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

Helen M. Hansen, Yuanyuan Xiao, Terri Rice, Paige M. Bracci, Margaret R. Wrensch, Jennette D. Sison, Jeffery S. Chang, Ivan V. Smirnov, Joseph Patoka, Michael F Seldin, Charles P. Quesenberry, Karl T. Kelsey, John K. Wiencke

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish (US)
Article numberddq268
Pages (from-to)3652-3661
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number18
DOIs
StatePublished - Jun 29 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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