Abstract
Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other variants on 15q25 associated with lung cancer susceptibility in Chinese. Two-stage case-control studies were conducted in subjects derived from both Northern and Southern China. The first-stage, consisting of 576 cases and 576 controls, was to discover novel risk variants using a haplotype-tagging SNP approach, and these variants were then replicated in the second-stage, consisting of 2,989 cases and 2,880 controls. Associations were estimated by logistic regression models, and function of the variants was examined by biochemical assays. We found that the three risk SNPs reported in Caucasians were not associated with lung cancer risk in Chinese. However, we identified four novel SNPs (rs2036534C>T, rs667282C>T, rs12910984G>A, and rs6495309T>C) that were associated with significantly increased lung cancer risk and smoking behavior, which were all confirmed in the replication analyses [odds ratios (95% confidence intervals) in the dominant model: 1.39 (1.23-1.57; P = 2.3 x 10(-7)), 1.52 (1.35-1.71; P = 2.0 x 10(-12)), 1.44 (1.28-1.63; P = 2.7 x 10(-9)), and 1.43 (1.27-1.61; P = 2.6 x 10(-9)), respectively]. We characterized the rs6495309T>C change in the CHRNA3 promoter as a functional variant because it affected the Oct-1 binding ability, resulting in increased CHRNA3 expression. These results support 15q25 as a susceptibility region for lung cancer in Chinese but underscore the difference in genetic markers among different ethnic populations.
Highlights
Lung cancer is the leading cause of cancer-related deaths all over the world
By examining the HapMap data, we found that the risk single nucleotide polymorphisms (SNPs), rs8034191, rs1051730, and rs16969968 identified in previous genome-wide association studies (GWAS) are extremely rare in Asians, suggesting that the role these SNPs play in risk of lung cancer in Asian populations, if any, may not be as important as they do in Caucasians
We discovered four novel SNPs associated with lung cancer risk in Chinese populations, which are different from those reported in the GWAS in Caucasian populations
Summary
Lung cancer is the leading cause of cancer-related deaths all over the world. In many countries, including China, the morbidity and mortality of lung cancer have been increasing rapidly in recent years, which is believed to be mainly due to continuous increase in tobacco consumption [1, 2]. Nicotinic acetylcholine receptors expressed in the key regions of the brain play an important role in controlling smoking behavior [10, 11]. These receptors are expressed in epithelial cells of the lung, where they execute signal transduction upon binding to nicotine and/ or its carcinogenic derivatives [e.g., 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone, NNK], resulting in cell proliferation and neoplastic transformation [12,13,14,15]. It seems plausible that genetic variations, such as single nucleotide polymorphisms (SNP) in nicotinic acetylcholine receptors that affect the gene expression or protein function, would be associated with smoking behavior and the risk of smoking-related lung cancer
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