Variations in the WFS1 gene, known to affect both the survival and function of insulin-producing cells in the pancreas, can be linked to type 2 diabetes susceptibility, according to a new study from Cambridge.

The study has two major implications – it identifies a new risk factor in a disease reaching epidemic levels worldwide while also showing that variations in a gene – and not only mutations – can lead to type 2 diabetes.

The importance of the last finding resides in the fact that gene variations – contrary to the extremely rare mutations – are relatively common in the population. Also interesting is the fact that this gene, when mutated, is known to lead to a rare syndrome while the new study show that relatively common variations can predispose to diabetes revealing a larger spectrum of effects than previously thought.

Diabetes – which name comes from the Greek word “siphon” due to the excessive urination of patients – results from incapacity of using the glucose in the blood. The metabolism of glucose is mediated by insulin –a hormone produced by the beta cells in the pancreas – which controls the passage of this sugar from the blood and into the cells where it can be used as energy. When this does not happen, the glucose accumulates in the blood leading to the long-term health problems associated with diabetes, including eye, kidney, and nerve damage.

Type 2 diabetes - one of the two major types of diabetes accounting for 90% of all the cases– is caused by a combination of insulin resistance (where the cells of the body do not respond to the hormone) and low insulin production. The disease results from genetic and environmental factors where an unhealthy diet and decreased physical activity habits act on genetically susceptible individuals and although it used to be mostly prevalent on adults after the age of 40 but now, with the increasing obesity epidemic, cases among young children are becoming more and more common. At the moment there is no cure for diabetes consequently, studies to better understand the disease causing mechanisms so to improve control of its potentially catastrophic health and economic problems are now a major priority around the world.

Genetic approaches have so far been limited and although the disease is believed to be affected by multiple genes until last year only three had been identified. Recent large scale studies have led to five more genes being associated with the disease, but still much remains to be understood on the causes of type 2 diabetes.

And studies that search for disease causes, by comparing the full genome of patients and healthy controls, can, for example, miss genetic “variations” with mild effects on disease susceptibility. In this case, alternative studies capable of high-powered analysis of specific genes, such as those with functions directly related to the biology of the disease, can complement the genome-wide approaches allowing a more detailed idea of the disorder. Furthermore, the genome-wide approaches are not only expensive but also difficult to perform in large numbers of individuals.

With this in mind Manjinder S Sandhu, Inês Barroso and colleagues at Cambridge in collaboration with other groups in the UK, US and Israel, decided to look at 84 genes thought to be involved in beta-cell development, growth, function and/or survival, searching for associations with type 2 diabetes. Since beta-cells produce insulin and type 2 diabetes patients are known for their insulin problems, these genes seemed ideal candidates as possible susceptibility factors.

The study used a new weapon of genetic analysis called single nucleotide polymorphisms (SNPs). Nucleotides are the structural units of DNA, being DNA like a long chain of beads and each nucleotide one bead, while SNPs are, like the name indicates, variations in the DNA sequence of only one single nucleotide. SNPs, contrary to mutations, are relatively common with each variation existing in at least 1% of the population, and it is this abundance that makes them perfect tools to create ultra-fine-resolution genetic maps in humans associating different variations with distinct disorders.

Sandhu, Barroso and colleagues' study started by looking into four different groups - three UK and one North European Jewish population – and were able to describe the existence of 1536 different SNPs in the 84 genes linked to the insulin-producing beta cells of the pancreas.

In order to confirm the importance of these SNPs in disease, the next step was to analyse their presence in the diabetic and the healthy individuals. initially in the 3 UK groups where 18 SNPs were significantly more common among the diabetic patients than among the healthy controls, suggesting that they could in fact contribute to disease.

The next step, in order to confirm the link of these 18 SNPs to disease, was to test them against a population with a totally different genetic makeup, in this case a group of Ashkenazi individuals, which are a central and north Europeans descendant Jewish population. From this analysis only two SNPs remained linked to type 2 diabetes and interestingly, both variations in the same gene - the Wolfram syndrome 1or WFS1 gene.

WFS1 is a gene active in the pancreas where is known to affect the survival and proper function of the beta-cells. Mutation in this gene can cause a rare syndrome called the Wolfram syndrome 1, a genetic neurodegenerative disease with several diabetic-like symptoms.

Also interesting was the fact that none of two SNPs associated with type 2 diabetes affected the sequence of the protein produced by WFS1, which is the most common way to lead to disease, hhighlighting how little is still known on the roles of different types of DNA both in health and in human disease.

In conclusion, while genome-wide studies are good to find genetic alterations with a strong effect on disease, for variations with a milder effect, like WFS1, approaches based on higher-powered studies, using large numbers of individuals, may be a useful complement to find correlations that could be otherwise missed.

“Our study reinforces the idea that knowledge-based genetics can uncover the foundation of common disease,” - said Dr Barroso, a Portuguese researcher and the leading author of the study - “Our targeted approach efficiently surveys many of the genes that we consider might lead to onset of diabetes”.

Sandhu, Barroso and colleagues´ study is particularly interesting because not only it identifies a new risk factor to a disease with serious health and economical implications - the World Health Organization calculates that in 2006 more than 180 million type 2 diabetics exist worldwide – but also because it shows how a single gene, depending if it is mutated or simply have different variations, can result in totally different outcomes in the different individuals.

Source: “Common variants in WFS1 confer risk of type 2 diabetes”