An association between a variant of PON-1 gene and diabetic microvascular complications

Y Kao 1,2 JF Knight 2 K Donaghue 1,3 A Chan 1 M Silink 1,3

1. Ray Williams Institute of Paediatric Endocrinology, Diabetes and Metabolism
2. Centre for Kidney Research, Royal Alexandra Hospital for Children, Westmead
3. University of Sydney

Serum paraoxonase is a glycoprotein which binds to high-density lipoproteins (HDL) and may prevent oxidation of low density lipoprotein (LDL) by hydrolysing lipid peroxides. LDL is toxic to retinal capillary endothelial cells and pericytes. A case-control study of early diabetic retinopathy found that those without retinopathy had higher HDL-cholesterol, which protects LDL from oxidation. The accumulation of modified HDL as well as LDL in the mesangium directly triggers intracellular events associated with mesangial cell proliferation, leading to the accumulation of extracellular matrix. LDL oxidation may therefore also be involved in diabetic nephropathy through this mechanism. Two polymorphisms identified in the paraoxonase gene (Met-Leu 54 and Gln-Arg 192) have been associated with cardiovascular disease. We have reported an association of the M/L 54 polymorphism with early diabetic retinopathy in adolescents (JCEM 1998, 83, 2589-92). The frequencies of allele L and L/L genotype were significantly higher in those with retinopathy than in those without retinopathy. The relative risk for retinopathy between L and M homozygotes was 10. The current project investigated the correlation between variants of PON1 and mild elevation of urine albumin excretion (>7.5mcg/min), considered the earliest sign of diabetic nephropathy. A total 235 patients with IDDM were divided into two subgroups according to timed albumin excretion rates: 156 patients <7.5mcg/min; 79 patients>7.5mcg/min. PCR-RFLP was used to determine the genotype of the M/L 54 PON1 polymorphism. Both genotype and haplotype were not significantly different between the two groups. Our results suggest that this variant of the PON1 gene is a risk factor for diabetic retinopathy but not for diabetic nephropathy.

Presented at the Australian and New Zealand Society of Nephrology, Brisbane, March 1999

Correspondence
Dr John Knight
jfk@xodkonja.com