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To the Editor: The development of diabetic retinopathy has been related to hyperglycemia-induced oxidative stress.¹ Haptoglobin (HP) is 1 of many known antioxidant proteins and is encoded by 2 different alleles, whose products differ markedly in their antioxidant ability.² Patients who are homozygous for the 1 allele (HP 1-1) form dimeric HP molecules, whereas patients who are heterozygous (HP 1-2) or homozygous (HP 2-2) for the 2 allele form multimers of 2 or more HP molecules. These multimeric HP complexes are sterically hindered from binding to hemoglobin and also have less access to the extravascular space. Thus, we hypothesized that HP genotype may predict susceptibility to diabetic retinopathy.

Methods
We determined the HP genotype and assessed for the presence of diabetic retinopathy in 52 consecutive patients with type 1 diabetes mellitus of at least 10 years' duration who presented to an outpatient clinic at the Rambam Medical Center in Haifa, Israel. Sixty percent of the patients were Jewish, of either European or Middle Eastern descent, and 40% were Arabic. Haptoglobin genotype was determined from 10 µL of serum by gel electrophoresis.³ The presence of diabetic retinopathy was determined by 7-field stereoscopic fundal imaging. Patients were diagnosed as having diabetic retinopathy if there was evidence of macular edema, hard exudates, blot hemorrhages, microaneurysms, venous beading, intraretinal microvascular abnormalities, cotton-wool spots, or neovascularization.

Results
Twenty-five patients (48%) had evidence of diabetic retinopathy. The relationship of diabetic retinopathy to HP genotype is shown in Table 1. There was significantly lower prevalence of diabetic retinopathy in patients with the HP 1-1 genotype vs those with the HP 2-1 and 2-2 genotypes (1 of 12 vs 24 of 40; P<.002). There were no significant differences in the age, sex, hemoglobin A_IC, age of onset, or duration of diabetes between patients with and without the HP 1-1 genotype.

View this table: [in this window] [in a new window] Table. Number of Patients With Haptoglobin Genotype and Diabetic Retinopathy

Comment
The importance of HP genotype has been demonstrated in other diseases whose pathophysiology is linked to oxidative stress. For example, patients with the HP 2-2 genotype have a significantly higher prevalence of atherosclerotic coronary artery disease.³ We propose that increased protection against diabetic retinopathy provided by the HP 1-1 genotype is caused by the superior antioxidative and hemoglobin-binding capacity of the HP 1-1 genotype. We believe that a prospective trial of vigorous antioxidant therapy to prevent the development of diabetic retinopathy in patients with type 1 diabetes mellitus and the HP 2 allele would be warranted.

Farid M. Nakhoul, MD; Stuart Marsh, MD; Irit Hochberg, BS; Rina Leibu, MD; Benjamin P. Miller, MD; Andrew P. Levy, MD, PhD
Rappaport Faculty of Medicine and Research Institute
Technion-Israel Institute of Technology Rambam Medical Center
Haifa

1. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996;19:257-267. ABSTRACT 2. Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42:1589-1600. FREE FULL TEXT 3. Wassell J, Keevil B. A new method for haptoglobin phenotyping. Ann Clin Biochem. 1999;36:609-612.

Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Phil B. Fontanarosa, MD, Executive Deputy Editor.

JAMA. 2000;284:1244-1245.

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