BioWorld International Correspondent

LONDON - A total of 24 new genetic locations are now known to be associated with an increased risk of developing one of seven common human diseases, following the publication last week of a study of human genetic variation on an unprecedented scale.

The genes, or variants of genes, that lie at those locations will provide fertile opportunities for researchers who want to find out the genetic causes of the diseases concerned, and thus the mechanisms by which those diseases are caused. Work to identify targets for new drugs to treat conditions that affect vast numbers of people worldwide will not be far behind.

Costing £9 million and examining DNA from 17,000 people across the UK, the Wellcome Trust Case Control Consortium found 24 genes that were associated with bipolar disorder (one), coronary artery disease (one), Crohn's disease (nine), rheumatoid arthritis (three), Type I diabetes (seven) and Type II diabetes (three).

The consortium, which comprised 50 leading research groups including 200 scientists specializing in human genetics, published its findings in the June 7 edition of Nature, in a paper titled: "Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls." (See BioWorld Today, June 8, 2007.)

Using the powerful method known as genome-wide association, the project involved analyzing DNA samples to identify single nucleotide polymorphisms (SNPs). Together with data from the pre-existing HapMap, which provides information on which SNPs tend to be inherited with which parts of the genome, that made it possible to find out which genes were statistically significantly associated with which diseases.

The new findings include confirmation that four chromosomal regions contain genes that can predispose to type 1 diabetes and that there are three new genes for Crohn's disease. For the first time, the researchers have found a gene linking these two autoimmune diseases, called PTPN2.

Papers reporting the findings were published in the June 6 Nature Genetics. Their titles are: "Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility" and "Robust associations of four new chromosome regions from genome-wide analysis of type 1 diabetes."

Miles Parkes, consultant gastroenterologist at Addenbrooke's Hospital, Cambridge, who led the study into Crohn's disease, told BioWorld International: "There is now a lot of work to do in terms of the down-stream functional characterization and potential clinical impact of the pathways that have been flagged by the genetic results. At this stage, we don't even have fundamental information such as whether the predisposing variants cause upregulation or downregulation of activity of the gene products in question."

The gene pinpointed as important in both Crohn's disease and Type I diabetes, PTPN2, encodes a T-cell protein tyrosine phosphatase. The protein is known to be a key negative regulator of inflammation. In gene knockout studies, animals lacking functional copies of PTPN2 develop widespread inflammation, Parkes said.

Other genes identified as predisposing those who inherit them to develop Crohn's disease include those encoding the cytokine IL12 and the receptor for IL23.

"IL12 and IL23 play key roles in balancing the early host immune response to pathogens,"Parkes said. "Genetic knockout studies using a mouse model of intestinal inflammation have shown that those animals lacking IL23 fail to develop intestinal inflammation as expected."

Studies have suggested, he added, that knocking out the function of IL23 can be done without affecting systemic immunity. "This suggests that you may be able to achieve a fairly clean abrogation of the disease process without causing widespread systemic immunosuppression and all the problems associated with that," Parkes said.

Parkes and his team are embarking on a meta-analysis that will include data from a Belgian and a North American consortium. "We have 12 loci already," he said, "but we are now lining up the datasets to drill out additional genes for Crohn's disease."

Commenting on the link between Type I diabetes and Crohn's disease, John Todd, of the University of Cambridge, who led the study into Type I diabetes, said, "This is one of the most exciting findings to emerge. It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood, and we hope that progress in treating Crohn's disease may give us clues on how to treat Type I diabetes in the future."