title: The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling.
abstract: The objective of this study is to identify and characterize the genetic variants related to the glomerular filtration rate (GFR) linkage on 2q37. Of the positional candidate genes, we selected IRS1 and resequenced its 2-kb promoter region and exons for sequence variants in 32 subjects. A total of 11 single nucleotide polymorphisms (SNPs) were identified. To comprehensively cover the 59-kb-long intron-1, eight additional tagging SNPs were selected from the HapMap. All the 19 SNPs were genotyped by TaqMan Assay in the entire data set (N = 670; 39 families). Association analyses between the SNPs and GFR and type 2 diabetes-related traits were performed using the measured genotype approach. Of the SNPs examined for association, only the Gly(972)Arg variant of IRS1 exhibited a significant association with GFR (P = 0.0006) and serum triglycerides levels (P = 0.003), after accounting for trait-specific covariate effects. Carriers of Arg972 had significantly decreased GFR values. Gly(972)Arg contributed to 26% of the linkage signal on 2q. Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling.
authors.affiliation: Division of Nephrology, The University of Texas Health Science Center, San Antonio, Texas, USA. thameem@uthscsa.edu
authors.forename: Farook
authors.initials: F
authors.lastname: Thameem
authors.forename: Sobha
authors.initials: S
authors.lastname: Puppala
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schneider
authors.forename: Basant
authors.initials: B
authors.lastname: Bhandari
authors.forename: Rector
authors.initials: R
authors.lastname: Arya
authors.forename: Nedal H
authors.initials: NH
authors.lastname: Arar
authors.forename: Tetyana L
authors.initials: TL
authors.lastname: Vasylyeva
authors.forename: Vidya S
authors.initials: VS
authors.lastname: Farook
authors.forename: Sharon
authors.initials: S
authors.lastname: Fowler
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt