Trends in Genetics
ReviewHLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved?
Section snippets
Type 1 diabetes
Diabetes mellitus is a group of heterogeneous disorders characterized by hyperglycaemia (high blood sugar). The incidence of these disorders is increasing worldwide.
Type 1 diabetes (previously called insulin-dependent diabetes mellitus; IDDM) can affect people in all age groups. It is a multifactorial disease involving multiple genes, with unidentified environmental factors contributing to the pathogenesis 2. Through what is believed to be an autoimmune process, the disease results in the
The HLA complex
The HLA complex is the major histocompatibility complex (MHC) in human and its complete sequence was presented in 1999 9. This, a milestone in our understanding of this complex, should facilitate further studies aimed at dissecting the complex nature of HLA associations with several complex diseases including type 1 diabetes. The HLA complex is a densely packed gene cluster containing at least 128 genes (not including the extended class I region where the number of genes is not known in detail)
HLA-DRB1, -DQA1 and -DQB1 genes are directly involved in the predisposition to type 1 diabetes
Type 1 diabetes was initially associated with some HLA class I alleles, namely the alleles encoding the B8 and B15 molecules 12., 13.. Later, a stronger association with the HLA class II alleles encoding DR3 and DR4 was found, and it was concluded that the class I associations observed previously were secondary to LD with these high-risk DR alleles 14., 15.. Similarly, B7 was found to be decreased among type 1 diabetes patients, and later this negative association was found to be even stronger
Analytical methods to look for additional disease susceptibility genes in the HLA complex
Several lessons should be learnt from the history of HLA associations in type 1 diabetes. First, one must expect to find associations with virtually all genes in the HLA complex because of LD with high-risk DR and DQ alleles. The important question is: are there other HLA complex genes that have effects independent or additional to the involved DR and DQ genes? To address this question, LD must be taken into account Box 2. One has to make sure that the potential associations observed are not
Are HLA complex genes other than DR and DQ involved in the predisposition to type 1 diabetes?
In the past few years, there have been several studies applying methods able to eliminate the effects of LD to DR and DQ genes. These studies have demonstrated that there are indeed additional genes in the HLA complex involved. Among the first to show this were Robinson et al.29 who applied the homozygous parent test to families with type 1 diabetes. They found evidence for heterogeneity in terms of genetic risk on different DR3 and DR4 haplotypes implying the presence of genetic susceptibility
Conclusion
The HLA complex is characterized by a high gene density, genetic complexity and strong LD. Several common complex genetic diseases, in particular most autoimmune diseases, have a major genetic component encoded within this complex. Current evidence suggests that, for type 1 diabetes, there are at least four genes involved. The class II genes DQA1, DQB1, DRB1 are the most important ones, but in addition there is at least one unidentified gene most probably located telomeric to the class
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The major histocompatibility complex: A model for understanding graft-versus-host disease
2013, BloodCitation Excerpt :Strong positive LD among SNPs gives rise to “blocks” of short SNP haplotypes that can be readily identified by genotyping 1 representative “tag SNP” for the block. TagSNPs that have portability across ethnically diverse populations are particularly powerful tools for mapping disease-susceptibility genes35-37 (Figure 138,39). The MHC is a prime region of interest for the exploration of novel GVHD determinants because of the density of genes with immune function that currently are not tested in routine clinical practice.11,40,41
Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations
2011, Veterinary JournalCitation Excerpt :One postulated mechanism for the large number of associations between autoimmune diseases and the class II genes is allele-specific presentation of autoantigens to T cells (Raymond et al., 2005; Thorsby and Lie, 2005; Ettinger et al., 2006). According to this theory, differential presentation of antigens (which allows presentation of autoantigens) is a consequence of the amino acid sequence in the peptide-binding cleft of the heterodimer (Holmdahl, 2000; Weyand and Goronzy, 2000; Zanelli et al., 2000; Undlien et al., 2001; Ettinger et al., 2006). However, since in multiple sclerosis, for example, all common HLA-DRB1 haplotypes are associated with either increased or decreased susceptibility, it is unlikely that the peptide sequence determines disease status (Ramagopalan and Ebers, 2009).
The pathophysiology of diabetes mellitus
2023, Management of Diabetes Mellitus Based on Natural ProductsAtlas of Diabetes Mellitus, Fourth Edition
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2023, The Diabetes Textbook: Clinical Principles, Patient Management and Public Health Issues, Second Edition