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.
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.
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Authors: H G Knaus; K Folander; M Garcia-Calvo; M L Garcia; G J Kaczorowski; M Smith; R Swanson Journal: J Biol Chem Date: 1994-06-24 Impact factor: 5.157
Authors: A T DeWan; D K Arnett; L D Atwood; M A Province; C E Lewis; S C Hunt; J Eckfeldt Journal: Am J Hum Genet Date: 2000-12-12 Impact factor: 11.025
Authors: Anna Köttgen; Nicole L Glazer; Abbas Dehghan; Shih-Jen Hwang; Ronit Katz; Man Li; Qiong Yang; Vilmundur Gudnason; Lenore J Launer; Tamara B Harris; Albert V Smith; Dan E Arking; Brad C Astor; Eric Boerwinkle; Georg B Ehret; Ingo Ruczinski; Robert B Scharpf; Yii-Der Ida Chen; Ian H de Boer; Talin Haritunians; Thomas Lumley; Mark Sarnak; David Siscovick; Emelia J Benjamin; Daniel Levy; Ashish Upadhyay; Yurii S Aulchenko; Albert Hofman; Fernando Rivadeneira; André G Uitterlinden; Cornelia M van Duijn; Daniel I Chasman; Guillaume Paré; Paul M Ridker; W H Linda Kao; Jacqueline C Witteman; Josef Coresh; Michael G Shlipak; Caroline S Fox Journal: Nat Genet Date: 2009-05-10 Impact factor: 38.330
Authors: K H Buetow; M Edmonson; R MacDonald; R Clifford; P Yip; J Kelley; D P Little; R Strausberg; H Koester; C R Cantor; A Braun Journal: Proc Natl Acad Sci U S A Date: 2001-01-02 Impact factor: 11.205
Authors: Mathias Gorski; Adrienne Tin; Maija Garnaas; Gearoid M McMahon; Audrey Y Chu; Bamidele O Tayo; Cristian Pattaro; Alexander Teumer; Daniel I Chasman; John Chalmers; Pavel Hamet; Johanne Tremblay; Marc Woodward; Thor Aspelund; Gudny Eiriksdottir; Vilmundur Gudnason; Tamara B Harris; Lenore J Launer; Albert V Smith; Braxton D Mitchell; Jeffrey R O'Connell; Alan R Shuldiner; Josef Coresh; Man Li; Paul Freudenberger; Edith Hofer; Helena Schmidt; Reinhold Schmidt; Elizabeth G Holliday; Paul Mitchell; Jie Jin Wang; Ian H de Boer; Guo Li; David S Siscovick; Zoltan Kutalik; Tanguy Corre; Peter Vollenweider; Gérard Waeber; Jayanta Gupta; Peter A Kanetsky; Shih-Jen Hwang; Matthias Olden; Qiong Yang; Mariza de Andrade; Elizabeth J Atkinson; Sharon L R Kardia; Stephen T Turner; Jeanette M Stafford; Jingzhong Ding; Yongmei Liu; Cristina Barlassina; Daniele Cusi; Erika Salvi; Jan A Staessen; Paul M Ridker; Harald Grallert; Christa Meisinger; Martina Müller-Nurasyid; Bernhard K Krämer; Holly Kramer; Sylvia E Rosas; Ilja M Nolte; Brenda W Penninx; Harold Snieder; M Fabiola Del Greco; Andre Franke; Ute Nöthlings; Wolfgang Lieb; Stephan J L Bakker; Ron T Gansevoort; Pim van der Harst; Abbas Dehghan; Oscar H Franco; Albert Hofman; Fernando Rivadeneira; Sanaz Sedaghat; André G Uitterlinden; Stefan Coassin; Margot Haun; Barbara Kollerits; Florian Kronenberg; Bernhard Paulweber; Nicole Aumann; Karlhans Endlich; Mike Pietzner; Uwe Völker; Rainer Rettig; Vincent Chouraki; Catherine Helmer; Jean-Charles Lambert; Marie Metzger; Benedicte Stengel; Terho Lehtimäki; Leo-Pekka Lyytikäinen; Olli Raitakari; Andrew Johnson; Afshin Parsa; Murielle Bochud; Iris M Heid; Wolfram Goessling; Anna Köttgen; W H Linda Kao; Caroline S Fox; Carsten A Böger Journal: Kidney Int Date: 2014-12-10 Impact factor: 10.612