Susceptibility loci in lung cancer and COPD: association of IREB2 and FAM13A with pulmonary diseases

Abstract

Genome-wide association studies have identified loci at 15q25 (IREB2) and 4q22 (FAM13A), associated with lung cancer (LC) and chronic obstructive pulmonary disease (COPD). The aim of our research was to determine the association of IREB2 and FAM13A SNPs with LC and severe/very severe COPD patients. We examined IREB2 variants (rs2568494, rs2656069, rs10851906, rs13180) and FAM13A (rs1903003, rs7671167, rs2869967) among 1.141 participants (468 LC, 149 COPD, 524 smoking controls). The frequency of the minor IREB2 rs2568494 AA genotype, was higher in LC vs controls (P = 0.0081, OR = 1.682). The FAM13A rs2869967 was associated with COPD (minor CC genotype: P = 0.0007, OR = 2.414). The rs1903003, rs7671167 FAM13A variants confer a protective effect on COPD (both P < 0.002, OR < 0.405). Haplotype-based tests identified an association of the IREB2 AAAT haplotype with LC (P = 0.0021, OR = 1.513) and FAM13A TTC with COPD (P = 0.0013, OR = 1.822). Cumulative genetic risk score analyses (CGRS), derived by adding risk alleles, revealed that the risk for COPD increased with the growing number of the FAM13A risk alleles. OR (95% CI) for carriers of ≥5 risk alleles reached 2.998 (1.8 to 4.97) compared to the controls. This study confirms that the IREB2 variants contribute to an increased risk of LC, whereas FAM13A predisposes to increased susceptibility to COPD.

Figure 1. Significant influences of IREB2 and FAM13A SNPs on COPD and lung cancer according to age and sex.

A multiple linear regression analysis was performed for IREB2 (rs2568494, rs10851906, rs13180) genotypes in LC and FAM13A (rs7671167, rs1903003, rs2869967) genotypes in COPD. The odds ratios with 95% confidence intervals (O.R. with 95%CI) for genotypes of selected SNPs are displayed. Control group was set as reference group. All results for age variable were statistically significant. LC: lung cancer; COPD: chronic obstructive pulmonary disease.

Figure 2. Pairwise linkage disequilibrium between SNPs in IREB2 gene and FAM13A gene.

Figure 3. Cumulative genetic risk score (CGRS) analysis of FAM13A SNPs.

The effect of unweighted cumulative genetic risk score on COPD and COPD with LC+COPD was calculated using logistic regression analysis. The odds ratios (black symbols) with 95% confidence intervals (range bars) for the number of risk alleles at each of FAM13A SNPs are represented from unweigheted analysis. COPD: chronic obstructive pulmonary disease; LC: lung cancer; COPD with LC+COPD: COPD with 40% admixture of subjects with concomitant LC.