Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 127, Issue 6, Pages 1457-1465Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2011.01.056
Keywords
Asthma; genetics; asthma severity; meta-analysis; FEV1; FVC; FEV1/FVC; HHIP; FAM13A; PTCH1
Categories
Funding
- National Institutes of Health (NIH) [HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, UL1RR024992, M01RR018390, M01RR07122, M01RR03186, HL087665, HL091762, HL87665]
- Genentech, Inc
- Novartis Pharmaceuticals Corp
- National Institute of Allergy and Infectious Diseases
- National Heart, Lung, and Blood Institute (NHLBI)
- Novartis
- AstraZeneca
- GlaxoSmithKline
- MedImmune
- Boehringer Ingelheim
- Pfizer
- Merck
- Asthmatx
- Amgen
- Ception
- Genentech
- Medical Research Council (United Kingdom)
- Wellcome Trust
- Asthma UK
- NIH/NHLBI
- Medical Research Council [G1000758B, G0801056B, G1000758] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10212] Funding Source: researchfish
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Background: Two recent large meta-analyses of genome-wide association studies of lung function in general populations of European descent identified 11 candidate genes/regions. The importance of these genes in lung function in white and African American subjects with asthma is unknown. Objectives: To determine whether genes that regulate lung function in general populations are associated with lung function abnormalities in subjects with asthma from different racial groups. Methods: Single nucleotide polymorphisms (SNPs) were tested in 5 asthma populations (N = 1441) for association with pulmonary function, and meta-analysis was performed across populations. The SNPs with the highest significance were then tested for association with bronchodilator reversibility and bronchial hyperresponsiveness to methacholine. A joint analysis of consistently replicated SNPs was performed to predict lung function in asthma. Results: Hedgehog interacting protein (HHIP) on chromosome 4q31 was associated with lung function in all 5 populations (rs1512288: P-meta = 9.62E-05 and 3.23E-05 for percent predicted FEV1 [ppFEV(1)] and percent predicted forced vital capacity [ppFVC], respectively). The SNPs in HHIP were also associated with reversibility (P < .05) but not bronchial hyperresponsiveness to methacholine. Because of differences in linkage disequilibrium in the African American subjects, the most relevant SNPs in HHIP were identified. A subset of normal lung function genes, including HHIP, family with sequence similarity 13, member A (FAM13A), and patched homolog 1 (PTCH1), together predict lung function abnormalities, a measure of severity in white and African American subjects with asthma. Conclusion: A subset of the genes, including HHIP, that regulate lung function in general populations are associated with abnormal lung function in asthma in non-Hispanic white and African American subjects. (J Allergy Clin Immunol 2011;127:1457-65.)
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