The Gly(972)Arg Variant of Human IRS1 Gene Is Associated With Variation in Glomerular Filtration Rate Likely Through Impaired Insulin Receptor Signaling
- Farook Thameem1⇓,
- Sobha Puppala2,
- Jennifer Schneider2,
- Basant Bhandari1,
- Rector Arya3,
- Nedal H. Arar1,4,
- Tetyana L. Vasylyeva1,
- Vidya S. Farook2,
- Sharon Fowler5,
- Laura Almasy2,
- John Blangero2,
- Ravindranath Duggirala2 and
- Hanna E. Abboud1,4
- 1Division of Nephrology, The University of Texas Health Science Center, San Antonio, Texas
- 2Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
- 3Department of Pediatrics, The University of Texas Health Science Center, San Antonio, Texas
- 4South Texas Veterans Healthcare System, San Antonio, Texas
- 5Division of Clinical Epidemiology, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas
- Corresponding author: Farook Thameem, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1078/-/DC1.
- Received August 9, 2011.
- Accepted March 20, 2012.
- © 2012 by the American Diabetes Association.
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