Genome-wide association study of lung function phenotypes in a founder population - 25/12/13
, Gaixin Du, MS a, Lide Han, PhD a, Ying Sun, MS a, Donglei Hu, PhD c, James J. Yang, PhD d, Rasika Mathias, ScD e, Lindsey A. Roth, MA c, Nicholas Rafaels, MS e, Emma E. Thompson, PhD a, Dagan A. Loisel, PhD a, Rebecca Anderson, MS a, Celeste Eng, BS c, Maitane Arruabarrena Orbegozo, RN a, Melody Young, RN f, James M. Klocksieben, BA g, Elizabeth Anderson, RN h, Kathleen Shanovich, MS, RN h, Lucille A. Lester, MD f, L. Keoki Williams, MD, MPH i, Kathleen C. Barnes, PhD e, Esteban G. Burchard, MD, MPH c, j, Dan L. Nicolae, PhD a, f, k, Mark Abney, PhD a, ∗, Carole Ober, PhD a, ⁎∗ Abstract |
Background |
Lung function is a long-term predictor of mortality and morbidity.
Objective |
We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function.
Methods |
We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs.
Results |
Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10−8 to 3.4 × 10−9). Nine SNPs at or near 4 additional loci had P < 10−5 with FEV1/FVC. Only 2 SNPs were found with P < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of β-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B.
Conclusion |
This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.
Le texte complet de cet article est disponible en PDF.Key words : FEV1/FVC, FEV1, FVC, GWAS, LASSO regression, GRAIL
Abbreviations used : COPD, FVC, GWAS, LASSO, SNP
Plan
| Supported by the National Institutes of Health grant R01 HL085197 (C.O.) and grant R01 HG002899 (M.A.). |
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| Disclosure of potential conflict of interest: L. Han, J. J. Yang, R. Mathais, E. E. Thompson, D. A. Loisel, R. Anderson, M. A. Orbegozo, M. Young, J. M. Klocksieben, L. A. Lester, K. C. Barnes, M. Abney, and C. Ober have received grants from the National Institutes of Health (NIH). C. Eng has received grants from the NIH and the National Heart Lung and Blood Institute. L. K. Williams has received grants from the NIH, the National Institute of Allergy and Infectious Disease, and the National Institute of Diabetes and Digestive and Kidney Diseases, and has received payment for lectures from Merck & Company. E. G. Burchard has received grants from the NIH and the National Heart Lung and Blood Institute. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 133 - N° 1
P. 248 - janvier 2014 Retour au numéro
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