Polymorphism in Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 Gene (ENPP1/PC-1) and Early Development of Advanced Diabetic Nephropathy in Type 1 Diabetes

Polymorphism in Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 Gene ( ENPP1/PC-1 ) and Early Development of Advanced Diabetic Nephropathy in Type 1 Diabetes Luis H. Canani , Daniel P.K. Ng , Adam Smiles , John J. Rogus , James H. Warram and Andrzej S. Krolewski From the Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts Abstract A polymorphism in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene ( ENPP1 ) (previously known as PC-1 ), resulting in an amino acid change from lysine to glutamine at codon 121 (K121Q), is associated with insulin resistance. A small follow-up study of patients with type 1 diabetes and proteinuria found that renal function declines more rapidly in carriers of the Q variant than in noncarriers. To examine this finding further, we conducted a large case-control study and a family-based study. Genomic DNA was obtained from 659 patients: 307 with normal urinary albumin excretion despite diabetes duration of >15 years (control subjects) and 352 with advanced diabetic nephropathy, of whom 200 had persistent proteinuria and 152 had end-stage renal disease (ESRD). Individuals were genotyped for Q and K variants using a previously described protocol. The frequency of Q variant carriers was 21.5% in control subjects, 31.5% in subjects with proteinuria, and 32.2% in subjects with ESRD ( P = 0.012). In a stratified analysis according to duration of diabetes, the risk of early-onset ESRD for carriers of the Q variant was 2.3 times that for noncarriers (95% CI, 1.2–4.6). The Q variant was not associated with late-onset ESRD. Similar findings were obtained in a family-based study. We conclude that carriers of the Q variant of ENPP1 are at increased risk for developing ESRD early in the course of type 1 diabetes. Footnotes Address correspondence and reprint requests to Andrzej S. Krolewski, Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: andrzej.krolewski{at}joslin.harvard.edu . Received for publication 31 July 2001 and accepted in revised form 4 January 2002. ACR, albumin/creatinine ratio; ESRD, end-stage renal disease; GFR, glomerular filtration rate; IRS, insulin receptor substrate; TDT, transmission disequilibrium test. DIABETES