A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the β1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure - forced expiratory volume (FEV1) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV1 in both cohorts of asthmatics among males but not females (Pcombined = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the β1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health [HL078885 (E.G.B.), HL078860 and HL068546 (R.S.)], HL082197 (B.W.), Flight Attendant Medical Research Institute (FAMRI) (E.G.B.), RWJ Amos Medical Faculty Development Award, NCMHD Health Disparities Scholar, Extramural Clinical Research Loan Repayment Program for Individuals from Disadvantaged Backgrounds, 2001–2003, (E.G.B.), Chicago Initiative to Raise Asthma Health Equity (CHIRAH) is funded by the National Heart Lung and Blood Institute (NHLBI), 5U01 HL072478-05, The Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University and the Sandler Asthma Basic Research Center (SABRE), Sandler Program for Asthma Research (SPAR) and the Sandler Family Supporting Foun- dation. Support for genotyping was provided by the National Center for Minority Health Disparities Center of Excellence in Nutritional Genomics (P60 MD00022).