NOS3 polymorphisms are associated with arterial stiffness in children with type 1 diabetes.
OBJECTIVE
Type 1 diabetes is associated with endothelial dysfunction, arterial stiffness, and an increased risk of cardiovascular disease (CVD) events. We previously demonstrated increased arterial stiffness in children with type 1 diabetes compared with control subjects. However, traditional CVD risk factors did not explain the difference in arterial stiffness. Furthermore, children with type 1 diabetes displayed notable within-group variation in arterial stiffness. We hypothesized that polymorphisms in the NOS3 gene may be associated with the differences seen in arterial stiffness within the population of children with type 1 diabetes.


METHODS
Thirty-six consecutively enrolled subjects aged 10-21 years with type 1 diabetes were studied. Subjects underwent radial tonometry in a fasting state. A corrected augmentation index (AI75) was the primary measure of arterial stiffness. Genotypes were determined for the NOS3 -786T-->C and Glu298-->Asp polymorphisms by pyrosequencing. AI75 values by genotype groups were compared by ANOVA and multivariate analysis.


RESULTS
Median (interquartile range) AI75 values for -786TT and -786C carriers were -3.5 (-8.8 to 2.3) and 11.0 (6.0 to 14.4), respectively (P = 0.01); AI75 values for Glu298Glu patients and Asp298 carriers were 2.3 (-4.0 to 13.0) and 7.3 (-2.0 to 11.5), respectively (P = 0.59). In univariate analysis, age, sex, BMI percentile, and -786T-->C genotype were significantly associated with AI75. The multivariate model, which included these four variables, was significantly associated with AI75 (P = 0.002, R2 = 0.40).


CONCLUSIONS
This is the first reported association between -786T-->C and arterial stiffness in type 1 diabetes. Larger studies are needed to confirm this observation for potential translation to risk assessment.
Zineh
Issam
I
Department of Pharmacy Practice and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, Florida, USA.
Beitelshees
Amber L
AL
Haller
Michael J
MJ
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001157:Arterial Occlusive Diseases / Q000201:enzymology / Q000235:genetics*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D015999:Multivariate Analysis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III