Human Molecular Genetics Advance Access originally published online on June 4, 2008
Human Molecular Genetics 2008 17(17):2681-2690; doi:10.1093/hmg/ddn168
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An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity
1 Department of Medicine 2 Biopharmaceutical Sciences 3 Lung Biology Center 4 Department of Epidemiology and Biostatistics 5 Institute for Human Genetics 6 Department of Pediatrics, University of California San Francisco (UCSF), San Francisco, CA 94143-2911, USA 7 Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA 8 Children’s Hospital Oakland Research Institute (CHORI), Oakland, CA, USA 9 Bay Area Pediatrics, Oakland, CA, USA 10 The James A. Watson Wellness Center, Oakland, CA, USA 11 Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA 12 Children’s Memorial Hospital 13 Institute for Health Care Studies 14 Department of Medicine of Northwestern University, Chicago, IL, USA
* To whom correspondence should be addressed. Tel: +1 4155149929; Fax: +1 4155144365; Email: mseibold{at}medsfgh.ucsf.edu
Received April 23, 2008; Revised April 23, 2008; Accepted June 3, 2008
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.
The authors wish it to be known that, in their opinion, these authors should be regarded as joint Authors.
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