The Gly972→Arg IRS-1 Variant Is Associated With Type 1 Diabetes in Continental Italy
- Massimo Federici1,
- Antonio Petrone2,
- Ottavia Porzio3,
- Carla Bizzarri4,
- Davide Lauro1,
- Rossella D’Alfonso1,
- Ippolita Patera4,
- Marco Cappa4,
- Lorenza Nisticò5,
- Marco Baroni2,
- Giorgio Sesti6,
- Umberto di Mario2,
- Renato Lauro1 and
- Raffaella Buzzetti2
- 1Department of Internal Medicine, University of Rome “Tor Vergata,” Rome, Italy
- 2Department of Clinical Sciences, University of Rome “La Sapienza,” Rome, Italy
- 3Clinical Biochemistry Unit, University of Rome “Tor Vergata,” Rome, Italy
- 4Istituto di Ricerca e Cura e Carattere Scientifico Ospedale Bambino Gesù, Rome, Italy
- 5Istituto Superiore di Sanità, Immunogenetics Laboratory, Rome, Italy
- 6Department of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia,” Catanzaro, Italy
Abstract
The Arg972 insulin receptor substrate-1 (IRS-1) variant has been hypothesized to play a role in pancreatic β-cell stimulus-coupled insulin secretion and survival. We analyzed the relations between type 1 diabetes and the Arg972 IRS-1 variant. The frequency of the IRS-1 Arg972 variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. In the former group, frequency of the IRS-1 Arg972 variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg972 IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). Arg972 IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. Arg972 IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 ± 0.058, n = 34, and 0.76 ± 0.066, n = 134, respectively [means ± SE]; P = 0.051). Our findings suggest a role for Arg972 IRS-1 in conferring risk for the development of type 1 diabetes.
Footnotes
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Address correspondence and reprint requests to Renato Lauro, MD, or Massimo Federici, MD, Department of Internal Medicine, University of Rome “Tor Vergata,” via Montpellier 1, 56100, Rome, Italy. E-mail: lauro{at}uniroma2.it or federicm{at}uniroma2.it.
Received for publication 30 September 2002 and accepted in revised form 2 December 2002.
A.P. has a fellowship from the Italian Society of Diabetes.
IRS-1, insulin receptor substrate-1; PI3, phosphatidylinositol-3; PPV, positive predictive value; TDT, transmission disequilibrium test.
- DIABETES
