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A Disease Haplotype for Advanced Nephropathy in Type 2 Diabetes at the ACE Locus

¹ Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore
² Centre for Molecular Epidemiology, National University of Singapore, Singapore
³ Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁵ Department of Hypertension, Warsaw Medical University, Warsaw, Poland

Address correspondence and reprint requests to Andrzej S. Krolewski, MD, PhD, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: andrzej.krolewski{at}joslin.harvard.edu

Abbreviations: ACR, albumin-to-creatinine ratio; CRF, chronic renal failure; ESRD, end-stage renal disease; Ins/Del, insertion/deletion; MAF, minor allele frequency

Previous investigations of the ACE gene as a susceptibility factor for diabetic nephropathy have primarily focused on its insertion/deletion (Ins/Del) polymorphism. In a departure from these earlier studies, we used three tagging markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus to test for disease haplotype associations. A case-control study design was used where case subjects were type 2 diabetic patients with advanced diabetic nephropathy, as indicated by the presence of proteinuria or chronic renal failure/end-stage renal disease, while control subjects were normoalbuminuric, despite >6 years of diabetes. None of the individual markers showed significant disease association when considered on their own. However, haplotype analyses revealed a near doubling in the prevalence of the A.T.D risk haplotype in case subjects (0.136) compared with control subjects (0.075) (P = 0.009), thus providing first evidence for a disease haplotype for advanced diabetic nephropathy at the ACE locus.

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