Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy

Background. A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. Methods. We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean ± SD) 41 ± 10 years, diabetes duration 28 ± 8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43 ± 10 years, diabetes duration 27 ± 9 years). Results. Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P < 0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P = 0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (ε2/ε3/ε4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0.152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic ε4-allele compared with 12% in patients with the ε3,ε3 genotype, P < 0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. Conclusions. The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.