Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans
Open Access
- 29 June 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (18), 3652-3661
- https://doi.org/10.1093/hmg/ddq268
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.Keywords
This publication has 30 references indexed in Scilit:
- Patrocles: a database of polymorphic miRNA-mediated gene regulation in vertebratesNucleic Acids Research, 2009
- Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individualsInternational Journal of Epidemiology, 2009
- Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5Human Molecular Genetics, 2009
- SNPLogic: an interactive single nucleotide polymorphism selection, annotation, and prioritization systemNucleic Acids Research, 2008
- Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1Nature Genetics, 2008
- PolymiRTS Database: linking polymorphisms in microRNA target sites with complex traitsNucleic Acids Research, 2006
- A Genomewide Single-Nucleotide–Polymorphism Panel with High Ancestry Information for African American Admixture MappingAmerican Journal of Human Genetics, 2006
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- The International HapMap ProjectNature, 2003
- Statistical significance for genomewide studiesProceedings of the National Academy of Sciences of the United States of America, 2003