The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia

Abstract

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11)). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11)). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20), allelic risk = 1.54, 95% Confidence Interval (CI) 1.41-1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87), and 2.35 (95% CI: 1.95-2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

Figure 1. Genome-wide association results in the GELAC study.

(A) Quantile-quantile plot for lower 90% of −log P-values, (B) upper 10% of −log P-values, and (C) scatter plot of P-values in−log scale from the trend test for 457,504 genotyped variants comparing 584 cases and 585 controls.

Figure 2. Risk of lung adenocarcinoma associated with rs2736100 for never-smoking female cases and never-smoking female controls from East Asia.

Forest plot representing lung adenocarcinoma risk and the rs2736100 genotype. Odds ratios (OR) and 95% confidence intervals (CI) for lung adenocarcinoma are derived from the per-allele model. All models are adjusted for age and study center. GELAC: Genetic Epidemiological Study of Lung Adenocarcinoma (in Taiwan); CAMSCH: Chinese Academy of Medical Sciences Cancer Hospital Study; SNU: Seoul National University study; SWHS: Shanghai Women's Health Cohort Study; WHLCS: Wuhan Lung Cancer Study; KNUH: Kyungpook National University Study; KUMC: Korea University Study.

Figure 3. LD structure and association results for the chr5p15 region and lung adenocarcinoma.

LD structure and regional association results for 15 SNPs genotyped in the 5p15 region. SNPs included were tagged with r ₂≥0.8 in HapMap CHB .