Relation of gene expression (allotypes) of the fourth component of complement to insulin dependent diabetes and its microangiopathic complications.

About a quarter of insulin dependent diabetics have low concentrations of the fourth component of complement (C4), and a low concentration of C4 is associated with diabetic microangiopathy. The variability of the expression of the C4 gene was compared in insulin dependent diabetics with and without microangiopathy and controls. Of the two genes coding for C4, the A gene (C4A) was not expressed--that is, C4A null--in 16 (13%) of the 126 insulin dependent diabetics compared with none of the 93 controls (p less than 0.001), and all these 16 subjects had low concentrations of C4. Lack of expression of the other C4 gene (C4B) was not associated with insulin dependent diabetes, but a rare variant, C4B3, was significantly increased in the diabetics (21/126; 17%) compared with the controls (none) (p less than 0.001). The prevalence of C4B3 was also increased in the diabetics with complications when compared with those without (14/50 (28%) v 7/76 (9%), p less than 0.01). Low plasma C4 concentrations in insulin dependent diabetics are at least partly due to variation in the expression of the C4 gene. The association of the rare C4B3 variant with microangiopathy suggests a genetic component of its aetiology.