Genetic polymorphisms in nitric oxide synthase 3 gene and implications for kidney disease: a meta-analysis.
OBJECTIVE
The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes.


METHODS
We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available.


RESULTS
A novel association was identified in the discovery collection (rs1800783, p(genotype) = 0.006, p(allele) = 0.002, OR = 1.26, 95% CI: 1.08-1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r² = 0.96 with rs1800783) in the replication collection (p(genotype) = 0.002, p(allele) = 0.0006, OR = 1.27, 95% CI: 1.10-1.45).


CONCLUSIONS
The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene.
McKnight
A J
AJ
Nephrology Research Group, Centre for Public Health, Queen's University of Belfast, Belfast, UK. a.j.mcknight@qub.ac.uk
Patterson
C C
CC
Sandholm
N
N
Kilner
J
J
Buckham
T A
TA
Parkkonen
M
M
Forsblom
C
C
Sadlier
D M
DM
Groop
P H
PH
Maxwell
A P
AP
D000483:Alleles; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011507:Proteinuria; D012307:Risk Factors
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III