Eli Ben David
Direct link to this page: https://www.hayadan.org.il/sukeret2gene.html
International research teams, examining two separate population groups, have found different versions of genes that predispose them to type 2 diabetes, the more common type of the disease. The researchers, who receive extensive cooperation in their work, report their findings in a collection of articles in the April edition of Diabetes.
"This is an excellent example of how scientists, using the tools of modern biology, understand the causes of our national, and most devastating, disease." said Dr. Elias A. Elias A. Zerhouni, director of the National Institutes of Health (NIH). "As researchers continue to build on the foundation laid by the Human Genome Project, we may expect even more rapid progress in our efforts to understand, treat and ultimately prevent complicated conditions such as diabetes, heart disease and mental illness."
The analysis on a wide band of chromosome 20, which was also found in previous studies as a probable susceptibility factor for type 2 diabetes, allowed the teams to identify 4 genetic variables called: Single nucleotide polymorphisms (SNPs) (in biochemistry: a component found in the nucleic acid), related to type 2 diabetes in communities of Ashkenazi Jews and Finns.
All 4 groups of SNPs in the regulatory region of the single gene, alpha-4 factor of the hepatocyte nucleus (liver tissue cell) HNF4A, a transcription factor that acts as a "master switch" that regulates the operation of hundreds of genes. The HNF4A "turns on and off" in many tissues, including the liver and pancreas. In the beta cells of the pancreas, it affects the secretion of insulin in response to glucose.
"It's a nice fusion of findings," said Dr. Francis S. Collins, director of the National Genome Research Institute (NHGR) and senior author of the paper describing the outcome of the Finnish study. "What we discovered here is a common variation of the garden. If you have this variable, you are at a 30 percent risk of having type 2 diabetes. It will not cause you diabetes except in combination with what still needs to be identified as a genetic-susceptibility factor, along with environmental effects such as obesity and physical inactivity."
The translation of the discovery into treatment, which will help type 2 diabetes patients and those in the risk group, is years away from us "We still need to learn a lot about the gene and how to modulate its function," warned Dr. Collins.
The Finnish-American Investigation of NIDDM Genetics (FUSION) study is led by Dr. Michael Boehnke at the University of Michigan, and Drs.: Jaakko Tuomilehto and Timo T. Valle at the National Institute of Public Health in Helsinki, Dr. Richard N. Bergman at the University of Southern California and Dr. Collins at NHGRI. PhDs: Kaisa Silander, Karen L. Mohlke both of NHGRI, were the authors of the study. The team examined polymorphisms in 793 Finnish adults diagnosed with typical type 2 diabetes (formerly known as adult-onset or non-insulin dependent diabetes - NIDDM) and 413 non-diabetic controls. The researchers identified a total of 10 SNPs in and around the HNF-4A gene associated with type 2 diabetes in the Finnish population. The most significant results were obtained in the area of the DNA (called the "promoter") that regulates gene expression in the distribution of insulin in the pancreatic cells. Individuals who inherited the risk variables tended to have higher fasting blood glucose levels and two hours after a glucose challenge.
"We believe that these 4 variables mark a regulatory region that determines the expression level of the HNF4A," said Dr. Fremot. "We are now checking if this region of DNA is the expression of an influencing gene in some way."
A scientific publication of an NIH-funded study describes how polymorphisms in the HNF4A promoter may confer susceptibility to type 2 diabetes. In this work, Dr. Richard A. Young of the Whitehead Institute for Biomedical Research in Boston and research colleagues examined gene regulation by several HNF transcription factors. They found HNF4A to be a highly active transcription factor, regulating a surprising number of beta cell and liver cell genes in humans. They concluded that a false step in the location of the connection to other transcription factors in the HNF4A promoter, may result in "improper regulation of HNF4A expression down the road, leading to defective beta cell function and diabetes".
"The observations made by these teams mark a breakthrough in understanding the genetics of diabetes and may offer a blueprint for finding genes for other complicated diseases," said Dr. Catherine McKeon of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which funded three studies. "The work builds on progress in basic cell biology, studies in human populations, and new gene mapping technologies."
Other teams need confirmation of their findings, suggest Drs Collins and Fermot. In fact, scientists are already testing the variables in other populations. "We have already emailed our findings in precise detail to scientists at the International Type 2 Diabetes Analysis Consortium," said Dr. Boehnke, who co-led the NIDDK-funded consortium - a group of scientists around the world mapping the genes that are vulnerable to type 2 diabetes. You will actually increase the speed at which the results will be confirmed or denied," he added. Other studies will test whether people with the risk variables show signs of beta cell deficiency and will also test the function of HNF4A in animals.
Scientists have known for years that mutations of a single gene, usually in the function of beta cells, contribute to a rare form of diabetes, including 6 types of "adult-onset diabetes of the young" or (MODY - Maturity Onset Diabetes of the young). Such mutations are responsible for 2 or 3 percent of all diabetes cases. A mutation in the coding region of HNF4A causes MODY type 1, a rare form of diabetes that begins before the age of 25 in people of normal weight.
Anyway, unlike MODY, type 2 diabetes usually starts after the age of 40 in people who are overweight, lack physical activity and is more common in people with a family history of diabetes. In the US, type 2 diabetes disproportionately affects African Americans, and Americans of Hispanic and Native American descent. While affecting 17 million people, this form of diabetes accounts for 90 to 95 percent of all diabetes cases in the United States. The explosiveness of the disease has been on a steady rise for the past 30 years and its impact on young people and children is on the rise. Bookmark: insulin resistance - the inability of target tissues to respond to insulin - and a gradual failure of beta cells to produce insulin.
Scientists have come a long way in understanding the basis of diseases resulting from single gene mutations. Understanding the genetic basis of common polygenic diseases (diseases caused by many genes) such as diabetes, has been much more difficult.
"We could scan the coding region of each gene on chromosome 20 by editing it sequentially on many patients and come up with nothing," said Dr. Fremot. "This is because the problem is not in the gene itself but in the regulatory region, far from the gene. This study suggests that the expression level of the genes being examined will expand our understanding of genetic risk factors. Also, it shows us that even if we closely examine the garden from beginning to end, we are still not done. We need to look at polymorphic markers surrounding the gene for changes in these markers in cases and supervision". A major research project, The International HapMap Consortium, (details on the website: http://www.hapmap.org) is developing a map of the human variables across all chromosomes, and will significantly accelerate the achievement of this goal.
The FUSION study was led by researchers from the National Human Genome Research Institute, the University of Michigan, the University of Southern California, the National Institute of Public Health in Finland, and the Wellcome Trust Fund of the Sanger Institute of Great Britain. The research was funded by NHGRI and NIDDK. The Academy of Finland, Burroughs Wellcome, and the American Diabetes Association provided additional support.
Dr. Latisha D. Love-Gregory from the University of Washington was the lead author of the study on the Ashkenazi Jewish population, which was carried out by researchers from the University of Washington and by the Hadassah-Hebrew University in Israel. This research was funded by NIDDK.
credits:
The study in Science by Dr. Duncan T. Odom and coworkers was funded by NHGRI, NIDDK, and the National Institute of General Medical Sciences (NIGMS), all institutes of the National Institutes of Health under the Department of Health and Human Services. The study also received support from the Howard Hughes Medical Institute, the Juvenile Diabetes Research Foundation International, and the Sloan Foundation/US Department of Energy Program for Computational Molecular Biology.
The American Diabetes Association, which publishes the journal Diabetes, lifted the normal embargo on the papers. All other reports in the April issue of the journal remain under the normal embargo. Full text of the papers can be found at http://diabetes.diabetesjournals.org/rapidpubs.shtml.
The news was adapted from a press release of the National Human Genome Research Institute NIH/National Human Genome Research Institute.
For information on the Science Daily website
He knew genetic medicine
https://www.hayadan.org.il/BuildaGate4/general2/data_card.php?Cat=~~~801558200~~~25&SiteName=hayadan
