Paraoxonase gene cluster is a genetic marker for early microvascular complications in Type 1 diabetes

Abstract

Background: Paraoxonase is a serum enzyme, which prevents oxidation of low-density lipoprotein (LDL) by hydrolyzing lipid peroxides. Two polymorphisms in PON1 gene have been associated with cardiovascular and microvascular diseases in both diabetic and non-diabetic patients. Aims: The current project was designed to investigate the association between the polymorphisms of two PON genes and diabetes microvascular diseases (retinopathy and microalbuminuria) and any potential linkage between Met54Leu of PON1 and Cys311Ser ofPON2 gene. Methods: Diabetic retinopathy and albumin excretion rate were assessed in 372 adolescents with Type 1 diabetes who were genotyped for the two polymorphisms. Results: We confirmed the increased susceptibility for diabetic retinopathy for the Leu/Leu genotype (odds ratio (OR) 3.34 (confidence interval (CI) 1.95, 5.75), P < 0.0001). The Ser/Ser genotype was significantly more common in those patients with microalbuminuria (albumin excretion rate ≥ 20 μg/min) compared with those with albumin excretion rate < 20 μg/min (OR 4.72 (CI 2.65, 8.41),P < 0.0001). The Ser311 ofPON2 was in strong linkage disequilibrium with Leu54 of PON1 gene (δ = 23 × 104,P < 0.001). The delta value was higher for those without complications (28 × 104,P < 0.001) compared with those with complications (15.5 × 104,P < 0.001). Conclusions: This study supports the hypothesis that diabetic microangiopathy is genetically heterogeneous. PON1 Leu/Leu increases the risk for retinopathy and PON2 Ser/Ser increases the risk for microalbuminuria.