Hans, Bisschops, Raf, Krishnadath, Kausila, Siersema, Peter D, van Baal, Jantine W P M, Middleton, Mark, Petty, Russell, Gillies, Richard, Burch, Nicola, Bhandari, Pradeep, Paterson, Stuart, Edwards, Cathryn, Penman, Ian, Vaidya, Kishor, Ang, Yeng, Murray, Iain, Patel, Praful, Ye, Weimin, Mullins, Paul, Wu, Anna H, Bird, Nigel C, Dallal, Helen, Shaheen, Nicholas J, Murray, Liam J, Koss, Konrad, Bernstein, Leslie, Romero, Yvonne, Hardie, Laura J, Zhang, Rui, Winter, Helen, Corley, Douglas A, Panter, Simon, Risch, Harvey A, Reid, Brian J, Sargeant, Ian, Gammon, Marilie D, Smart, Howard, Dhar, Anjan, McMurtry, Hugh, Ali, Haythem, Liu, Geoffrey, Casson, Alan G, Chow, Wong-Ho, Rutter, Matt, Tawil, Ashref, Morris, Danielle, Nwokolo, Chuka, Isaacs, Peter, Rodgers, Colin, Ragunath, Krish, MacDonald, Chris, Haigh, Chris, Monk, David, Davies, Gareth, Wajed, Saj, Johnston, David, Gibbons, Michael, Cullen, Sue, Church, Nicholas, Langley, Ruth, Griffin, Michael, Alderson, Derek, Deloukas, Panos, Hunt, Sarah E, Gray, Emma, Dronov, Serge, Potter, Simon C, Tashakkori-Ghanbaria, Avazeh, Anderson, Mark, Brooks, Claire, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas, Trynka, Gosia, Wijmenga, Cisca, Cazier, Jean-Baptiste, Atherfold, Paul, Nicholson, Anna M, Gellatly, Nichola L, Glancy, Deborah, Cooper, Sheldon C, Cunningham, David, Lind, Tore, Hapeshi, Julie, Ferry, David, Rathbone, Barrie, Brown, Julia, Love, Sharon, Attwood, Stephen, MacGregor, Stuart, Watson, Peter, Sanders, Scott, Ek, Weronica, Harrison, Rebecca F, Moayyedi, Paul, de Caestecker, John, Barr, Hugh, Stupka, Elia, Vaughan, Thomas L, Peltonen, Leena, Spencer, Chris C A, Tomlinson, Ian, Donnelly, Peter, and Jankowski, Janusz A Z
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
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50. Birth Weight, Head Circumference, and Prenatal Exposure to Acrylamide from Maternal Diet : The European Prospective Mother-Child Study (NewGeneris)

Author: Pedersen, Marie, von Stedingk, Hans, Botsivali, Maria, Agramunt, Silvia, Alexander, Jan, Brunborg, Gunnar, Chatzi, Leda, Fleming, Sarah, Fthenou, Eleni, Granum, Berit, Gutzkow, Kristine B., Hardie, Laura J., Knudsen, Lisbeth E., Kyrtopoulos, Soterios A., Mendez, Michelle A., Merlo, Domenico F., Nielsen, Jeanette K., Rydberg, Per, Segerback, Dan, Sunyer, Jordi, Wright, John, Törnqvist, Margareta, Kleinjans, Jos C., Kogevinas, Manolis, Pedersen, Marie, von Stedingk, Hans, Botsivali, Maria, Agramunt, Silvia, Alexander, Jan, Brunborg, Gunnar, Chatzi, Leda, Fleming, Sarah, Fthenou, Eleni, Granum, Berit, Gutzkow, Kristine B., Hardie, Laura J., Knudsen, Lisbeth E., Kyrtopoulos, Soterios A., Mendez, Michelle A., Merlo, Domenico F., Nielsen, Jeanette K., Rydberg, Per, Segerback, Dan, Sunyer, Jordi, Wright, John, Törnqvist, Margareta, Kleinjans, Jos C., and Kogevinas, Manolis
Abstract: BACKGROUND: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. OBJECTIVES: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother child study. METHODS: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006-2010. Maternal diet was estimated through food-frequency questionnaires. RESULTS: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g (95% CI: -207, -56); the corresponding difference for head circumference was -0.33 cm (95% CI: -0.61, -0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for Factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. CONCLUSIONS: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. IF confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women., AuthorCount:24
Published: 2012
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