specific association of hladr4 with increased prevalence and level of insulin autoantibodies in firstdegree relatives of patients with type i diabetes firstdegree relatives of patients with insulindependent type i diabetes n 264 from 106 families were evaluated with hla typing and determination of competitive insulin autoantibodies ciaas and islet cell autoantibodies icas the levels of ciaas in 30 relatives exceeded our upper limit of normal greater than or equal to 39 numl and 30 had hightiter icas greater than or equal to 40 juvenile diabetes foundation units jdf u eleven of the hlatyped relatives developed diabetes during followup twentythree percent 28 of 123 of the relatives with at least one hladr4 allele were ciaa ciaa greater than or equal to 39 numl versus 4 6 of 141 among dr4 relatives p less than 00001 twentyone of 22 of the highest ciaa values were all in the dr4 group dr4 vs dr4 p 0003 wilcoxons ranksum test hladr3 did not correlate with the level of ciaas and neither dr3 nor dr4 correlated with titer of icas measured in jdf u we conclude that in firstdegree relatives of patients with type i diabetes there is a striking association with hladr4 in both the prevalence of relatives exceeding the normal ciaa range and in the level of ciaas these data suggest that a gene on hladr4 haplotypes contributes to the level of antiinsulin autoimmunity and we hypothesize that dr4associated diabetes susceptibility distinct from dr3associated susceptibility may be secondary to this influence