Genome-wide association study on the FEV₁/FVC ratio in never-smokers identifies HHIP and FAM13A.

Abstract

Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group exclusively. The aim of this study was to identify common genetic variants associated with FEV₁ and its ratio to forced vital capacity (FVC) in never-smokers. Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results (P < 10^-5) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n = 1966). Furthermore, we aimed to assess the effects of the replicated variants in more detail by performing genetic risk score, expression quantitative trait loci, and variant*ever-smoking interaction analyses. We identified associations between the FEV₁/FVC ratio and 5 common genetic variants in the identification cohort, and 2 of these associations were replicated. The 2 variants annotated to the genes hedgehog interacting protein (HHIP) and family with sequence similarity 13 member A (FAM13A) were shown to have an additive effect on FEV₁/FVC levels in the genetic risk score analysis; were associated with gene expression of HHIP and FAM13A in lung tissue, respectively; and were genome-wide significant in a meta-analysis including both identification and 4 verification cohorts (P < 2.19 × 10^-7). Finally, we did not identify significant interactions between the variants and ever smoking. Results of the FEV₁ identification analysis were not replicated. The genes HHIP and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease.