CHROMOSOME 7Q35 AND SUSCEPTIBILITY TO DIABETIC MICROVASCULAR COMPLICATIONS

Aldose reductase (ALR2), the first enzyme of the polyol pathway, may p lan an important role in the pathogenesis of diabetic microvascular co mplications, The gene coding for ALR2 has been localized to chromosome 7q35. Using an ALR2 probe in conjunction with the restriction endonuc lease Bam-HI, we have investigated the ALR2 locus of 128 patients with type I diabetes. A significant decrease in the frequency of the 8.2 k ilobase (kb) Bam-HI ALR2 genotype and 8.2 kb allele was found in patie nts with nephropathy (nephropaths) compared to those with retinopathy alone (retinopaths) (p < 0.05 and 0.25, respectively). We have previou sly shown that an RFLP of the T-cell antigen receptor constant beta-ch ain (TCRBC) locus, which is also localized to chromosome 7q35, is stro ngly associated with susceptibility to microvascular complications. Th e 128 patients were genotyped using the restriction endonuclease Bgl-I I and a TCRBC probe. The 10/9.2-8.2 kb TCRBC-ALR2 genotype was signifi cantly decreased in the nephropaths compared to the retinopaths (13.7% versus 43.6%, chi(2) = 10.1, P < 0,0025). The 10/9.2 and 9.2/9.2 kb T CRBC-ALR2 haplotypes were increased in the nephropaths compared to the retinopaths (32.5% versus 8.9% chi(2) = 10.9, p < 0,001). These resul ts suggest that chromosome 7q35 harbors a gene(s) that is involved in the pathogenesis of microvascular complications. Interestingly, the ge ne coding for endothelial nitric oxide synthase has recently been loca lized to the same chromosomal region as ALR2.