Diabetes susceptibility genes, part 2: Candidate genes 21/4/05. Fernando Gibson and Philippe Froguel In part 1 of their five-part, in-depth series exploring the search for diabetes susceptibility genes, Fernando Gibson and Philippe Froguel looked at the complexity of diabetes. In part 2, they examine studies of 'candidate genes' for diabetes.

One of the most useful strategies in the search for genes underlying complex diseases such as diabetes is to look at candidate genes. These are selected because, on the basis of their known or presumed functions, they are thought to have some plausible role in the disease. This strategy has proved to be particularly useful in the study of type 1 diabetes.

The major histocompatibility complex and type 1 diabetes

The genes at the human leukocyte antigen (HLA) locus on human chromosome 6 play a key role in helping the immune system to distinguish between 'self' (such as the beta cells of the pancreas) and non-self (such as bacteria and viruses).

Associations between type 1 diabetes and alleles in the HLA region were first documented in the 1970s by serological HLA typing, which used antibodies against specific HLA antigens.

Inheriting certain HLA alleles increases the probability that immune cells will attack the body's own beta cells, thereby predisposing to type 1 diabetes. The HLA genes encode the major histocompatibility complex (MHC) proteins, of which there are two main classes. The HLA-DR class II MHC genes are most strongly associated with type 1 diabetes. So while only 50 per cent of the normal population carry either an HLA-DR3 or a DR4 allele, 95 per cent of all Caucasian people with type 1 diabetes have at least one such allele.

Feature: The major histocompatibility complex

The inheritance of HLA alleles accounts for nearly half of the genetic risk of developing type 1 diabetes, and is the only diabetes locus of major effect to have been identified.

The genes at this locus are known as insulin-dependent diabetes mellitus 1 (IDDM1). However, type 1 diabetes is complex: alleles at other loci, together with permissive environmental factors, are also required for the disease to develop. Only about 10 per cent of individuals with the highest-risk MHC genotype (a DR3 or DR4 allele on both chromosomes) develop type 1 diabetes.

Other diabetes candidate genes

Another plausible type 1 diabetes candidate gene is the insulin gene on chromosome 11. A variable number of tandem repeats (VNTR) polymorphism upstream of the insulin gene has been reproducibly associated with susceptibility to type 1 diabetes.

The insulin VNTR locus is known as IDDM2 and the predisposing VNTR alleles confer an approximately three-fold increased risk of disease.

Feature: Type 1 diabetes and the insulin VNTR allele

For type 2 diabetes, only two functional susceptibility alleles of minor effect have been definitively identified: a variant of the pancreatic beta-cell ATP-sensitive potassium channel gene (KCNJ11) on chromosome 11, which regulates the secretion of insulin (1.2-fold risk); and a variant of the peroxisome proliferator activated receptor gamma gene (PPARG) on chromosome 3 (1.25-fold risk). The protein produced by the latter gene is the target of the thiazolidinedione class of anti-diabetic drugs that act by improving insulin sensitivity.

The idea that type 2 diabetes results from obesity-induced insulin resistance in muscle and liver, combined with declining function of the pancreatic beta cells, is now widely accepted. Recent studies have looked at gene expression profiles in muscle biopsies, and found that that people with type 2 diabetes have subtle decreases in expression of a subset of genes involved in mitochondrial oxidative phosphorylation (OXPHOS).

The subset of downregulated OXPHOS genes is known to be regulated by the PPARG coactivators-1a and -1b (PGC-1a and PGC-1b). This reduction in the PGC-1–regulated OXPHOS pathway is consistent with previous observations that mitochondrial structure, number, and oxidative phosphorylation capacity is reduced in the muscle of people with type 2 diabetes.

Thus, these studies have opened up novel molecular pathways that will inform future candidate gene studies of type 2 diabetes.

Part 3 of the five-part series examines genome-wide searches for type 1 diabetes susceptibility genes.

Related links

Diabetes susceptibility genes, part 1: The search for genes

Diabetes susceptibility genes, part 4: Genome-wide searches for type 2 genes

Diabetes susceptibility genes, part 5: Animal models of diabetes