Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.
OBJECTIVE
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.


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 microg/min (n = 336). Overt DN = AER>200 microg/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 microg/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.
Möllsten
Anna
A
Department of Clinical Sciences, Umeå University, Umeå, Sweden. anna.mollsten@pediatri.umu.se
Wessman
Maija
M
Svensson
Maria
M
Forsblom
Carol
C
Parkkonen
Maikki
M
Brismar
Kerstin
K
Groop
Per-Henrik
PH
Dahlquist
Gisela
G
D000328:Adult; D000419:Albuminuria / Q000235:genetics*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D005387:Finland; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D013223:Statistics as Topic; D011795:Surveys and Questionnaires; D013548:Sweden; D013997:Time Factors
D005819:Genetic Markers; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III