New genes linked to diabetes and triglycerides

Scientists from the Broad Institute of Harvard and MIT, Lund University and Novartis have discovered three unsuspected regions of human DNA that contain clear genetic risk factors for type 2 diabetes and another that is associated with elevated blood triglycerides.

The study, appearing in the April 26 advance online edition of Science, is among the first to apply a suite of genomic resources to clinical research, including the Human Genome Project, the SNP and HapMap Projects, and genome-scale laboratory and analytical tools.

"For the first time, it is possible to look across the human genome and discover new clues about the root causes of common, devastating diseases that arise from a combination of genes, environment and behaviour," said senior author David Altshuler, a principal investigator of the Diabetes Genetics Initiative (DCI). "The confirmed genetic contributors we and our collaborators have found open surprising new avenues for disease research, treatment and prevention."

With the ageing of the population and the frequent excesses of modern lifestyles, type 2 diabetes and cardiac risk factors constitute a looming threat to human health, particularly in industrialised nations. Solutions to this burgeoning problem must include new, more effective treatments and the ability to identify "at risk' individuals " each of which requires innovative directions for future research.

The DGI study is one of the first large-scale studies of human genetic variability, aiming to reveal genetic connections to type 2 diabetes and other cardiovascular risk factors such as blood insulin levels, cholesterol levels, blood pressure and body weight. Each of these traits is considered complex because it involves a mix of inherited, environmental and behavioural factors.

The scientists' approach, known as a "genome-wide association study', involves scanning thousands of individuals' genomes for single letter changes, called single nucleotide polymorphisms (SNPs). Due to the block-like nature of the human genome, certain SNPs can serve as signposts, highlighting pieces of nearby DNA that may play a causal role in disease.

The DGI team and their collaborators identified and confirmed three novel regions of the genome that influence the risk of type 2 diabetes, as well as a genomic region that is linked with blood triglyceride levels. Perhaps the most intriguing result involves a DNA region that lies far from any known annotated genes. Such genomic "outsiders' would have been incredibly difficult to find by traditional hypothesis-driven approaches.

The other regions linked to diabetes lie near genes with known biochemical functions, but ones never before connected to the disease. Interestingly, the region implicated in triglyceride levels involves a gene that has long been known to play a role in modulating blood glucose.

"This collaboration brings together biologists, geneticists, statisticians and physicians. This interdisciplinary team approach may be the best way to understand complex disorders and quickly turn that to therapeutic advantage," said Thomas Hughes, head of diabetes and metabolism research at the Novartis Institutes for Biomedical Research.

Genome-wide association studies are the realisation of a long-term effort to understand how human genetic variation impacts health. Built on the Human Genome Project, the studies have been made possible in the last year, driven by the recent completion of the Hapmap Project and availability of large-scale research tools. Already, scientists from around the world have used the approach to identify genetic differences that influence a variety of disorders, including Crohn's disease, obesity, age-related macular degeneration and prostate cancer.