Claire Palles and Ian Tomlinson, from Wellcome Trust and Oxford, have been approved to use BEACON GWAS data as part of a larger consortium to investigate and fine map the previously reported signal at the MHC region to determine whether classical HLA alleles or amino acid positions can explain the association. BEACON members can access the proposal on the member page.
Published: Polymorphisms in genes in the androgen pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma.
Ek WE1,2, Lagergren K3, Cook M4, Wu AH5, Abnet CC6, Levine D7, Chow WH8, Bernstein L9, Risch HA10, Shaheen NJ11, Bird NC12, Corley DA13, Hardie LJ14, Fitzgerald RC15, Gammon MD16, Romero Y17, Liu G18, Ye W19, Vaughan TL20, MacGregor S2, Whiteman DC21, Westberg L22, Lagergren J3,23.
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.
Funding opportunities have been announced for the NIH’s new Precision Medicine Cohort.
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.
Lagergren K1, Ek WE2, Levine D3, Chow WH4, Bernstein L5, Casson AG6, Risch HA7, Shaheen NJ8, Bird NC9, Reid BJ10, Corley DA11, Hardie LJ12, Wu AH13, Fitzgerald RC14, Pharoah P15, Caldas C16, Romero Y17, Vaughan TL18, MacGregor S19, Whiteman D20, Westberg L21, Nyren O22, Lagergren J23.
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.
Cancer Epidemiology Biomarkers and Prevention. 2015 Sep 12. pii: cebp.0596.2015. [Epub ahead of print]
Lee E, Stram D, Ek WE, Onstad LE, Macgregor S, Gharahkhani P, Ye W, Lagergren J, Shaheen NJ, Murray LJ, Hardie LJ, Gammon MD, Chow WH, Risch HA, Corley DA, Levine DM, Whiteman DC, Bernstein L, Vaughan TL, Wu A.
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 (BE).
METHODS: We examined the associations between risks of EA and BE and 387 single nucleotide polymorphisms (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 BE) 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 BE. 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 BE.
IMPACT: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and BE.
Copyright © 2015, American Association for Cancer Research.
Cancer Epidemiology Biomarkers and Prevention. 2015 2015 Sep 16. pii: cebp.0507.2015. [Epub ahead of print]
A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett’s esophagus.
Dai JY, Tapsoba JD, Buas MF, Onstad LE, Levine DM, Risch HA, Chow JW, Bernstein L, Ye W, Lagergren J, Bird NC, Corley DA, Shaheen NJ, Wu AH, Reid BJ, Hardie LJ, Whiteman DC, Vaughan TL.
BACKGROUND: Important risk factors for esophageal adenocarcinoma (EA) and its precursor, Barrett’s esophagus (BE) include gastroesophageal reflux disease, obesity, and cigarette-smoking. Recently, genome-wide association studies have identified seven germline single nucleotide polymorphisms (SNPs) that are associated with risk of BE and EA. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear.
METHODS: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1516 EA case patients, 2416 BE case patients, and 2187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate odds ratios for these risk factors stratified by SNP genotype, separately for BE and EA.
RESULTS: The odds ratio for BE associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal p-value=0.0005, false discovery rate=0.042). Odds ratios (95% confidence intervals) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91,7.56), 3.56 (2.85,4.44), and 3.97 (2.47,6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index.
CONCLUSIONS: Reflux symptoms are more strongly associated with BE risk among persons homozygous for the major allele of rs2687201, which lies ~75 kb downstream of the transcription factor gene FOXP1.
IMPACT: The novel gene-exposure interaction discovered in this study provides new insights to the etiology of esophageal adenocarcinoma.
Copyright © 2015, American Association for Cancer Research.