Gene Implicated That Confers Risk For Type 2 Diabetes

Understanding how genetic variation causes disease can be like climbing a mountain. Monogenic disorders, in which a defect in a single gene is necessary and sufficient to cause disease, are like the Mont Blanc: challenging but straightforward. One requires stamina and some experience to reach the top --although cunning strategy and advanced technical skills are not necessary. Such diseases tend to be rare and include cystic fibrosis and Huntington disease.

Complex disorders, on the other hand, are quite different. Were they mountains, they would be dotted with false summits, sheer, featureless walls and avalanches; those who attempt them run the risk of hypothermia owing to an inability to advance. Complex disorders are common and subsume massive 'pie-slices' of healthcare budgets. They include type 2 diabetes, asthma and Alzheimer's disease. They represent the greatest challenge to human genetics. This is demonstrated by the fact that no genes have yet been proven to cause complex disorders in humans, and only two have been reported in rodents. Only a few genes have been implicated by association, wherein one observes a correlation between a variation in (or near) a predictable gene and having a particular disorder. A new study by Graeme Bell, Nancy Cox and colleagues (of the University of Chicago) represents a shift in the landscape [Nature Genetics - October 2000]. Through a sophisticated, detailed, original and painstaking approach, these investigators have implicated a gene that confers risk for type 2 diabetes, a gene with little by way to render it an obvious candidate.

The classic approach to identifying a gene whose mutation causes a monogenic trait is through a method called 'positional cloning', so called because it relies on narrowing down the position of the gene to a point wherein the implicated chromosomal interval is so small that it houses only a few genes. It relies on having a fair number of families in which the disorder is prevalent. By comparing and contrasting markers on the chromosomes of family members with and without the disease, the chromosome segment that houses the 'responsible' gene can be refined. Once the interval is whittled away to a manageable size, the genes inside of it can be compared and contrasted between individuals --and the 'culprit' gene identified through its aberration in affected individuals. It is only by positional cloning that researchers are able to implicate genes whose defining characteristics (for example, gene function or site of expression) do not make them obvious candidates

Complex disorders are so called because the pattern of their inheritance is not straightforward or even discernable. Whereas it is usually clear that there is a genetic component (one is at greater risk of disease if one has an affected relative), the extent of risk is murky. This is because complex disorders require several and perhaps many 'hits' to manifest. These may be variations in several genes that have been inherited at birth or acquired later in life, perhaps as a consequence of environmental insult. Bell and colleagues have nonetheless implicated --through a positional cloning approach--variations in CAPN10, a gene that encodes an enzyme called a calpain protease in a Mexican-American population that has an extraordinarily high incidence of type 2 diabetes (risk is approximately 50%). Strengthening the case for CAPN10 being a 'susceptibility gene', they replicate the association between the implicated CAPN10 variations and French and Finnish samples --although the variants that predispose towards susceptibility are not as common in these groups as they are among Mexican Americans.

These findings represent excellent material for those who seek to understand why and how type 2 diabetes occurs. They also provide insight into how complex complex disorders can be, as described in an accompanying News & Views article by David Altshuler, Mark Daly (of the Whitehead Institute, Boston) and Leonid Kruglyak (of the Fred Hutchinson Cancer Institute, Seattle). Whereas one cannot claim causality with the same degree of conviction that is common to studies of monogenic disease, the advance represents a holy grail of human genetics --a summit in the range of complex disorders that is unlikely to be false. A Commentary by Joseph Terwilliger (Columbia University) and Kenneth Weiss (Penn State University) discusses the substantive challenges that face geneticists who hope to ferret out genetic variations that can be unequivocally associated with complex traits.

CONTACTS:
(Authors)
Dr. Graeme I. Bell
University of Chicago
Howard Hughes Medical Institute
Chicago, Illinois
USA
Telephone: +1 (773) 702-9116
Fax : +1 (773) 702-9237
E-mail:g-bell@uchicago.edu

Nancy J. Cox
University of Chicago
Departments of Human Genetics and Medicine
Chicago, Illinois, USA
Telephone: +1 (773) 834 1001
Fax: +1 (773) 834-0505
E-mail: nancy@hhmi.bsd.uchicago.edu

(News & Views)
Dr. Leonid Kruglyak
Fred Hutchinson Cancer Research Center
Seattle, Washington
USA
Telephone : 1 (206) 667-3120
Fax: 1 (206) 667-2383
E-mail: leonid@fhcrc.org

(Other Contact)
Dr. Eric S. Lander
Massachusetts Institute of Technology
Whitehead Institute for Biomedical Research
The Center for Genome Research
Cambridge, Massachusetts, USA
Telephone: +1 (617) 252-1905
Fax +1 (617) 252-1933
E-mail: lander@genome.wi.mit.edu

(C) Nature Genetics press release.

Message posted by: Trevor M. D'Souza