Study of cis and trans interactions between extended HLA‐haplotypes in insulin‐dependent diabetes

Abstract

From the study of HLA, A, B, C, DR, Bf and C4A, C4B alleles in 287 insulin-dependent diabetes mellitus patients and 108 controls, comparisons were made between 424 diabetic and 216 normal extended haplotypes. In the "cis" situation (haplotype), the highest relative risks (RR) for IDDM were borne by multiloci allelic associations, mainly DR/complement alleles, rather than by DR3 or DR4 considered alone. Susceptibility was strongly associated with two extended haplotypes (Aw30, Cw5, B18, C4BQ0, C4A3, BfF1, DR3 and A2, Cw3, B15, C4Bx, C4A3, BfS, DR4) or their smaller segments. Two haplotypes, S31 associated with DR2 or DR5 and F31 associated with DRw6 or DR7 had a protective effect. In the "trans" situation (opposite haplotype) the large excess of DR3/DR4 heterozygotes was not the only distortion observed. An excess of DR1 (57%) and of C4BQ0 (40%) was noted among non DR3, non DR4 haplotypes in diabetics compared to normal individuals (26% and 23%, respectively, P less than 0.01, 0.05). Homozygotes for DR3 or DR4 were not increased, and other homozygotes were decreased compared to controls. The protective antigens HLA DR2, DR5 and DR7 seemed not to be distributed randomly: their putative protective effect was not observed in the case of combination with DR1 or a B18, DR3 haplotype. DR2 was never found homozygous or combined with DR5. These results suggest that susceptibility to IDDM is generated by both cis and trans interactions between genes or gene products of the HLA region.

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

“…No difference was observed between the patients of simplex and multiplex families with respect to B15 and complement allotypes of paternal and maternal DR4 haplotypes which were comparable to those described elsewhere [4].…”

“…This could possibly be a consequence of the strong association between Type 1 diabetes and the DR3, DR4 heterozygous state [2][3][4]6], not observed for other DR3 and DR4 phenotypes. Thus, in DR3, DRX and DR4, DRX phenotypes, a secondary enhancing event may not become visible.…”

“…The risk for disease is greater in both unrelated subjects and in siblings of diabetic children [1][2][3][4][5][6][7][8] with a heterozygous DR3, DR4 phenotype. These observations have led to the hypothesis that two susceptibility genes associated with the DR3 and DR4 haplotype are involved in the inheritance of the disease [2,[9][10][11][12][13].…”

“…The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.Key words: Type 1 (insulin-dependent) diabetes mellitus, HLA DR3, 4, shared haplotypes, segregation, multiple affected siblings, risk for siblings, maternal effect.Susceptibility to Type 1 (insulin-dependent) diabetes mellitus is associated with the HLA antigens, DR3 and DR4 [1][2][3][4] in Caucasian populations. The risk for disease is greater in both unrelated subjects and in siblings of diabetic children [1-8] with a heterozygous DR3, DR4 phenotype.…”

“…Susceptibility to Type 1 (insulin-dependent) diabetes mellitus is associated with the HLA antigens, DR3 and DR4 [1][2][3][4] in Caucasian populations. The risk for disease is greater in both unrelated subjects and in siblings of diabetic children [1][2][3][4][5][6][7][8] with a heterozygous DR3, DR4 phenotype.…”