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

Diabetologia. 2006 Dec;49(12):2892-9. doi: 10.1007/s00125-006-0436-8. Epub 2006 Oct 3.


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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / genetics
  • Amino Acid Substitution
  • Aryldialkylphosphatase / genetics*
  • Blood Pressure
  • Creatinine / blood
  • Creatinine / urine
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / enzymology
  • Diabetic Nephropathies / genetics*
  • Disease Progression
  • Ethnicity
  • Female
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Polymorphism, Single Nucleotide


  • Creatinine
  • Aryldialkylphosphatase