Trends in Genetics
Volume 17, Issue 2, 1 February 2001, Pages 93-100
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HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved?

https://doi.org/10.1016/S0168-9525(00)02180-6Get rights and content

Abstract

The predisposition to develop a majority of autoimmune diseases is associated with specific genes within the human leukocyte antigen (HLA) complex. However, it is frequently difficult to determine which of the many genes of the HLA complex are directly involved in the disease process. The main reasons for these difficulties are the complexity of associations where several HLA complex genes might be involved, and the strong linkage disequilibrium that exists between the genes in this complex. The latter phenomenon leads to secondary disease associations, or what has been called ‘hitchhiking polymorphisms’. Here, we give an overview of the complexity of HLA associations in autoimmune disease, focusing on type 1 diabetes and trying to answer the question: how many and which HLA genes are directly 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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