Novel genetic variants in the chromosome 5p15.33 region associate with lung cancer risk

Abstract

Chromosome 5p15.33 has been identified by genome-wide association studies as one of the regions that associate with lung cancer risk. A few single-nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes located in this region have shown consistent associations. We performed dense genotyping of SNPs in this region to refine the previously reported association signals for lung cancer risk. Two hundred and fifteen SNPs were genotyped on an Illumina iSelect panel, in a hospital-based case-control study of 1681 lung cancer cases and 1235 unaffected controls. Association was tested using unconditional logistic regression, while adjusting for age, sex and pack-years smoked. Furthermore, since many of the SNPs were in linkage disequilibrium (LD), haplotype blocks were constructed, from which tagging SNPs at an r(2) threshold of ≥0.95 were included in a stepwise forward selection logistic regression model. Of the 215 SNPs, 69 were significant at P < 0.05 in univariate analysis; of these, 35 SNPs meeting the r(2) threshold were included in the multiple logistic regression model. Two SNPs, rs370348 (odds ratio = 0.76, P = 1.6 × 10(-6)) and rs4975538 (odds ratio = 1.18, P = 0.005), significantly associated with risk in the overall sample. Among ever smokers, rs4975615 (odds ratio = 0.75, P = 1.2 × 10(-4)) and rs4975538 (odds ratio = 1.26, P = 0.002) were significant, whereas among never-smokers, rs451360 (odds ratio = 0.62, P = 7.6 × 10(-5)) was significant. We refined the consistent association signal in this region, allowing for the considerable LD between SNPs and identified four novel SNPs that were independently and significantly associated with lung cancer risk. Results of these analyses strongly suggest effects on risk from several loci in the TERT/CLPTM1L region.

Fig. 1.

Strategy for analysis of the densely genotyped SNPs in the 5p15.33 region.

Fig. 2.

Association of 35 selected SNPs on chromosome 5p15.33 with lung cancer. (A) Association of SNPs with lung cancer, adjusted for sex, age and number of pack-years smoked. Empty squares indicate SNPs significantly associated with lung cancer risk in previously published GWAS (rs2736100: the most consistently replicated SNP). Chromosomal position is on the x-axis and negative logarithm to the base 10 of the P values from logistic regression analysis is on the y-axis. (B) Genes in the analyzed region and patterns of LD, denoted by r² values and shading. Higher r² values and darker shading indicate greater correlation between the SNPs.

Fig. 3.

Association of selected SNPs on chromosome 5p15.33 with lung cancer risk overall and stratified by histological subtype and smoking status. (A) The panel includes four SNPs selected by stepwise forward selection logistic regression analysis and eight previously published GWAS SNPs. Association of SNPs with lung cancer, adjusted for sex, age and number of pack-years smoked in the overall analysis and analysis by histological subtype. Analysis by smoking status adjusted for age and sex. Chromosomal position is on the x-axis and negative logarithm to the base 10 of the P values from logistic regression analysis is on the y-axis. (B) Patterns of LD, denoted by r² values and shading.