title: KCNQ1 gene variants in the risk for type 2 diabetes and impaired renal function in the Spanish Renastur cohort.
abstract: Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta-cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non-diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFR<60, n = 90 vs. eGFR≥60, n = 591; II vs ID + DD genotypes, p = 0.031, OR = 2.06, 95%CI = 1.12-4.14). We also performed a next generation sequencing search of variants in the coding regions of the KCNQ1 gene in 100 individuals with the extreme eGFR values. We found two rare amino acid changes (p.K393N and p.P408A) and the 393 Asn variant was found only among diabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted.
authors.affiliation: Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Riobello
authors.affiliation: Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Gómez
authors.affiliation: Pediatría, HUCA, Oviedo, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Gil-Peña
authors.affiliation: Centro de Salud ElCristo, Oviedo, Asturias, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Tranche
authors.affiliation: Cardiología-Fundación Asturcor, HUCA, Oviedo, Spain.
authors.forename: Julián R
authors.initials: JR
authors.lastname: Reguero
authors.affiliation: Cardiología-Fundación Asturcor, HUCA, Oviedo, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: de la Hera
authors.affiliation: Endocrinología, HUCA, Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Delgado
authors.affiliation: Cardiología-Fundación Asturcor, HUCA, Oviedo, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Calvo
authors.affiliation: Cardiología-Fundación Asturcor, HUCA, Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Morís
authors.affiliation: Pediatría, HUCA, Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.affiliation: Dermatología, HUCA, Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Coto-Segura
authors.affiliation: Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Iglesias
authors.affiliation: Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Alonso
authors.affiliation: Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.affiliation: Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain; Universidad de Oviedo, Oviedo, Spain; Red investigacion renal (REDINREN), Madrid, Spain. Electronic address: eliecer.coto@sespa.es.
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D007438:Introns; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: Estimated glomerular filtration rate; Gene polymorphisms; KCNQ1 gene; Next generation sequencing; Potassium channels; Type 2 diabetes