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DOI: 10.2337/db06-0698
© 2007 by the American Diabetes Association
A Functional Polymorphism in the Manganese Superoxide Dismutase Gene and Diabetic Nephropathy
1 Department of Clinical Sciences, Pediatrics, Clinical Chemistry, Umeå University, Umeå, Sweden
2 Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden
3 Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
4 Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland
5 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
6 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Address correspondence and reprint requests to A. Möllsten, Department of Clinical Sciences, Paediatrics, Umeå University, S-90185 Umeå, Sweden. E-mail: anna.mollsten{at}pediatri.umu.se
Abbreviations:
AER, albumin excretion rate; MnSOD, manganese superoxide dismutase; ROS, reactive oxygen species
Oxidative stress has been suggested to contribute to the development of diabetic nephropathy. Manganese superoxide dismutase (MnSOD) protects the cells from oxidative damage by scavenging free radicals. The demand for antioxidants is increased by smoking, which could disturb the balance between antioxidants and radicals. The present study aimed to determine whether a valine/alanine polymorphism in MnSOD (V16A, rs4880), alone or in combination with smoking, can contribute to development of diabetic nephropathy in 1,510 Finnish and Swedish patients with type 1 diabetes. Overt diabetic nephropathy (n = 619) was defined as having an albumin excretion rate (AER) >200 µg/min or renal replacement therapy; incipient diabetic nephropathy was defined as having an AER of 20–200 µg/min (n = 336). The control subjects had diabetes duration of 
20 years, without albuminuria (AER <20 µg/min) and without antihypertensive treatment (n = 555). In addition to male sex and elevated A1C, smoking was significantly associated with diabetic nephropathy (overt plus incipient), odds ratio (OR) 2.00 (95% CI 1.60–2.50). When controlling for age at onset, diabetes duration, A1C, smoking, and sex, the Val/Val genotype was associated with an increase in risk of diabetic nephropathy (1.32 [1.00–1.74], P = 0.049). When evaluating the combined effect of genotype and smoking, we used logistic regression with stratification according to smoking status and genotype. The high-risk group (ever smoking plus Val/Val genotype) had 2.52 times increased risk of diabetic nephropathy (95% CI 1.73–3.69) compared with the low-risk group, but no departure from additivity was found. Our results indicate that smoking and homozygosity for the MnSOD Val allele is associated with an increased risk of diabetic nephropathy, which supports the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.
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