NOS3 Polymorphisms Are Associated With Arterial Stiffness in Children With Type 1 Diabetes

  1. Issam Zineh, PHARMD1,
  2. Amber L. Beitelshees, PHARMD, MPH2 and
  3. Michael J. Haller, MD3
  1. 1Department of Pharmacy Practice and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, Florida
  2. 2Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
  3. 3Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida
  1. Address correspondence and reprint requests to Michael J. Haller, MD, Pediatric Endocrinology, P.O. Box 100296, Gainesville, FL 32610. E-mail: hallemj{at}


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.

RESEARCH DESIGN AND 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.


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    • Accepted November 22, 2006.
    • Received August 10, 2006.
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