Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A.
van der Plaat, DA
de Jong, K
Lahousse, L
Faiz, A
Vonk, JM
van Diemen, CC
Nedeljkovic, I
Amin, N
Brusselle, GG
Hofman, A
Brandsma, C-A
Bossé, Y
Sin, DD
Nickle, DC
van Duijn, CM
Postma, DS
Boezen, HM
Vonk, JM
van Diemen, CC
Nedeljkovic, I
Amin, N
Brusselle, GG
Hofman, A
Brandsma, C-A
Bossé, Y
Sin, DD
Nickle, DC
van Duijn, CM
Postma, DS
Boezen, HM
- Publisher:
- Elsevier
- Publication Type:
- Journal Article
- Citation:
- Journal of Allergy and Clinical Immunology, 2017, 139, (2), pp. 533-540
- Issue Date:
- 2017-02
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| 1-s2.0-S0091674916308958-main.pdf | 834.16 kB |
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BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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