Importance of hedgehog interacting protein and other lung function genes in asthma

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.