Dec. 25, 2000 Medical College of Wisconsin researchers have discovered an area on the human chromosome-3 that may hold the key to understanding the genetic basis for obesity and its related health problems of diabetes, high blood pressure and coronary heart disease.
The results are published in the Dec. 19, 2000 issue of the Proceedings of the National Academy of Science by Ahmed Kissebah, M.D., professor of medicine and chief of the division of endocrinology, metabolism and clinical nutrition at the Medical College, with collaborators nation-wide. They report finding a region on chromosome-3 that harbors a yet to be determined number of genes that could be responsible for several obesity-related traits. These traits are commonly clustered in individuals and families with high risk for developing diabetes, high blood pressure, coronary heart disease and, in some cases, can be life-threatening.
"We searched the entire human genome and have narrowed it to a small area on chromosome-3," says Dr. Kissebah, who practices at Froedtert Hospital, a major teaching affiliate of the Medical College.
"The study would not have been possible without the enthusiastic participation of TOPS Club, Inc. (Take off Pounds Sensibly). They were a major factor in the success of the study," Dr. Kissebah says.
Dr. Kissebah and his colleagues analyzed blood DNA samples of more than 2,000 TOPS individuals from approximately 500 families of predominantly northern European descent. From the blood samples taken, 400 molecular markers were used to search the DNA of each individual thus resulting in the analysis of approximately one million markers to arrive at this conclusion.
TOPS Club, Inc, founded in 1948, is the oldest non-profit, non-commercial, weight loss support group with over 240,000 members worldwide and is headquartered in Milwaukee.
The area identified by the researchers contains molecular markers highly statistically linked with a number of features fundamental to the form of obesity that commonly triggers related health problems. These include body weight; degree of fatness from body mass index; pattern of fat distribution across the body frame from waist and hip circumferences; and ineffectiveness of insulin in promoting glucose consumption as well as insulin blood levels, both strong predictors of glucose intolerance and diabetes.
The area identified by markers is known as a QTL or quantitative trait locus. DNA QTLs help provide a road map researchers can use to hunt for genes responsible for the features of interest. What is interesting is that a study just reported by French scientists has found that this same area on chromosome-3 is also linked to the presence of established diabetes in a smaller cohort of French families.
The Medical College researchers found that the genetic region on chromosome-3 works in concert with another region on chromosome-17 to produce the adverse features of obesity. This interaction, known as epistasis, suggests genes are in communication.
"It means that whatever genes are involved on these two chromosomes seem to belong to the same pathway subserving those biological mechanisms leading to the obesity related features," says Dr. Kissebah.
Dr. Kissebah notes that while this research does not have immediate practical implications, it is a milestone that helps put together the complex parts of the puzzle to address a major public health problem. Focus on the genetics of obesity can lead to better understanding and eventually methods of intervening. Such efforts need wide scientific collaboration, he says.
"The genetic data from these individuals and families not only comprises the largest collection ever done, but also represents a spectrum of individuals from families who have both obese and non-obese members. This is the ideal study design that should facilitate definite detection of the chromosomal region and potentially the genes that distinguish the obese from the non-obese," states Dr. Kissebah. "The database," says Dr. Kissebah, "is an important national resource, because it provides the foundation for understanding the genetics behind obesity."
"We're providing information to the rest of the world to help us look at all possible relevant genes present in the locus on chromosome-3 and their cross-interactions with those on chomosome-17. These efforts would require enormous levels of resources and expertise."
In ongoing research, Dr. Kissebah and his colleagues have used the world-wide genetics database to identify genes residing in these two chromosomal areas and could be suspected candidates for causing the obesity traits. One such novel gene on the chomosome-3 area is exclusively expressed by fat tissue and its protein product is secreted into the blood and, like hormones, is destined to affect multiple body systems such as those that exacerbate the obesity features. Researchers at the Medical College have established collaboration with other scientists in the USA and abroad to determine blood levels of this gene product as well as gene variations that correlate with the obesity-related traits.
For three decades, Dr. Kissebah's research has been driven by a passion devoted to understanding the causes and health risks of obesity. His earlier landmark research has shown that abdominal obesity is a risk factor for the body's impaired ability to metabolize glucose or glucose intolerance, a high risk for obesity. He found the apple versus pear shape is a strong risk factor for diabetes and other features predictive of high blood pressure, adverse blood fats levels and coronary heart disease.
Other researchers from the Medical College of Wisconsin involved in the current study include Gabriele E. Sonnenberg, M.D., Howard J. Jacob, Ph.D., Joel Myklebust, Ph.D., Michael Goldstein, Ph.D., Glenn R. Krakower, Ph.D., Roland James, and Jacqueline A. Marks. From the Marshfield Medical Research Foundation, Marshfield, Wis., Karl Broman, Ph.D. and James Weber, Ph.D.; and from the Southwest Foundation for Biomedical Research in San Antonio, Tex., Lisa Martin, Ph.D., Anthony G. Comuzzie, Ph.D., and John Blangero, Ph.D. Consultants for the study were Jules Hirsch, M.D., Rockefeller University, N.Y., Rudolph L. Leibel, Columbia University, College of Physicians and Surgeons, N.Y., and Daniel Cohen, M.D., Ph.D., Center for Genomic Research, GENSET, Paris, France.
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