Association between PON 1 polymorphisms, PON activity and diabetes complications.
The paraoxonase (PON) gene cluster maps to human chromosome 7q21-22. In the PON 1 gene, several polymorphisms in the promoter and coding regions have been identified and are known to influence gene expression levels. Promoter polymorphisms have been shown to have the strongest influence on paraoxonase activity levels. Paraoxonase, a high-density lipoprotein associated enzyme, protects lipoproteins from oxidation. Lipid oxidation may play an important role in the development of micro- and macrovascular disease. There is evidence that paraoxonase activity is reduced in patients with diabetes. We therefore hypothesise that PON 1genotypes influence paraoxonase activity levels and increase the risk of microvascular disease in type 1 diabetes. Genotyping of 156 Caucasian adolescents with diabetes for seven PON 1 polymorphisms was performed, including that of a novel PON 1 promoter polymorphism A(-1074)G. PON genotypes were related to paraoxonase and arylesterase activities and diabetes complication status. There was strong linkage disequilibrium between the PON 1 promoter polymorphisms. Both promoter and coding region polymorphisms strongly influenced activity levels and were associated with diabetes complications. PON 1 genotypes Leu/Leu 54, AA(-162) and GG(-1074) were associated with higher urinary albumin loss, while the genotype GG(-907) was protective for retinopathy.
Hofer
Sabine E
SE
Department of Endocrinology, The Children's Hospital at Westmead and University of Sydney, Sydney, Australia. sabine.e.hofer@uibk.ac.at <sabine.e.hofer@uibk.ac.at>
Bennetts
Bruce
B
Chan
Albert K
AK
Holloway
Bethwyn
B
Karschimkus
Connie
C
Jenkins
Alicia J
AJ
Silink
Martin
M
Donaghue
Kim C
KC
D000293:Adolescent; D000328:Adult; D000419:Albuminuria / Q000201:enzymology / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications / Q000201:enzymology / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic
D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human