Genetics of diabetes: concepts of risk rather than cause.

Abstract

The performance of genes contributing to a person’s risk of developing diabetes has been difficult to determine. The development of diabetes is complex and multifactorial involving genetics (alleles, or genetic variants), nutrition, activity level and the nutritional status and neonatal environment during gestation. However, people with an affected parent have a 3.5 fold risk of developing Diabetes compared to individuals with no affected family members.1 Despite the powerful role played by genetics in the development of diabetes, genetists have failed to find a single diabetes gene. In the early 1980s, after the breakthrough in the understanding of childhood diabetes, the hunt for other underlying genetic causes for diabetes started. Diabetes in most people has been characterized into type-1, type-1.5 or type-2.2 Other forms of insulin resistant Diabetes also can be seen in gestational Diabetes, polycystic ovary disease, acanthosis nigricans, and Maturity-Onset Diabetes of the Young or MODY. These rare forms like MODY are inherited in a Mendelian manner either dominant (needing one of two mutant alleles) or recessive (needing two of two mutant alleles). Insulin resistant Diabetes can also be unmasked by medications like prednisone. In rare cases, nonresistant forms of Diabetes may also be seen following trauma to the pancreas or pancreatic surgery.3 Nearly 20 different regions of the genome may be involved in genetic susceptibility to type-1 Diabetes (T1D). Two of the best studied genes in type-1 Diabetes are the HLA (human leukocyte antigen) region and the insulin gene. The HLA region has several hundred genes which are known to be involved in immune response. Those most strongly associated with the disease are the HLA class II genes (i.e., HLA-DR, DQ, DP).2 There are at least two genes in the HLA region (HLA-DQB1, locus: 6p21.3) that account for 40 to 50 percent of the diabetes risk that people inherit from their parents. Different versions (or alleles) of these genes called DR can put a person at risk for or prevent them from developing type-1 Diabetes. People can inherit one form of DR from their mother and one form of DR from their father. It is the combination of these two forms of the gene that determine a person's overall risk. Two forms of DR, designated DR3 and DR4, are present in 95 percent of type-1 Diabetics, and 30 percent have inherited both DR3 and DR4. The two alleles DR3 and DR4 alleles cause slight differences in the disease.4 People who inherit DR3 (but not DR4) develop Diabetes at an older age, and tend to have antibodies against pancreatic beta cells but not against insulin. These people are also more likely to develop thyroid autoimmune disease. People with allele DR4 (but not DR3) tend to develop diabetes earlier in life and have an immune reaction against insulin. People with both alleles DR3 and DR4 develop diabetes at the youngest age and have the highest levels of antibodies against insulin. In terms of absolute risk, Caucasian individuals with two susceptibility haplotypes have an approximately 6% chance of developing T1D through age 35 years compared to < 1% among Asians.