Genetics of type I diabetes. Inheritance Features

There are two main types of diabetes: type I (insulin-dependent – IDDM) and type II (non-insulin-dependent – IDDM), which make up 10 and 88% of all cases, respectively. They differ in typical age of onset, concordance of identical twins and association with specific alleles of the main histocompatibility complex (MHC – major histocompatibility complex). Family accumulation is observed in both types of diabetes, but only I or II type is usually present in one family. 

Type I diabetes mellitus occurs in the white population with a frequency of about 1 in 500 (0.2%), less often in African and Asian populations. It is usually found in childhood or adolescence and is caused by an autoimmune lesion of pancreatic b-cells that produce insulin. The vast majority of sick children already in early childhood, long before the development of obvious manifestations of the disease, develop numerous autoantibodies against a number of endogenous proteins, including insulin. 

Association of the main histocompatibility complex for type I diabetes

In type I diabetes mellitus, there is a confirmation of the role of genetic factors: identical twin twins are approximately 40%, which far exceeds 5% of mixed twins. The risk of type I diabetes for sibling patients with a proband is about 7%, which gives an heritability rate of hs = 7% / 0.2% = – 35. It has long been known that the MHC locus is the main genetic factor in diabetes, since about 95% of all patients with type I diabetes mellitus (compared to about 50% in the normal population) – heterozygous carriers of the HLA-DR3 or HLA-DR4 alleles at the HLA class II locus in the MHC [HLA – human leucocyte antigens].  

The first study to show the association of HLA-DR3 and HLA-DR4 with type I diabetes mellitus using standard methods for verifying the differences between different HLA alleles was carried out by in vitro immunoassay. Later, this method was replaced by direct determination of the DNA sequence of different alleles. Sequencing of the histocompatibility locus in a large number of patients revealed that the “alleles” of DR3 and DR4 are not just alleles.    

Both DR3 and DR4 can be subdivided into dozens of alleles located at the locus, now called DRB1, and determined at the DNA sequence level. In addition, it became clear that the association between certain DRB1 alleles and type I diabetes mellitus is partially caused by an allele at another class II locus, DQB1, located about 80 kilobases from DRB1, together forming a common haplotype (due to non-equilibrium linkage; see Chapter 10) together. DQB1 encodes a b-chain, one of the chains forming the dimer of class II DQ protein. It turns out that the presence of aspartic acid (Asp) at position 57 of the DQ b-chain is closely related to resistance to type I diabetes, while other amino acids in this position (alanine, valine, or series) determine susceptibility.   

About 90% of patients with type I diabetes are homozygous for the DQB1 alleles that do not encode aspartic acid at position 57. Since the DQ molecule, and specifically the 57th position of the p-chain, is critical for linking the antigen and peptide and the T-cell response, it seems that the differences in antigen attachment determined by the particular amino acid at the 57th position of the DQ p-chain directly contribute to the autoimmune response that destroys the insulin pancreatic producing cells. Nevertheless, other loci and alleles in the MHC are also important, as can be seen from the fact that some patients with type I diabetes mellitus have aspartic acid in the DQ b-chain position.  

Genes that differ from the loci of the main histocompatibility complex of class II in type I diabetes

The MHC haplotype is only responsible for part of the genetic contribution to the risk of type I diabetes mellitus in proband siblings. Family studies show that even when siblings have the same MHC class II haplotypes, the risk of illness is approximately 17%, which is significantly lower than the identical twin concordance rate of approximately 40%. Thus, there must be other genes in the genome that also predispose to the development of type I diabetes mellitus and differ in identical twins and siblings that have similar environmental conditions. 

In addition to the MHF , changes are suggested in more than a dozen loci that increase susceptibility to type I diabetes, but only three of them are reliably confirmed. This is the variability of the number of tandem repeats in the promoter of the insulin gene and simple nucleotide polymorphism in the gene of the immune regulator CTLA4 and in the gene PTPN22 encoding protein phosphatase. Identification of other susceptibility genes for type I diabetes mellitus both within and outside the MHC is an object of intensive research. Currently, the nature of non-genetic risk factors for type I diabetes is largely unknown. 

Genetic factors alone, however, do not cause type I diabetes mellitus, since the rate of concordance in identical twins is not 100%, but only about 40%. Until a more complete picture of the involvement of genetic and non-genetic factors in the development of type I diabetes mellitus, risk assessment counseling remains empirical. 

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