Identification of FAM13A gene associated with the ratio of FEV 1 to FVC in Korean population by genome-wide association studies including gene-environment interactions

Chronic obstructive pulmonary disease (COPD) is a complex, multifactorial disease. Although smoking is a main risk factor for obstructive impairment, not all smokers develop this critical disease. We conducted a genome-wide association study to identify the association between genetic variants and pulmonary function and also examined how these variants relate to lung impairment in accordance with smoking behaviors. Using two community-based cohorts, the Ansan cohort (n=4319) and the Ansung cohort (n=3674), in the Korean Genome Epidemiology Study, we analyzed the association between genetic variants (single-nucleotide polymorphisms and haplotypes) and the ratio of FEV 1 to FVC (FEV 1 /FVC) using multivariate linear regression models. Similar analyses were conducted after stratification by smoking status. Four genome-wide significant signals in the FAM13A gene (the strongest signal at rs2609264, P=1.76 × 10 -7 in a combined set) were associated with FEV 1 /FVC. For the association with ratio, the effect size in the CTGA haplotype (risk haplotype) was -0.57% (s.e., 0.11; P=2.10 × 10 -7) as compared with the TCAG haplotype (reference haplotype) in a combined set. There was also a significant interaction of FAM13A haplotypes with heavy smoking on FEV 1 /FVC (P for interaction=0.028). We confirmed the previously reported association of FAM13A in 4q22.1 with pulmonary function. The FAM13A haplotypes also interacted with heavy smoking to affect the risk of reduced pulmonary function.