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Molecular Genetic Testing in Mainstream Medicine Vol. 14: Spring, 1997 |
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Molecular Genetic Testing in Mainstream Medicine Vol. 14: Spring, 1997 |
These are exciting times in genetic research on type 1 (insulin-dependent) diabetes mellitus. Over the past two years at least eleven new genetic loci have been linked to type 1 diabetes. What should we make out of this and what should we be telling people concerned about type 1 diabetes affecting their families?
Of the 55,000 children born in Colorado every year, an estimated 33 will develop type 1 diabetes by age 6, and 180 will be diagnosed by the of 20 years. After asthma and mental retardation, type 1 diabetes ranks as the third most common chronic childhood disease, affecting 1,600 Colorado children and 123,000 in the U.S. The cause of type 1 diabetes is multifactorial and includes the effects of perhaps as many as 11 to 16 genes, interacting with unknown environmental agents. However, the IDDM1 locus (including the HLA-DR and DQ genes) is the only major genetic determinant, accounting for up to 50% of the familial clustering of type 1 diabetes. Among non-HLA loci, the IDDM2 locus near the insulin gene on chromosome 11p is currently partially characterized.
The remaining loci, reported from genome screening of affected sibling pairs, are only tentatively mapped to wide regions on several chromosomes. It may turn out that some of these findings are falsely-positive, and for the loci truly associated with IDDM, it may take years before the actual genes and their functions are known. However, even with the incomplete information available today, HLA-DR and DQ typing can help to predict who is at risk.
While only 2% of the general population have the DRB1*0301,DQB1*0201/ DRB1*04,DQB1*0302 genotype, it is present in 30-40% of type 1 diabetes patients, including up 50% of those who develop diabetes in the first 10 years of life. A relatively simple and highly reliable PCR-based test for detection of this genotype and other type 1 diabetes susceptibility and protection genotypes has been developed by a group of investigators from Roche Molecular Systems, Alameda, CA and from the University of Colorado, HSC. This test, in combination with a screening for autoantibodies against pancreatic beta-cell antigens (insulin, GAD or IA-2), can detect 95% of future cases of type 1 diabetes and is effective in determining who is not at risk for diabetes.
For example, persons with the HLA-DQB1*0602 allele are very unlikely to develop type 1 diabetes even if they develop autoantibodies that typically precede the onset of clinical diabetes.
These tests are currently available on a research basis at the Department of Preventive Medicine & Biometrics, University of Colorado, HSC [contact Dr. Marian Rewers at (303)-270-7553] or at the Barbara Davis Center for Childhood Diabetes in Denver [contact Dr. George Eisenbarth at (303)-270-6165]. Since 1994 a pilot project genetic screening of cord blood has been accomplished for 10,000 births at St. Joseph Hospital in Denver. We are planning to make these tests available in 1997-98 to all Colorado children (90% of type 1 diabetes cases occur in families with no family history of type 1 diabetes). With early prediction, detection and treatment, almost all new patients can be started on insulin and given diabetes education on an outpatient basis. This could eliminate onset mortality and substantially decrease morbidity and hospitalization costs. It could also potentially increase the frequency and duration of remissions. Finally, drug interventions are now being evaluated to prolong remission in newly diagnosed diabetics, and to prevent diabetes in relatives of persons with type 1 diabaetes who have high-risk genes and autoantibodies. For information concerning current prevention trials call Dr. Peter Chase at (303)270-6399.
While progress in understanding the genetics of type 1 diabetes has been impressive, the genes responsible for type 2 (non-insulin dependent) diabetes (the more frequent form of diabetes affecting at least 14,000,000 Americans) have been harder to find. More than 250 candidate genes have been tested, with little success. While one promising locus (NIDDM1) has been mapped to chromosome 2 among Mexican Americans, this could not be confirmed in other populations.
Currently, there is nothing yet to offer to a person who wants to know the precise risk of developing type 2 diabetes. A middle-aged or older person who is obese, hypertensive, has a family history of type 2 diabetes, or who is just concerned about his/her risk of diabetes, should complete a standard oral glucose tolerance test. This will diagnose asymptomatic cases of type 2 diabetes and detect impaired glucose tolerance that is associated with a 40% risk of developing type 2 diabetes in 3-5 years.
Contributed by Marian Rewers, M.D., Ph.D. (CO)
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Molecular Genetic Testing in Mainstream Medicine:
Table of Contents
Introduction
Venous Thrombosis and the Factor V (Leiden) Mutation
DNA Testing for Hereditary Hemochromatosis
APO E Genotype Testing for Broad Beta Disease (Type III Hyperlipoproteinemia)
Fetal Rh Testing for Maternal-Fetal Incompatibility
Type 1 (insulin-dependent) Diabetes Mellitus
Adult Onset Neurodegenerative Disorders: CAG Triplet Repeat Expansion Mutations
Genetic Testing for Prader-Willi and Angelman Syndromes
Clinical and Applied Molecular Genetics Laboratories -
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