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The aim of this study was to investigate whether or not the inherited polymorphism of complement C4 is associated with genetic susceptibility to microvascular complications in IDDM as previously reported.We determined C4 phenotypes in 241 patients with IDDM and 140 healthy control subjects by agarose gel electrophoresis and immunoprecipitation. C4 allotype frequencies were compared between patients and healthy control subjects. In addition, we compared allotype frequencies of 83 patients with nephropathy with those of 80 patients without nephropathy and compared those of 50 patients with proliferative retinopathy with those of 68 patients without retinopathy or background retinopathy. Duration of IDDM in control patients was at least 21 years.Patients and healthy control subjects differed at both the C4A (P less than 0.00001) and C4B (P less than 0.0005) loci. The C4 null allele C4AQ0 was significantly increased in IDDM patients (26.8 vs. 11.8 percent, P less than 0.005). C4B2 was more frequently observed in patients (14.5 vs. 6.8 percent, P less than 0.05) compared with healthy control subjects. No differences were observed in C4 allotype distribution between patients with and without nephropathy or retinopathy.These data confirm previous reports of an association between the C4 null allele C4AQ0 and IDDM. Our results do not support an association of the inherited polymorphism of complement C4 with genetic susceptibility to microvascular complications in patients with IDDM.