In the genetically homogeneous Danish population, 27 HLA-DR3,4 heterozygous patients with
insulin-dependent diabetes mellitus (
IDDM) and 19 DR3,4 heterozygous controls without family history of
IDDM were investigated for HLA-region markers and Gm and Km
immunoglobulin allotypes. The aim was to define susceptibility factors for
IDDM development other than
HLA-DR using a number of techniques: lymphocytotoxicity (
HLA-DR and DQ
antigens), cellular methods (Dw and DP typing), restriction fragment length polymorphism (DQ alleles), electrophoresis and immunofixation (BF and C4 allotypes), and passive hemagglutination inhibition (Gm and Km
immunoglobulin allotypes). The
complement allotype C4A3 and the
HLA-DQw8 (DQw3.2)
antigen were found in all of the patients, whereas this was the case for only 8 of the 19 controls (P = 6 x 10(-6)): five lacked C4A3, five others lacked DQw8, and one of the controls lacked both of these factors. Fourteen of the patients had the
complement allotype C4B3 versus three of the controls (P = 0.01). Previously reported family studies suggest that these alleles are part of the following haplotype: B15, BFS, C4A3, C4B3, DR4, Dw4, DQw8, and these factors were found together in ten of the patients versus one of the controls (P = 0.01). The markers usually associated with DR3 did not show significant differences between
IDDM patients and controls, and the non-HLA markers studied showed no significant deviation from what was expected. In addition to the susceptibility factor DQw8, the study suggests the existence of susceptibility genes for
IDDM near the
complement C4 genes on DR4-carrying haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)