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Abstract
Background and aims. The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO‐production can be affected by polymorphisms in the endothelial NO‐synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients.
Patients and methods. A total of 1510 Finnish and Swedish T1D patients were included in a cross‐sectional case‐control study. Incipient DN was defined as an albumin excretion rate (AER) of 20–200 µg/min (n = 336). Overt DN = AER>200 µg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration ⩾20 years, AER<20 µg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983).
Results. Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu‐allele of the Glu298Asp‐polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12–1.91). The variables smoking (OR = 2.13; 95% CI = 1.63–2.78), male sex (OR = 1.61; 95% CI = 1.23–2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02–1.03), systolic (OR = 1.05; 95% CI = 1.04–1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02–1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a‐allele was not associated with DN.
Conclusions. The Glu/Glu‐genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.
| Abbreviations | ||
| T1D | = | type 1 diabetes |
| DN | = | diabetic nephropathy |
| NO | = | nitric oxide |
| eNOS | = | endothelial nitric oxide synthase |
| NOS3 | = | endothelial nitric oxide synthase gene |
| OR | = | odds ratio |
| Abbreviations | ||
| T1D | = | type 1 diabetes |
| DN | = | diabetic nephropathy |
| NO | = | nitric oxide |
| eNOS | = | endothelial nitric oxide synthase |
| NOS3 | = | endothelial nitric oxide synthase gene |
| OR | = | odds ratio |
Acknowledgements
This project was supported by grants from the Swedish Medical Research Council (project number 07531), Swedish Diabetes Association, Swedish Diabetes Foundation, Samaritan Foundation, Swedish Society of Medicine, Swedish Society of Nephrology, Children's Diabetes Foundation, Sven Jerring Foundation, Oskar Foundation, Ronald McDonalds Child Foundation and Family E. Persson Foundation, Folkhälsan Research Foundation, Wilhelm and Else Stockmann Foundation, the Research Funds of the Helsinki University, Sigrid Juselius Foundation, the Academy of Finland (00213 to MW) and Liv och Hälsa.
We wish to thank Dr E‐L Stattin, Nurse E Sjöström‐Fahlén, Professor JW Eriksson, Umeå University hospital, Biomedical Laboratory Technologists E‐L Forsberg, A Skogholm and A Reinholdsson, Karolinska Hospital, for their kind help with collecting the samples.
We warmly thank all the patients participating in the FinnDiane Study and gratefully acknowledge the assistance of the members of the Finnish Diabetic Nephropathy Study Group [35].