Susceptibility to Type 1 (insulin-dependent) diabetes mellitus in Spanish patients correlates quantitatively with expression of HLA-DQ ? Arg 52 and HLA-DQ ? non-Asp 57 alleles

Abstract

HLA-DQ alpha and beta alleles were chosen as the most sensitive Type 1 (insulin-dependent) diabetes mellitus susceptibility markers for evaluating the disease associations and Type 1 diabetes risk in a population-based registry from Madrid. The absence of aspartic acid in position 57 of the DQ beta chain (non-Asp 57), and the presence of arginine in position 52 of the DQ alpha chain (Arg 52) were found to be reliable markers of Type 1 diabetes susceptibility among the Spanish population, with significantly higher frequencies among the cases of Type 1 diabetes compared to randomly selected non-diabetic control subjects from the general Madrid population. While non-Asp 57 homozygosity conferred an absolute risk of 32.3 per 100,000 per year and Arg 52 of 31.5 per 100,000 per year, the risk for double homozygotes for both non-Asp 57 and Arg 52 was estimated as 101.7 per 100,000 per year. Individuals homozygous for only one of these alleles, and heterozygous at the other locus, had a markedly lower Type 1 diabetes risk (12.8 per 100,000 per year), approximating the general population incidence for Madrid. Thus, susceptibility to Type 1 diabetes in Spanish patients is associated, quantitatively, with non-Asp 57 DQ beta and Arg 52 DQ alpha alleles.

Genetics of Type 1A Diabetes

“…It was hypothesized that the presence of aspartic acid at position 57 of the DQ-beta chain determines protection from diabetes (Morel et al, 1988). Further reports suggested that an arginine at position 52 of the DQ-alpha chain determined susceptibility to type IA diabetes, as it is found on the DQA1*0301-DQB 1*0302 and DQA I*050 1 -DQB 1*020 1 haplotypes (Gutierrez-Lopez, 1992;Khalil et al, 1990Khalil et al, ,1992. However, the DQAl*0401-DQB1*0402 haplotype is also associated with diabetes risk.…”

Superantigens in insulin-dependent diabetes mellitus

“…Genetic predisposition to IDDM was found to increase proportionally with the number of both a-and/3-susceptible alleles present at the cell surface of activated T and B cells in a given individual [63,88].…”

Molecular mechanisms involved in the etiology and pathogenesis of autoimmune diseases

“…Recently, a new, more sensitive approach was conceived in which two diallelic systems are used for determining the IDDM association [31,33]. The first marker determination examines position 57 of the DQ fl-chain for Asp/non-Asp status, while the second determination examines position 52 of the DQ e-chain for Arg/non-Arg status.…”

“…It is interesting, however, to mention that there is a hierarchical scale of susceptibility within both the group of the non-Asp 57 and the group of Arg 52 alleles, as the susceptibility conferred by the individual alleles of each group is not equally strong. The same consideration is valid for the groups of the Asp 57 and non-Arg 52 alleles and the degree of protection they confer [31,33,62]. In the heterozygotes, a sort of competition for the antigen might take place between different molecules, with certain alleles of one group prevailing in their effects over alleles of the other group.…”