Human Molecular Genetics Advance Access published online on June 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn168
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An African-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity
,1,2,4,7,31 Department of Medicine, CA, University of Texas Health Science Center at San Antonio, San Antonio, TX 2 Biopharmaceutical Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 3 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 4 Lung Biology Center, Oakland, CA 5 Children's Hospital Oakland Research Institute (CHORI), Oakland, CA 6 Department of Epidemiology and Biostatistics 7 Institute for Human Genetics 8 Bay Area Pediatrics, Oakland, CA 9 The James A. Watson Wellness Center, Oakland CA 10 Department of Pediatrics of the University of California San Francisco (UCSF), San Francisco 11 Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 12 Children's Memorial Hospital 13 Institute for Health Care Studies 14 Department of Medicine of Northwestern University, Chicago, IL
Correspondence and reprint requests should be addressed to: Max A. Seibold, University of California, San Francisco, San Francisco, California 94143-2911; telephone: 415-514-9929, fax: 415-514-4365, e-mail: 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 tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in airway smooth muscle. 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 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 FEV1 % of predicted. 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.
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Each of these authors contributed equally to this manuscript
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