title: Targeted sequencing of chromosome 15q25 identified novel variants associated with risk of lung cancer and smoking behavior in Chinese.
abstract: Previous genome-wide association studies (GWAS) in populations of European descent identified a lung cancer susceptibility locus at 15q25 that was biologically associated with nicotine addiction. However, the allele frequency of susceptibility variants identified in this region varied dramatically across European and Asian populations, suggesting that additional risk single nucleotide polymorphism (SNPs) in Asians need to be identified. Thus, we conducted a fine-mapping study of chromosome 15q25 using targeted resequencing of 200 lung cancer cases and 300 controls of Chinese descent. An approximate conditional and joint analysis of the discovery data revealed two novel SNPs with independent effects (rs6495304: OR = 1.79, P = 9.37 × 10-4; and rs74733525: OR = 1.68, P = 8.05 × 10-3). Both variants were common in Asians but rare or monomorphic in Whites. These results were further supported by in silico validation including 8047 cases and 8898 controls from multiethnic lung cancer genome-wide association studies (GWASs) (rs6495304: OR = 1.32, P = 1.21 × 10-11; and rs74733525: OR = 1.29, P = 4.29 × 10-4); however, rs6495304 demonstrated significant effects only in ever-smokers (P = 0.004 for heterogeneity test of smoking). Mediation analysis indicated that smoking behavior may mediate the effect of rs6495304 on lung cancer risk. Furthermore, expression quantitative trait loci analysis showed the risk allele (A) of rs6495304 was significantly associated with lower mRNA expression of CHRNA3 (P = 0.029) in 81 hypothalamic tissue samples. This finding provides new insights into the association between lung cancer susceptibility and the 15q25 locus.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.|Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China and.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Liguo
authors.initials: L
authors.lastname: Geng
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.|Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China and.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.|Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China and.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.|Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China and.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.|Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China and.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002681:China; D002884:Chromosomes, Human, Pair 15; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000209:etiology* / Q000473:pathology; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics*