Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations.
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.
Wu
Chen
C
Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Hu
Zhibin
Z
Yu
Dianke
D
Huang
Liming
L
Jin
Guangfu
G
Liang
Jie
J
Guo
Huan
H
Tan
Wen
W
Zhang
Mingfeng
M
Qian
Ji
J
Lu
Daru
D
Wu
Tangchun
T
Lin
Dongxin
D
Shen
Hongbing
H
D016022:Case-Control Studies; D002681:China; D047369:Chromatin Immunoprecipitation; D002884:Chromosomes, Human, Pair 15; D024202:Electrophoretic Mobility Shift Assay; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics
D011978:Receptors, Nicotinic