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Several genome-wide association studies identified the chr15q25.1 region, which includes three nicotinic cholinergic receptor genes (CHRNA5-B4) and the cell proliferation gene (PSMA4), for its association with lung cancer risk in Caucasians. A haplotype and its tagging single nucleotide polymorphisms (SNPs) encompassing six genes fromIREB2 to CHRNB4were most strongly associated with lung cancer risk (OR = 1.3;P&lt; 10−20). In order to narrow the region of association and identify potential causal variations, we performed a fine-mapping study using 77 SNPs in a 194 kb segment of the 15q25.1 region in a sample of 448 African-American lung cancer cases and 611 controls. Four regions, two SNPs and two distinct haplotypes from sliding window analyses, were associated with lung cancer.CHRNA5rs17486278 G had OR = 1.28, 95% CI 1.07–1.54 andP= 0.008, whereasCHRNB4rs7178270 G had OR = 0.78, 95% CI 0.66–0.94 andP= 0.008 for lung cancer risk. Lung cancer associations remained significant after pack-year adjustment. Rs7178270 decreased lung cancer risk in women but not in men; gender interactionP= 0.009. For two SNPs (rs7168796 A/G and rs7164594 A/G) upstream ofPSMA4, lung cancer risks for people with haplotypes GG and AA were reduced compared with those with AG (OR = 0.56, 95% CI 0.38–0.82;P= 0.003 and OR = 0.73, 95% CI 0.59–0.90,P= 0.004, respectively). A four-SNP haplotype spanningCHRNA5(rs11637635 C, rs17408276 T, rs16969968 G) andCHRNA3(rs578776 G) was associated with increased lung cancer risk (P= 0.002). The identified regions contain SNPs predicted to affect gene regulation. There are multiple lung cancer risk loci in the 15q25.1 region in African-Americans.

Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans