Diabetes Health Article

Genetic profile

Like many common diseases, diabetes is caused by a combination of multiple environmental and genetic risk factors. The exact set of environmental and genetic factors that causes diabetes in any one individual is usually not known.

There are several known or suspected environmental factors that increase risk of developing diabetes and/or worsening complications. Environmental risk factors for developing IDDM are less well understood than for other types of diabetes. Infection by certain viruses has been implicated as a triggering event that can lead to the autoimmune reaction that causes disease in individuals with genetic susceptibility. Risk factors that are entirely or partially environmental have been implicated in NIDDM. These include obesity, low physical activity, poor dietary habits (high fat, salt, sugar intake), and alcohol and tobacco use. Cardiovascular risk factors—increased cholesterol and blood pressure, as well as others—also increase the chance for NIDDM to develop. Impaired glucose tolerance is a risk factor and can sometimes progress to NIDDM. For women, past history of gestational diabetes or delivery of a baby who was large-for-gestational-age also increases the chance of developing NIDDM. Ethnic background has a role in disease susceptibility for all types of diabetes, due to both genetic and environmental factors that may in part be affected by cultural practices.

Multiple genetic factors, both between individuals and often within a single affected individual, increase susceptibility to IDDM and NIDDM. Genetic factors are thought to be most important in individuals with a family history of the disease.

Heritability is the term that describes the genetic component causing a disease. It is a measure of the extent to which disease expression is the result of underlying genetic factors. One indication of the relative contribution of heritability in the causation of a particular disease is concordance.

Concordance describes the rate of similarity in disease expression between identical twins that share the same genetic material. As a general rule, the higher the concordance between identical twins, the greater the contribution of genetic factors to disease development. For example, the concordance for all types of diabetes ranges from 45-96%, indicating this percentage of diabetes can be attributed to genetic factors, with the remaining due to environmental factors. The specific genetic factors involved and their relative contributions toward diabetes development vary depending on the type of diabetes.

IDDM

Type I diabetes occurs when one's own immune system attacks and destroys the body's insulin-producing cells. There is a general population risk of 1/500 for developing IDDM. This risk increases when there is a family history or the presence of known genetic risk factors. The concordance for IDDM is generally thought to be less than 50%, suggesting that environmental factors must be present to trigger the development of the disease in individuals with genetic susceptibility. Even given this relatively low concordance, several genetic factors have been identified as established or suspected causes of IDDM susceptibility.

HLA ASSOCIATIONS HLA stands for human leukocyte antigens (also called major histocompatibility complex). HLA describes a group of proteins—genetically-determined and unique in each individual—that are important in helping the immune system distinguish 'self' from 'non-self' (foreign). Given their role in immunity, it seems intuitive that HLA types would be involved in susceptibility to this autoimmune form of diabetes. However, it is not yet clear if it is the HLA types themselves, or another closely linked gene, that increases risk.

There are several genes in the HLA gene family. Specific HLA-associations—consisting of variations of the HLA-DR gene—are thought to account for 60-70% of genetic susceptibility in IDDM. There is a significant understanding about the role of the HLA types, DR3 and DR4, in IDDM susceptibility.

HLA-DR alleles DR3 and DR4 are common in the general population. Almost half of all people in the United States have one or the other, which leads to a risk of 1/300 to 1/400 for developing IDDM. Two copies of DR3 or two copies of DR4—occuring in a very small percentage of the population—gives a risk of 1/150. Individuals having one copy each of DR3 and DR4 (1-3% of the population) is a combination that results in a 1/40 risk for developing IDDM. While less than 1% of individuals with these HLA types will develop diabetes, DR3 and/or DR4 are present in about 95% of all individuals with IDDM. While these HLA types confer susceptibility

to IDDM, other genetic or environmental factors must also be present in order for an individual to develop diabetes.

OTHER GENES ASSOCIATED WITH IDDM SUSCEPTIBILITY A genetic variation near the regulatory region of the insulin gene on chromosome 11 is widely accepted as a factor that confers IDDM susceptibility. This variation—called the 5' VNTR (variable number tandem repeat)—may contribute to susceptibility by influencing the regulation of the insulin gene, or by some other mechanism.

Several other genes or chromosomal locations have been identified and are being investigated as candidates that may contribute to genetic susceptibility for IDDM.

• Insulin receptor gene on chromosome 19
• Beta chain of the T-cell receptor on chromosome 7
• Immunoglobulin heavy chain (Gm) on chromosome 14
• Kidd blood group on chromosome 8
• IDDM3: chromosome 15 region
• IDDM4: chromosome 11 region near the fibroblast growth factor 3 gene
• IDDM5: chromosome 6 region
• IDDM7: chromosome 2 region near the HOXD8 gene
• IDDM8: chromosome 6 region
• Others: regions on chromosomes 3, 4, 13, and 18

It is thought that disease susceptibility is the result of these and other genetic factors acting independently and/or interacting with one another. There is still much to be learned about the identities, functions, and role in disease susceptibility for each of these implicated genes and chromosome regions.

SYNDROMES WITH IDDM AS A FEATURE In addition to susceptibility genes, there are several distinct syndromes that have IDDM as a potential feature. Additional characteristic features, aside from IDDM, mark these syndromes. The genetic basis for many of these conditions is known or suspected. These include syndromes with pancreatic disease (i.e. congenital absence of the pancreas and cystic fibrosis). There are multiple syndromes characterized by glucose intolerance due to or associated with a variety of other conditions including obesity, disease of the endocrine system, or diseases of metabolism. IDDM may also be seen in syndromes caused by mutations of the DNA of mitochondria—the cellular organelles that create energy. Mitochondrial DNA is only transmitted from the mother to each of her children, so such syndromes show a characteristic pattern of inheritance. IDDM (and NIDDM) tend to appear in conjunction with other features that are characteristic of these mitochondrial syndromes in affected families. MELAS syndrome—which is characterized by stroke-like episodes, muscle disease, and other symptoms—is one such example. It is caused by a mutation in the mitochondrial gene called tRNA Leu. Mutations in this gene can also result in a diabetes and deafness syndrome. A similar syndrome can also be caused by a large deletion of the mitochondrial DNA, called the 10.4kb deletion.