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OBJECTIVE-The vascular ectonucleotidase ENTPDl protects against renal injury and modulates glucose homeostasis in mouse models. We sought to determine whether human variation in ENTPDl influences predisposition to diabetes or diabetic nephropathy.
RESEARCH DESIGN AND METHODS-We analyzed ENTPDl single nucleotide polymorphisms (SNPs) in 363 African American control subjects, 380 subjects with type 2 diabetes and end-stage renal disease (DM-ESRD), and 326 subjects with ESRD unrelated to diabetes (non-DM-ESRD). Using human cell lines, we correlated disease-associated ENTPDl haplotypes with ENTPDl gene expression. Finally, we studied consequences of ENTPDl deletion in a mouse model of type 2 diabetes (db/db).
RESULTS-A common ENTPDl two-SNP haplotype was associated with increased risk for DM-ESRD (P = 0.0027), and an uncommon four-SNP haplotype was associated with protection against DM-ESRD (P = 0.004). These haplotypes correlated with ENTPDl gene expression levels in human cell lines in vitro. Subjects with high ENTPD 1 -expressing haplotypes were enriched in the DM-ESRD group. By crossing ENTPDl -null mice with db mice, we show that ENTPDl deletion has prominent effects on metabolic syndrome traits. Specifically, deletion of ENTPDl lowered glucose levels in control (db/-) mice with one functional leptin receptor and dramatically lowered weights in db/db mice with no functional leptin receptors. Similar effects were seen in aged ENTPDl-null mice with normal leptin receptors.
CONCLUSIONS-ENTPD1 polymorphisms appear to influence susceptibility to type 2 diabetes and/or diabetic nephropathy in African Americans. Studies in human cell lines and in vivo mouse data support a potential role for ENTPDl genetic variation in susceptibility to type 2 diabetes. Diabetes 58:999-1006, 2009
Diabetes and its complications are enormous sources of mortality, morbidity, and cost in the U.S. African Americans are especially prone to diabetes and diabetic kidney disease (1). Genetic variation plays a major role in susceptibility to both development of diabetes and onset of diabetic renal injury (2,3). Finding genes responsible for this predisposition to disease could help predict who may be at high risk and also identify important pathways involved in disease pathogenesis.
ENTPD1, also known as CD39, is an ectonucleotidase that hydrolyzes ATP and ADP to AMP, initiating an enzymatic cascade that leads to the generation of adenosine (4). By regulating nucleotide levels, ENTPDl controls the activity of both purinergic receptors (P2X and P2Y) and downstream adenosine (Pl)...