BACKGROUND:Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.METHODS:A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.RESULTS:The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.CONCLUSIONS:Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/610036 |
| Date | January 2013 |
| Creators | Himes, Blanca, Qiu, Weiliang, Klanderman, Barbara, Ziniti, John, Senter-Sylvia, Jody, Szefler, Stanley, Lemanske, Jr, Robert, Zeiger, Robert, Strunk, Robert, Martinez, Fernando, Boushey, Homer, Chinchilli, Vernon, Israel, Elliot, Mauger, David, Koppelman, Gerard, Nieuwenhuis, Maartje, Postma, Dirkje, Vonk, Judith, Rafaels, Nicholas, Hansel, Nadia, Barnes, Kathleen, Raby, Benjamin, Tantisira, Kelan, Weiss, Scott |
| Contributors | Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA, Partners HealthCare Center for Personalized Genetic Medicine and Harvard Medical School, Boston, MA, USA, Children’s Hospital Informatics Program, Boston, MA, USA, National Jewish Health and University of Colorado Denver School of Medicine, Denver, CO, USA, University of Wisconsin, Clinical Science Center, Madison, WI, USA, Kaiser Permanente Southern California Region, San Diego, CA, USA, Washington University School of Medicine, St. Louis, MO, USA, Arizona Respiratory Center, University of Arizona, College of Medicine, Tucson, AZ, USA, Division of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA, Department of Biostatistics, Penn State College of Medicine, Hershey, PA, USA, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, Department of Pulmonology and Tuberculosis, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, Department of Epidemiology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA |
| Publisher | BioMed Central |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2013 Himes et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) |
| Relation | http://www.biomedcentral.com/1471-2350/14/86 |
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