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“Overeating and physical inactivity are major causes of type 2 diabetes mellitus, but they affect only genetically susceptible individuals… [and]…recent research has suggested that specific genes may be associated with the risk of developing the disease,” writes the Editor of the international science journal Nature.

The comment refers to a suite of articles in that journal’s February 7, 2007 issue highlighting the emerging study of connections between variation in the human genome and factors such as diet in the development “of most common diseases.”

One study featured in this issue – “A genome-wide association study identifies novel risk loci for type 2 diabetes” (see abstract, below) – reports on identification of four previously unknown genes as risk factors for diabetes 2, and confirms the previously identified association with a gene referred to as TCF7L2.

The researchers postulate that this constellation of genes likely contributes significantly to diabetes 2 risk, and that further study to better understand their function – along with modified diet and exercise – should support development of new concepts in treatment.

Following is an abstract of the article.

A genome-wide association study identifies novel risk loci for type 2 diabetes

By R Sladek, et al

Journal: Nature. 2007 February 11. [E-pubication ahead of print.]

Authors and affiliations: R Sladek, G Rocheleau, J Rung, C Dina, L Shen, D Serre, P Boutin, D Vincent, A Belisle, S Hadjadj, B Balkau, B Heude, G Charpentier, TJ Hudson, A Montpetit, AV Pshezhetsky, M Prentki, BI Posner, DJ Balding, D Meyre, C Polychronakos, Philippe Froguel. Departments of Human Genetics, Medicine, McGill University; Genome Quebec Innovation Centre, Montreal, Canada.

PMID: 17293876

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants [polymorphisms], most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms.

We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort.

This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene.

These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4).

These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.

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Note: The full text of this article is available for a fee from the publisher, at www.nature.com/nature/journal/v445/n7130/edsumm/e070222-09.html