Diabetes susceptibility genes, part 4: Genome-wide searches for type 2 genes 21/4/05. Fernando Gibson and Philippe Froguel In part 3 of their five-part, in depth series, Fernando Gibson and Philippe Froguel looked at genome-wide searches for type 1 diabetes susceptibility genes. In part 4, they turn their attention to type 2 diabetes.

Type 2 diabetes has a later age of onset than type 1, the disease varies more in its severity, and there is a lower risk to first-degree relatives. These are all indications that environmental factors play a more prominent role in type 2 diabetes than they do in type 1. The corollary of this is that the challenge of identifying susceptibility genes is much tougher for type 2 diabetes than it is for type 1.

One of the earliest significant type 2 diabetes linkages (see part 3 for a description of genome-wide scans for linkage) was mapped to chromosome 2q in an isolated population of Mexican-Americans from Texas and was named NIDDM1 (non-insulin dependent diabetes mellitus 1).

In a landmark effort in 2000 to identify the type 2 diabetes susceptibility gene at NIDDM1, Graeme Bell (University of Chicago) and colleagues combined conventional association analysis of single nucleotide polymorphisms (SNPs) with a new statistical test 'association with the evidence of linkage'. This innovative test was based on the principle that in order to provide definitive evidence that the location of a gene has been pinned down, it is necessary to show that the associated variants account for the linkage signal – the increased risk of disease.

The authors implicated a variation (a polymorphism) in an intron of the gene encoding calpain 10 (CAPN10) with increased risk of type 2 diabetes. However, only people with one copy of the 'at-risk' variant (heterozygotes) were at increased risk; people with two copies (homozygotes) showed no evidence for increased risk.

In a further analysis, the authors identified a combination of three SNPs in the calpain 10 gene as carrying the highest risk (2.8-fold increased risk). Subsequent studies of these three polymorphisms in other populations have produced conflicting results, with association being observed in some populations (e.g. Pima Indian and South Indian) but not in others (e.g. UK, Chinese and Japanese).

Further large-scale, well-designed association studies are clearly warranted in order to provide reliable consensus evidence for or against the hypothesis that CAPN10 variants are associated with an increased risk of type 2 diabetes.

Almost 30 genome scans for type 2 diabetes loci have now been carried out in diabetic families with a wide diversity of ethnic origin, including families from the UK, French, Finnish, Mexican-American, Pima Indian, Utah Mormon, Amish, Chinese and Japanese populations. The chromosomal regions that have shown consistent replication of linkage to type 2 diabetes in several independent genome scans include 1, 3, 8, 12 and 20.

A meta-analysis of genome screens from four European populations (Swedish, Finnish, French and UK) was carried out by the European GIFT consortium, producing evidence for a novel type 2 diabetes susceptibility region on chromosome 17.

All regions are being subjected to intense study with the aim of identifying the genetic variants that are responsible for each of the linkage signals. However, it is now clear that, unlike type 1 diabetes, no 'major' susceptibility loci (conferring an increased risk of at least 3-fold) exist for type 2 diabetes.

In an exciting recent breakthrough, two independent studies in the April 2004 issue of the journal Diabetes reported that variations in the hepatocyte nuclear factor 4A gene (HNF4A) not only are associated with type 2 diabetes but explain the genome scan linkage signal on chromosome 20. Mutations in the HNF4A gene are known to cause maturity-onset diabetes of the young (MODY) type I, a rare, dominantly inherited early-onset form of type 2 diabetes, characterised by severe insulin secretory dysfunction.

These findings are tremendously important because they provide the first real demonstration that genes underlying rare monogenic forms of type 2 diabetes can also influence susceptibility to common, forms that involve many factors. Genes causing monogenic forms of early onset diabetes are shown in Table 2 below.

Part 5 of the series examines the analysis of animal models of diabetes.

Related links

Diabetes susceptibility genes, part 1: The search for genes

Diabetes susceptibility genes, part 2: Candidate genes

Diabetes susceptibility genes, part 3: Genome-wide searches for type 1 genes

References

Horikawa Y, et al. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26: 163-75 Abstract

McCarthy MI (2004) Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification. Hum Mol Genet 13 Spec No 1: R33-41. Abstract ; Full text

Latisha D. Love-Gregory LD, et al. (2004) A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4 Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population. Diabetes 2004 53: 1134-1140. Abstract ; Full text

Kaisa Silander K, et al. (2004) Genetic Variation Near the Hepatocyte Nuclear Factor-4 Gene Predicts Susceptibility to Type 2 Diabetes. Diabetes 2004 53: 1141-1149. Abstract ; Full text

• OMIM: Online Mendelian Inheritance in Man
• MODY: mature onset diabetes of the young
• APS: autoimmune polyglandular syndrome
• APECED: autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy
• MIDD: maternally inherited diabetes with deafness
• FPLD: familial partial lipodystrophy
• DM: diabetes mellitus
• AN: acanthosis nigricans
• IPEX: immunodysregulation, polyendocrinopathy and enteropathy
• EIF2: eukaryotic translation initiation factor 2.