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

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Abstract
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 3 10 27). 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.
Keywords
Genome-wide association study, chronic obstructive pulmonary disease, genetics, never-smokers, pulmonary function, OBSTRUCTIVE PULMONARY-DISEASE, LUNG-FUNCTION, GENERAL-POPULATION, COPD, POLYMORPHISMS, STANDARDIZATION, METAANALYSIS, ROTTERDAM, GENETICS, LEVEL

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MLA
van der Plaat, Diana A et al. “Genome-wide Association Study on the FEV1/FVC Ratio in Never-smokers Identifies HHIP and FAM13A.” JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 139.2 (2017): 533–540. Print.
APA
van der Plaat, D. A., de Jong, K., Lahousse, L., Faiz, A., Vonk, J. M., van Diemen, C. C., Nedeljkovic, I., et al. (2017). Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 139(2), 533–540.
Chicago author-date
van der Plaat, Diana A, Kim de Jong, Lies Lahousse, Alen Faiz, Judith M Vonk, Cleo C. van Diemen, Ivana Nedeljkovic, et al. 2017. “Genome-wide Association Study on the FEV1/FVC Ratio in Never-smokers Identifies HHIP and FAM13A.” Journal of Allergy and Clinical Immunology 139 (2): 533–540.
Chicago author-date (all authors)
van der Plaat, Diana A, Kim de Jong, Lies Lahousse, Alen Faiz, Judith M Vonk, Cleo C. van Diemen, Ivana Nedeljkovic, Najaf Amin, Guy Brusselle, Albert Hofman, Corry-Anke Brandsma, Yohan Bossé, Don D Sin, David C Nickle, Cornelia M van Duijn, Dirkje S Postma, and H Marike Boezen. 2017. “Genome-wide Association Study on the FEV1/FVC Ratio in Never-smokers Identifies HHIP and FAM13A.” Journal of Allergy and Clinical Immunology 139 (2): 533–540.
Vancouver
1.
van der Plaat DA, de Jong K, Lahousse L, Faiz A, Vonk JM, van Diemen CC, et al. Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. 2017;139(2):533–40.
IEEE
[1]
D. A. van der Plaat et al., “Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A,” JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 139, no. 2, pp. 533–540, 2017.
@article{8500280,
  abstract     = {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 3 10 27). 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.},
  author       = {van der Plaat, Diana A and de Jong, Kim and Lahousse, Lies and Faiz, Alen and Vonk, Judith M and van Diemen, Cleo C. and Nedeljkovic, Ivana and Amin, Najaf and Brusselle, Guy and Hofman, Albert and Brandsma, Corry-Anke and Bossé, Yohan and Sin, Don D and Nickle, David C and van Duijn, Cornelia M and Postma, Dirkje S and Boezen, H Marike},
  issn         = {0091-6749},
  journal      = {JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY},
  keywords     = {Genome-wide association study,chronic obstructive pulmonary disease,genetics,never-smokers,pulmonary function,OBSTRUCTIVE PULMONARY-DISEASE,LUNG-FUNCTION,GENERAL-POPULATION,COPD,POLYMORPHISMS,STANDARDIZATION,METAANALYSIS,ROTTERDAM,GENETICS,LEVEL},
  language     = {eng},
  number       = {2},
  pages        = {533--540},
  title        = {Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A},
  url          = {http://dx.doi.org/10.1016/j.jaci.2016.06.062},
  volume       = {139},
  year         = {2017},
}

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