An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity.
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 beta1-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 (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-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.
Department of Medicine, University of California San Francisco, San Francisco, CA 94143-2911, USA. mseibold@medsfgh.ucsf.edu
Max A
MA
Seibold
Bin
B
Wang
Celeste
C
Eng
Gunjan
G
Kumar
Kenneth B
KB
Beckman
Saunak
S
Sen
Shweta
S
Choudhry
Kelley
K
Meade
Michael
M
Lenoir
H Geoffrey
HG
Watson
Shannon
S
Thyne
L Keoki
LK
Williams
Rajesh
R
Kumar
Kevin B
KB
Weiss
Leslie C
LC
Grammer
Pedro C
PC
Avila
Robert P
RP
Schleimer
Esteban González
EG
Burchard
Robert
R
Brenner
D001741:Black or African American / Q000235:genetics; D001249:Asthma / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics*; D008168:Lung / Q000502:physiology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012495:San Francisco / Q000453:epidemiology; D012737:Sex Factors
C531905:KCNMB1 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits