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Risk for Cardiovascular Autonomic Neuropathy Is Associated with the HLA-DR3/4 Phenotype in Type I Diabetes Mellitus

Joshua Barzilay, MD; James H. Warram, MD, SCD; Lawrence I. Rand, MD; Michael A. Pfeifer, MD; and Andrzej S. Krolewski, MD, PhD
[+] Article and Author Information

Grant Support: In part by the National Institutes of Health (grants DK-41526 and EY-02636) and by the Joslin Diabetes Center.

Requests for Reprints: Andrzej S. Krolewski, MD, PhD, Section on Epidemiology & Genetics, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215.

Current Author Addresses: Dr. Barzilay: Kaiser Permanente, Northlake Medical Offices, 4053 LaVista Road, Tucker, GA 30084.

Drs. Warram, Rand, Krolewski: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215.

Dr. Pfeifer: Diabetes Research and Analysis Association, Inc., One Plaza East, 101 Prosperous Place, Suite 360, Lexington, KY 40509.


© 1992 American College of PhysiciansAmerican College of Physicians


Ann Intern Med. 1992;116(7):544-549. doi:10.7326/0003-4819-116-7-544
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Objective: To identify risk factors for the development of cardiovascular autonomic neuropathy in patients with juvenile-onset type I diabetes mellitus.

Design: Cross-sectional examination of an inception cohort 15 to 21 years after the onset of diabetes.

Setting: Outpatient diabetes clinic.

Patients: Seventy-nine patients with type I diabetes who experienced onset of disease before 21 years of age and who were followed for 15 to 21 years.

Measurements: Autonomic nerve function was evaluated in all patients using deep breathing and tilt tests. On the basis of these tests, an index of cardiovascular autonomic neuropathy was derived and patients were classified as having intact, mildly impaired, or significantly impaired autonomic function.

Results: The group with significantly impaired function had a higher mean hemoglobin A1 at the time of examination than the group without impairment, yet the groups did not differ regarding glycemie control during the first decade of diabetes. The HLA-DR3/4 phenotype was present in more than 50% of the patients with significant autonomic dysfunction and conferred relative odds of 6.2 (95% Cl, 1.7 to 23.3) for the development of autonomic neuropathy when compared with other HLA-DR phenotypes. Sex, percent ideal body weight, and smoking did not have a statistically significant effect on the development of autonomic neuropathy.

Conclusions: The development of cardiovascular autonomic neuropathy in type I diabetes mellitus is strongly associated with the HLA-DR3/4 phenotype. Thus, genetic predisposition may play an important role in the development of this complication.

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