Landmark DNA study of 3,000 people to unlock mystery of type 2 diabetes

From The Times – Mark Henderson, Science Editor
January 5, 2010

The genetic roots of type 2 diabetes are to be explored in unprecedented depth to help to find better ways to diagnose and treat a disease that affects more than 2 million people in Britain.

Type 2 diabetes, characterised by insulin resistance, can cause blindness and impotence

A £15 million study is to read the complete DNA of 3,000 people, more than ten times more than have so far had their genomes sequenced, The Times has learnt.

The research will provide insight into the biology of type 2 diabetes that can be exploited to develop new ways to treat and prevent the disorder, which can cause kidney and artery disease, blindness and impotence.

The Anglo-American project is the first in a new wave of studies using sophisticated methods of reading DNA that have only recently become affordable. The studies will investigate the influence of DNA onother conditions, such as heart disease, stroke and cancer.

“We are moving genomic research into a new phase,” said Mark McCarthy, Professor of Diabetes at the University of Oxford, who is leading the British side of the type 2 study. “We will be able to pin down many more genetic effects on disease, to understand the biology more completely and give the pharmaceutical industry new targets for drugs.”

Scientists currently hunt for links between DNA and disease by comparing snapshots of the genomes of patients with particular conditions and healthy control subjects. This approach has revealed hundreds of DNA variations that affect disease, including about three dozen linked to type 2 diabetes, but these explain only a fraction of the heritable factors known to play a part.

Much of this “missing heritability” is thought to be caused by variations that are too rare to be found by current techniques. To find these, scientists need to compare the entire genomes of patients and control subjects. However, this has always been prohibitively expensive.

A few years ago the cost of sequencing the thousands of individuals required for useful research would have been more than $1 billion.

The development of new sequencing technology has brought the cost down so sharply that each of the 3,000 genomes required for the research will now cost £5,000.

“This simply isn’t something we could have contemplated until now,” Professor McCarthy said.

Researchers will sequence the entire genomes of 1,500 people with type 2 diabetes and 1,500 people without the disease, then compare the results to look for variations that are significantly more common in the disease group.

The approach should pick up all the genetic variants carried by at least 1 in 100 people that affect the disease. The work should be complete by the middle of 2011.

DNAWellnessinfo.com Resource:  http://www.timesonline.co.uk/tol/news/science/genetics/article6975829.ece

Initial results from clinical trials of a DNA vaccine for type I diabetes are encouraging

Robert Scheinman – Denver Diabetes Examiner

June 10, 10:46 AM

Bayhill Therapeutics, Inc announced today that it is collaborating with Genentech in the production of a DNA based vaccine to treat type I diabetes. The vaccine, an antigen specific immunotherapy, is currently in phase I/II trials. Bayhill Therapeutics will finish out the ongoing trials and Genentech will then proceed with all future research and development of the vaccine.

The vaccine is currently referred to by the code BHT-3021. It was developed by Dr. Peter Gottleib, a physician scientist working in the Barbara Davis Center at the University of Colorado Denver. He recently presented interim clinical trial data at the American Diabetes Association 69th Scientific Session in New Orleans.  Type I diabetes patients who still retained some insulin production were given the vaccine by weekly intramuscular injections. A placebo group was similarly treated with an inactive substance. The study group showed a stabilization of the study group’s insulin production over the 12 week study period. All adverse effects were mild and the data suggests that BHT-3021 will be well tolerated.

BHT-3021 encodes the proinsulin gene and is designed to target immune cells that are attacking insulin secreting cells. Animal studies have shown that indeed this vaccine does modulate the immune system, restoring tolerance to beta cells. It is important to note that this vaccine will only work for type I diabetes patients who still retain some insulin production.

For more information, contact the Barbara Davis Center.

DNAWellnessinfo.com Resource:  http://www.examiner.com/x-10874-Denver-Diabetes-Examiner~y2009m6d10-Initial-results-from-clinical-trials-of-a-DNA-vaccine-for-type-I-diabetes-are-encouraging

Genes Play a Role in Glycemic Control in People With Type 1 Diabetes

earthtimes.com – Sat, 06 Jun 2009 13:15:23 GMT

NEW ORLEANS, LA — 06/06/09 — Researchers have proven that glycemic control in type 1 diabetes is not fully dependent on the individual’s behavior, but is in part subject to genetic influence, according to a presentation here today at the American Diabetes Association’s 69th Scientific Sessions. “We identified four genes related to glycemic control in type 1 diabetes,” said Andrew D. Paterson, MBChB, Senior Scientist in the Program for Genetics and Genome Biology, Hospital for Sick Children in Toronto, and lead author of the study. “Two of these genes also affect risk for complications — kidney, eye, and cardiovascular disease — and one gene has a strong effect on the rate of hypoglycemia.”

“This finding does not give people with diabetes the freedom to slack off on their careful nutrition, exercise, and medication regimens because behavior clearly plays the major role in glycemic control,” cautioned Dr. Paterson. “Eventually, the genetic variations we found may be used to identify individuals at risk for poor glycemic control and for diabetic complications, so that steps could be taken to intensify control or implement other measures. But in the interim, this knowledge may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications and lead us in new research directions to better understand the mechanisms of glycemic control.”

Nearly 24 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body’s ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputation. It is a leading cause of death by disease in the United States.

Type 1 is an immune-mediated form of diabetes involving destruction of the insulin-producing beta cells in the pancreas that typically leads to absolute insulin deficiency. Type 1 diabetes accounts for 5% to 10% of all diagnosed cases of diabetes and usually strikes children or young adults, although disease onset can occur at any age.

The first data suggesting that A1C, a measure of average glucose control over the prior two to three months, might be influenced by genetics came in 2001 in a British study looking at identical twins, where one twin had type 1 and the other did not, called discordance. “It was found that when the twin without diabetes had an A1C in the high normal range, the twin with diabetes would have an A1C in the high range for someone with diabetes,” said Dr. Paterson. “Essentially, they were playing to the same drummer but in a different key.”

In the current study, the researchers mined the extensive data available from one of the world’s most well-documented studies of people with type 1 diabetes: the Diabetes Control and Complications Trial (DCCT) — an NIH-sponsored study. It was initiated over 25 years ago and enrolled 1,441 people in a comparison of intensive versus conventional control of blood glucose. Conventional control during the DCCT required only one or two insulin injections and blood checks daily, with the aim of preventing overt diabetes symptoms, and typically yields A1C levels of 9% or more. Intensive control to bring A1C levels as close to normal as possible (6% or less) required at least three insulin injections a day or treatment with an insulin pump, guided by at least four glucose self-monitoring checks a day. The initial results, reported in 1993, demonstrated dramatic reductions in the development of eye, nerve, and kidney damage. Intensive control also lowered the risk of heart disease according to data published in 2005 as part of the follow-up study of DCCT participants, called the Epidemiology of Diabetes Interventions and Complications (EDIC) observation study, which is still continuing.

The researchers in this genetic study had access to every quarterly A1C test performed on people in the original DCCT over the course of an average of 6 1/2 years. To identify important genetic loci (the positions that genes occupy on a chromosome) influencing glycemic control in type 1, they performed high resolution genome-wide studies using the mean A1C values and capillary glucose of people in the conventional treatment group and compared loci of interest to people in the intensive treatment group.

They determined the genotypes of a million SNPs across the genome for over 1,300 participants in the DCCT. (SNPs are single-nucleotide polymorphisms, pronounced “snips” — DNA sequence variations in the genome.) Each of these SNPs was tested for association with the participants’ average A1Cs over the course of the trial.

They identified four major gene loci related to A1C levels. One in both treatment groups reached genome-wide significance — SORCS1 gene 10q25.1. Three achieved close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups; and 15q21.3 (WDR72) in the intensive group. Further, evidence indicated that SORCS1 was associated with hypoglycemia (low blood glucose), and BNC2 was associated with kidney and eye complications.

“While this information gives us insight into the mechanisms influencing glycemic control in people with type 1, it is important to remember that the overall influence of genes is small and may vary from person to person and, perhaps, in response to behavior,” Dr. Paterson explained. “For example, while the SORCS1 gene accounted for about 5% of the variability in glycemic control in the conventional treatment arm of the DCCT, A1C levels in people with type 1 diabetes have improved since those days as diabetes care teams and patients have learned about the value of more intensive control,” he said. “So we don’t know whether that number would be the same in a contemporary treatment setting.” For example, in the EDIC study, A1C levels of the former conventional control group dropped from 9% to 8.1% after they were taught intensive control at the end of the DCCT.

The American Diabetes Association is leading the fight against the deadly consequences of diabetes and fighting for those affected by diabetes. The Association funds research to prevent, cure and manage diabetes; delivers services to hundreds of communities; provides objective and credible information; and gives voice to those denied their rights because of diabetes. Founded in 1940, our mission is to prevent and cure diabetes and to improve the lives of all people affected by diabetes. For more information please call the American Diabetes Association at 1-800-DIABETES (1-800-342-2383) or visit www.diabetes.org. Information from both these sources is available in English and Spanish.

Abstract 58-OR

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DNAWellnessinfo.com Resource:  http://www.earthtimes.org/articles/show/genes-play-a-role-in,851904.shtml

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