Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer

Abstract

Three recent genome-wide association studies identified associations between markers in the chromosomal region 15q24-25.1 and the risk of lung cancer. We conducted a genome-wide association analysis to investigate associations between single-nucleotide polymorphisms (SNPs) and the risk of lung cancer, in which we used blood DNA from 194 case patients with familial lung cancer and 219 cancer-free control subjects. We identified associations between common sequence variants at 15q24-25.1 (that spanned LOC123688 [a hypothetical gene], PSMA4, CHRNA3, CHRNA5, and CHRNB4) and lung cancer. The risk of lung cancer was more than fivefold higher among those subjects who had both a family history of lung cancer and two copies of high-risk alleles rs8034191 (odds ratio [OR] = 7.20, 95% confidence interval [CI] = 2.21 to 23.37) or rs1051730 (OR = 5.67, CI = 2.21 to 14.60, both of which were located in the 15q24-25.1 locus, than among control subjects. Thus, further research to elucidate causal variants in the 15q24-25.1 locus that are associated with lung cancer is warranted.

Figure 1

Association between chromosome 15q24-25.1 and lung cancer. Associations are expressed as –log(P); P values were from Fisher exact tests. All statistical tests were two-sided. A) Association analysis of 194 familial case patients and 219 control subjects in chromosome 15. B) Enhanced view of association analysis in the 75- to 79-Mb region of chromosome 15. Several common variants, including rs8034191 and rs1051730, cluster on 15q24-25.1 and show strong associations with familial lung cancer. C) Physical map and haplotype blocks (ie, regions with no evidence of historical recombination). Pairwise linkage disequilibrium, measured as D′ (a measurement of the nonrandom association of alleles at two loci), was calculated with HapMap data from Utah residents with ancestry from northern and western Europe by the methods of Gabriel (21) as implemented with Haploview software (22). Shading represents the magnitude and statistical significance of the pairwise linkage disequilibrium, with a white-to-red gradient reflecting lower to higher linkage disequilibrium values. The single-nucleotide polymorphisms rs8034191 and rs1051730 were contained in the 84-kb block 4.