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

Abstract

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 from IREB2 to CHRNB4 were most strongly associated with lung cancer risk (OR = 1.3; P < 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. CHRNA5 rs17486278 G had OR = 1.28, 95% CI 1.07-1.54 and P = 0.008, whereas CHRNB4 rs7178270 G had OR = 0.78, 95% CI 0.66-0.94 and P = 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 interaction P = 0.009. For two SNPs (rs7168796 A/G and rs7164594 A/G) upstream of PSMA4, 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 spanning CHRNA5 (rs11637635 C, rs17408276 T, rs16969968 G) and CHRNA3 (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.

Figure 1.

D′ linkage map of 77 chr15q25.1 SNPs in African-Americans from the Northern California Lung Cancer Study. (A) Individuals with an African ancestral percentage of ≥90%. (B) Individuals with an African ancestral percentage of ≤60%.

Figure 2.

Map of the associated 15q24–25.1 region in lung cancer. (A) −Log₁₀(P) of significant sliding window haplotypes in the region. Global haplotypes are represented by blue lines, whereas individual haplotypes are represented by red lines. (B) Map of the 15q24–25.1 locus with rs17486278 and rs7178270; UCSC gene and SNP locations based on RefSeq, UniProt, GenBank, CCDS and comparative genomics. (C) Location of sliding window haplotypes in the region previously associated with familial lung cancer in Caucasians (10).