Genetics of Type 1a

Asian family

Type 1 diabetes is a complex genetic disorder.

There are now at least 20 insulin-dependent genes associated with the development of diabetes.

Type 1 diabetes is a complex genetic disorder. It occurs more frequently in families in which there are other relatives with type 1 diabetes and other autoimmune conditions.

Children have a 5% to 6% chance of developing diabetes if their father has type 1 diabetes, and a 3% to 4% chance if their mother has type 1 diabetes. It is thought that some of the mother’s chromosomal material, or DNA, gets inactivated when passed on to the child, thereby accounting for the difference in the children’s diabetes risk.

If a sibling has type 1 diabetes, the risk is 5-6%; however, if the sibling has identical MHC (Major Histocompatibility Complex) haplotypes, the risk increases. When one identical twin has diabetes, the risk of the other twin developing diabetes traditionally has been thought to be about 40%. Recent research suggests that the number may be much higher.

A number of genes have been identified that are associated with the development of diabetes. The chromosomal locations of these “diabetes genes” are called inherited susceptibility loci.

There are now at least 20 insulin-dependent diabetes mellitus (IDDM) susceptibility loci.

The most important are:

  • IDDM 1 (the major histocompatibility complex on chromosome 6)
  • IDDM 2 (the insulin gene locus on chromosome 11)
  • PTPN 22 (the protein tyrosine phosphatase gene) with a mutation at LYP (the lymphocyte-specific phosphatase gene) on chromosome 1 associated with susceptibility to multiple autoimmune disorders

IDDM 1

It is estimated that about 40-50% of the risk for type 1 diabetes is associated with the MHC complex or IDDM 1 loci. The MHC genes most associated with diabetes in white people are known as the human leukocyte antigens HLA DR3 and HLA DR4. Other racial groups are less well studied and may have different MHC gene profiles. More than 90% of European ancestry individuals with type 1 diabetes will have one or the other of these DR3 or DR4 haplotypes, but about 40% of the general population has one of these gene locations as well. The presence of high-risk haplotypes and evidence of positive antibodies, however, strongly predict the development of diabetes.

Specific high-risk genotypes are:

  • DR4 DQB1*0302
  • DR4 DQA1*0301
  • DR3 DQA1*0501 and
  • DR3 DQB1*0201

Interestingly, some MHC genes, such as HLA-DR2 DQB1*0602 and DR4 DRB1*1401, seem to be protective, and less than 1% of individuals with diabetes will have this gene type. The reason for the increased risk or protection is unknown, but it is thought to be related to which antigens or protein snippets the MHC protein can most easily bind and present to the immune cells. It has to be emphasized that there are multiple “at-risk” as well as protective haplotypes, and that calculating risk of diabetes based on HLA types is difficult.

IDDM 2

The IDDM 2 susceptibility locus confers approximately 10% of the familial risk for type 1 diabetes. This site refers to an area flanking the insulin gene that includes a variable number of tandem repeating (VNTR) nucleotide sequences. An increased risk of type 1 diabetes is associated with short sequences. These short repeating sequences appear to cause the thymus to under-express the insulin gene and thereby allow T cells with a T cell receptor that targets insulin to survive.

PTPN 22

A variation in the PTPN 22 gene locus may account for a little less than 10% of the genetic chance of developing type 1 diabetes. This variation – called a functional polymorphism – also increases the risk of someone developing rheumatoid arthritis and systemic lupus erythematosis.

Type 1 diabetes is associated with a number of other autoimmune conditions. The strongest association is with:

  • Celiac disease
  • Hashimoto’s disease, or hypothyroidism
  • Graves’ disease, or hyperthyroidism
  • Addison’s disease, or adrenal failure, and
  • Pernicious anemia

©2007-2017 Collective work Martha Nolte Kennedy,
The Regents of the University of California.
All rights reserved.