title: Common charge-shift mutation Glu65Lys in K+ channel β₁-Subunit KCNMB1: pleiotropic consequences for glomerular filtration rate and progressive renal disease.
abstract: BACKGROUND
  Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory β₁-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline.
  
  
  METHODS
  We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance).
  
  
  RESULTS
  The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019).
  
  
  CONCLUSIONS
  Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.
authors.affiliation: Department of Medicine, University of California at San Diego, Calif., USA. cyq@bjmu.edu.cn
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Maple M
authors.initials: MM
authors.lastname: Fung
authors.forename: Vibha
authors.initials: V
authors.lastname: Bhatnagar
authors.forename: Braj
authors.initials: B
authors.lastname: Pandey
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Jill
authors.initials: J
authors.lastname: Waalen
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lipkowitz
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D005919:Glomerular Filtration Rate / Q000235:genetics* / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009400:Nephrosclerosis / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D044465:White People / Q000235:genetics
chemical_list: C531905:KCNMB1 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits