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Common Charge-Shift Mutation Glu65Lys in K+ Channel beta(1)-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease
Chen, Yuqing1,2; Salem, Rany M.2; Rao, Fangwen2; Fung, Maple M.2,5; Bhatnagar, Vibha2,5; Pandey, Braj2,5; Mahata, Manjula2; Waalen, Jill6; Nievergelt, Caroline M.2,5; Lipkowitz, Michael S.7; Hamilton, Bruce A.2,4; Mahata, Sushil K.2,5; O′ Connor, Daniel T.2,3,4,5
关键词Glomerular filtration rate KCNMB1 Hypertensive nephrosclerosis African-American Study of Kidney Disease and Hypertension
刊名AMERICAN JOURNAL OF NEPHROLOGY
2010
DOI10.1159/000320131
32期:5页:414-424
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Urology & Nephrology
研究领域[WOS]Urology & Nephrology
关键词[WOS]KIDNEY-DISEASE ; BLOOD-PRESSURE ; AFRICAN-AMERICAN ; MESANGIAL CELLS ; CREATININE CLEARANCE ; BETA-1 SUBUNIT ; SMOOTH-MUSCLE ; HYPERTENSION ; POPULATION ; LINKAGE
英文摘要

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 Ca2+ influx, which is controlled by the regulatory beta(1)-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 similar to 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 similar to 0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for similar to 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 similar to 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. Copyright (C) 2010 S. Karger AG, Basel

语种英语
WOS记录号WOS:000284282900004
项目编号NIH RR00827 ; NIH MD000220 ; NIH DK079337
资助机构UCSD General Clinical Research Center ; UCSD Comprehensive Research Center in Health Disparities (CRCHD) ; UAB/UCSD O&prime ; Brien Kidney Disease Research Center ; International Society of Nephrology ; National Institutes of Health, Department of Veterans Affairs, International Society of Nephrology
引用统计
被引频次:6[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/60963
专题北京大学第一临床医学院_肾脏内科
作者单位1.Peking Univ, Div Renal, Hosp 1, Dept Med, Beijing 100034, Peoples R China
2.Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
3.Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
4.Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
5.VA San Diego Healthcare Syst, La Jolla, CA USA
6.Scripps Res Inst, La Jolla, CA 92037 USA
7.Mt Sinai Sch Med, New York, NY USA
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Chen, Yuqing,Salem, Rany M.,Rao, Fangwen,et al. Common Charge-Shift Mutation Glu65Lys in K+ Channel beta(1)-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease[J]. AMERICAN JOURNAL OF NEPHROLOGY,2010,32(5):414-424.
APA Chen, Yuqing.,Salem, Rany M..,Rao, Fangwen.,Fung, Maple M..,Bhatnagar, Vibha.,...&Connor, Daniel T..(2010).Common Charge-Shift Mutation Glu65Lys in K+ Channel beta(1)-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease.AMERICAN JOURNAL OF NEPHROLOGY,32(5),414-424.
MLA Chen, Yuqing,et al."Common Charge-Shift Mutation Glu65Lys in K+ Channel beta(1)-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease".AMERICAN JOURNAL OF NEPHROLOGY 32.5(2010):414-424.
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