Genetic susceptibility factors of Type 1 diabetes in Asians

Abstract

Type 1 diabetes is a multifactorial disease in which the insulin producing beta-cells of the pancreas are destroyed by the immune system, a process determined by the activity of major histocompatibility complex (MHC)-restricted T lymphocytes. Progress has been made in elucidating genetic factors involved in Type 1 diabetes in Caucasians, with less data available from Asia. For Asians, the human MHC locus (HLA region), especially the class II region, is the major susceptibility interval. The role of IDDM2, the insulin locus, has been questioned in Asia. In contrast to Caucasians, Asian populations have a very low incidence of Type 1 diabetes (0.4-1.1 cases/year/100 000 individuals). This low incidence rate in the Asian population may be related to the population frequency distribution of susceptible Type 1 diabetes genes, especially of HLA. The overall risk for Type 1 diabetes from HLA DR and DQ is determined by polymorphic residues (alleles) and particular combinations of alleles (haplotypes and genotypes) in a given individual. In Asians, it is very common that a protective DR4 allele is associated with susceptible DQ alleles while neutral/protective DQ alleles are associated with the susceptible DR4 alleles. Our analyses indicate that the counterbalancing between susceptible DRB1 and protective DQB1, and vice versa, is a factor that may contribute to the low incidence of diabetes in Asians. We find that identical HLA DRB1-DQB1 haplotypes of Asians and Caucasians have similar transmission to diabetic children and similar associations with diabetes. Moreover, the association with diabetes and transmission to a diabetic offspring of DR4 haplotypes varies depending on the haplotype borne on the homologous chromosome. This might contribute not only to the synergistic effect of DR3/4, but also to the susceptibility influence of DQB1*0401 haplotypes confined to DR4/X. High-risk DR4 subtypes were predominant in DR4/X, whereas protective DR4 subtypes were observed mainly in the DR3/4 genotype. Since in Asians DQB1*0401 is in linkage disequilibrium (LD) with DRB1*0405, we find more DRB1*0405-DQB1*0401 haplotypes in patients with DR4/X than in patients with DR3/4, suggesting that the contribution of the DRB1 locus may be greater in DR4/X than in DR3/4 genotypes. Several genome scans suggested additional susceptibility intervals and provided supporting evidence for several previously reported linkages. Other studies focused on the confirmation of linkage using multipoint sib-pair analyses with densely spaced markers and multiethnic collection of families. Although significant and consistent linkage evidence was reported for the susceptibility intervals IDDM12 (on 2q33) even in Asia, evidence for most other intervals varies in different data sets. LD mapping has become an increasingly important tool for both confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations. The examination of large and ethnically varied data sets including those of Asia has allowed identification ...

Genetic control of autoimmunity in Type I diabetes and associated disorders

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Association between (AC)n dinucleotide repeat polymorphism at the 5′-end of the aldose reductase gene and diabetic nephropathy: a meta-analysis

“…Type 1 diabetes is mainly characterized by the destruction of islet b-cells by the immune system, a process determined by the activity of major histocompatibility complex (MHC)-restricted T lymphocytes. The MHC locus (human leukocyte antigen (HLA) region) is the major susceptibility interval of the disease (Park & Eisenbarth 2001). Type 2 diabetes represents a complex and heterogeneous group of disorders, which has genetic heterogeneity underlying the common phenotypic endpoint of elevated blood glucose level, likely involving a large number of contributing genes (Tusié Luna 2005).…”

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“…Estes grupos diferiram quanto à distribuição da cor da pele. A inexistência da etnia amarela no grupo diabético não foi um achado inesperado, considerando que o DM tipo 1 ainda é uma doença rara entre os orientais (25). A associação da idade ao índice CPO-D na faixa etária estudada também era esperada, sendo conhecida a crescente incidência da cárie até que se atinja a idade adulta.…”