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A genome-wide gene-gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese.

ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chinese cohorts. We conducted a pairwise genetic interaction analysis of 591370 variants, using BOolean Operation-based Screening and Testing (BOOST), in an ongoing GWAS of lung cancer that includes 2331 cases and 3077 controls. Pairs of epistatic loci with P BOOST ? 1.00×10(-6) were further evaluated by a logistic regression model (LRM) with covariate adjustment. Four promising epistatic pairs identified at the screening stage (P LRM ? 2.86×10(-) (13)) were validated in two replication cohorts: the first from Beijing (1534 cases and 1489 controls) and the second from Shenyang and Guangzhou (2512 cases and 2449 controls). Using this combined analysis, we identified an interaction between rs2562796 and rs16832404 at 2p32.2 that was significantly associated with the risk of developing lung cancer (P LRM = 1.03×10(-13) in total 13 392 subjects). This study is the first investigation of epistasis for lung cancer on a genome-wide scale in Han Chinese. It addresses part of the missing heritability in lung cancer risk and provides novel insight into the multifactorial etiology of lung cancer.

SUBMITTER: Chu M

PROVIDER: S-EPMC3941747 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A genome-wide gene-gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese.

Chu Minjie M Zhang Ruyang R Zhao Yang Y Wu Chen C Guo Huan H Zhou Baosen B Lu Jiachun J Shi Yongyong Y Dai Juncheng J Jin Guangfu G Ma Hongxia H Dong Jing J Wei Yongyue Y Wang Cheng C Gong Jianhang J Sun Chongqi C Zhu Meng M Qiu Yongyong Y Wu Tangchun T Hu Zhibin Z Lin Dongxin D Shen Hongbing H Chen Feng F

Carcinogenesis 20131209 3

Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chine ...[more]

PMID: 24325914

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Project description:Occupational asbestos exposure has been found to increase lung cancer risk in epidemiologic studies.We conducted an asbestos exposure-gene interaction analyses among several Caucasian populations who were current or ex-smokers. The discovery phase included 833 Caucasian cases and 739 Caucasian controls, and used a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNP) with gene-asbestos interaction effects. The top ranked SNPs from the discovery phase were replicated within the International Lung and Cancer Consortium (ILCCO). First, in silico replication was conducted in those groups that had GWAS and asbestos exposure data, including 1,548 cases and 1,527 controls. This step was followed by de novo genotyping to replicate the results from the in silico replication, and included 1,539 cases and 1,761 controls. Multiple logistic regression was used to assess the SNP-asbestos exposure interaction effects on lung cancer risk.We observed significantly increased lung cancer risk among MIRLET7BHG (MIRLET7B host gene located at 22q13.31) polymorphisms rs13053856, rs11090910, rs11703832, and rs12170325 heterozygous and homozygous variant allele(s) carriers (P < 5 × 10(-7) by likelihood ratio test; df = 1). Among the heterozygous and homozygous variant allele(s) carriers of polymorphisms rs13053856, rs11090910, rs11703832, and rs12170325, each unit increase in the natural log-transformed asbestos exposure score was associated with age-, sex-, smoking status, and center-adjusted ORs of 1.34 [95% confidence interval (CI), 1.18-1.51], 1.24 (95% CI, 1.14-1.35), 1.28 (95% CI, 1.17-1.40), and 1.26 (95% CI, 1.15-1.38), respectively, for lung cancer risk.Our findings suggest that MIRLET7BHG polymorphisms may be important predictive markers for asbestos exposure-related lung cancer.To our knowledge, our study is the first report using a systematic genome-wide analysis in combination with detailed asbestos exposure data and replication to evaluate asbestos-associated lung cancer risk.

Dataset Information

A genome-wide gene-gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese.

Publications

A genome-wide gene-gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese.

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