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.