Top

10-03-2006 | Nephropathy | Article

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76

Journal: Diabetologia

Authors: R. Calle, M. I. McCarthy, P. Banerjee, E. Zeggini, C. A. Cull, K. I. Thorne, S. Wiltshire, S. Terra, D. Meyer, J. Richmond, J. Mancuso, P. Milos, D. Fryburg, R. R. Holman

Publisher: Springer-Verlag

Abstract

Aims/hypothesis

Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes.

Methods

We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors.

Results

rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54–0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11–1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27–0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus.

Conclusions/interpretation

We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

National Institute of Diabetes and Digestive and Kidney Diseases B, MD (2003) United States Renal Data System Annual Report 2003

Rippin JD, Patel A, Bain SC (2001) Genetics of diabetic nephropathy. Best Pract Res Clin Endocrinol Metab 15:345–358PubMedCrossRef

Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN (1996) The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 33:498–507PubMedCrossRef

Mochizuki H, Scherer SW, Xi T et al (1998) Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. Gene 213:149–157PubMedCrossRef

Ng CJ, Wadleigh DJ, Gangopadhyay A et al (2001) Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 276:44444–44449PubMedCrossRef

Lee HB, Yu M-R, Yang Y, Jiang Z, Ha H (2003) Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. J Am Soc Nephrol 14:S241–S245PubMedCrossRef

Hinokio Y, Suzuki S, Hirai M, Suzuki C, Suzuki M, Toyota T (2002) Urinary excretion of 8-oxo-7,8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy. Diabetologia 45:877–882PubMedCrossRef

Kakimoto M, Inoguchi T, Sonta T et al (2002) Accumulation of 8-hydroxy-2′-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats. Diabetes 51:1588–1595PubMed

Pinizzotto M, Castillo E, Fiaux M, Temler E, Gaillard RC, Ruiz J (2001) Paraoxonase 2 polymorphisms are associated with nephropathy in type II diabetes. Diabetologia 44:104–107PubMedCrossRef

10.

Hodgkinson AD, Millward BA, Demaine AG (2002) Response to: Pinizzotto M, Castillo E, Fiaux M, Temier E, Gaillard RC, Ruiz J (2001) Paraoxonase 2 polymorphisms are associated with diabetic nephropathy in type II diabetes. Diabetologia 44:104–107. Diabetologia 45:933–935

11.

Ioannidis JPA, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis JG (2003) Genetic associations in large versus small studies: an empirical assessment. Lancet 361:567–571PubMedCrossRef

12.

UK Prospective Diabetes Study Group (1991) UK Prospective Diabetes Study (UKPDS) VIII: Study design, progress and performance. Diabetologia 34:877–890CrossRef

13.

UK Prospective Diabetes Study Group (1994) UK Prospective Diabetes Study (UKPDS) XI: Biochemical risk factors in type 2 diabetic patients at diagnosis compared with age-matched normal subjects. Diabet Med 11:534–544CrossRef

14.

UK Prospective Diabetes Study Group (1993) UK Prospective Diabetes Study (UKPDS) X: urinary albumin excretion over 3 years in diet-treated type 2 (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia. Diabetologia 36:1021–1029CrossRef

15.

UKPDS Group (1998) UK Prospective Diabetes Study 30: diabetic retinopathy at diagnosis of type 2 diabetes and associated risk factors. Arch Ophthalmol 116:297–303

16.

Canani LH, Araki S, Warram JH, Krolewski AS (2001) Comment to: Pinizzotto M, Castillo E, Fiaux M, Temler E, Gaillard RC, Ruiz J (2001) Paraoxonase 2 polymorphisms are associated with diabetic nephropathy in type II diabetes. Diabetologia 44:104–107. Diabetologia 44:1062–1064

17.

Kockum I, Lernmark A, Dahlquist G et al (1996) Genetic and immunological findings in patients with newly diagnosed insulin-dependent diabetes mellitus. The Swedish Childhood Diabetes Study Group and the Diabetes Incidence in Sweden Study (DISS) Group. Horm Metab Res 28:344–347PubMedCrossRef

18.

Caramori ML, Fioretto P, Mauer M (2000) The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? Diabetes 49:1399–1408PubMed

19.

Nosadini R, Velussi M, Brocco E et al (2000) Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 49:476–484PubMed

20.

UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRef

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform.

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »