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Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

ABSTRACT: OBJECTIVES:Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. MATERIALS AND METHODS:We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2. RESULTS AND CONCLUSION:In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.

SUBMITTER: Zanetti KA

PROVIDER: S-EPMC4939239 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

Zanetti Krista A KA Wang Zhaoming Z Aldrich Melinda M Amos Christopher I CI Blot William J WJ Bowman Elise D ED Burdette Laurie L Cai Qiuyin Q Caporaso Neil N Chung Charles C CC Gillanders Elizabeth M EM Haiman Christopher A CA Hansen Helen M HM Henderson Brian E BE Kolonel Laurence N LN Marchand Loic Le LL Li Shengchao S McNeill Lorna Haughton LH Ryan Bríd M BM Schwartz Ann G AG Sison Jennette D JD Spitz Margaret R MR Tucker Margaret M Wenzlaff Angela S AS Wiencke John K JK Wilkens Lynne L Wrensch Margaret R MR Wu Xifeng X Zheng Wei W Zhou Weiyin W Christiani David D Palmer Julie R JR Penning Trevor M TM Rieber Alyssa G AG Rosenberg Lynn L Ruiz-Narvaez Edward A EA Su Li L Vachani Anil A Wei Yongyue Y Whitehead Alexander S AS Chanock Stephen J SJ Harris Curtis C CC

Lung cancer (Amsterdam, Netherlands) 20160513

<h4>Objectives</h4>Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new reg ...[more]

PMID: 27393504

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Project description:BackgroundGenome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.MethodsGenotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided.ResultsAssociations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer.ConclusionsIn this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

Project description:Background & aimsThe inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities.MethodsWe performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance.ResultsWe detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles.ConclusionsWe performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Dataset Information

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

Publications

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

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