title: Polymorphism in ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1/PC-1) and early development of advanced diabetic nephropathy in type 1 diabetes.
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.
authors.affiliation: Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Luis H
authors.initials: LH
authors.lastname: Canani
authors.forename: Daniel P K
authors.initials: DP
authors.lastname: Ng
authors.forename: Adam
authors.initials: A
authors.lastname: Smiles
authors.forename: John J
authors.initials: JJ
authors.lastname: Rogus
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D001900:Boston; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011507:Proteinuria / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics*; D012189:Retrospective Studies; D044465:White People
chemical_list: D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases