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New genes present drug targets for managing cholesterol and glucose levels
December 08, 2008ANN ARBOR, Mich.---Scientists have identified 12 new genes that are somewhat strange bedfellows: Some link gallstones and blood cholesterol levels, others link melatonin and sleep patterns to small increases in glucose levels and larger jumps in the risk of diabetes.
While these associations are surprising, all the genes are potential new drug targets and some of them could help explain conditions that have been a mystery. Nature Genetics will publish two papers explaining the findings online Dec 7, in advance of the January print edition.
The 12 new genes relate to cholesterol and glucose levels, but several point to somewhat surprising links between these traits and other conditions, said Goncalo Abecasis, associate professor of biostatistics at the University of Michigan School of Public Health who co-directed the cholesterol study. Cristen Willer, a postdoctoral researcher working with Michael Boehnke, a professor at the U-M SPH, was lead analyst and joint first author of the study along with Sekar Kathiresan of Massachusetts General Hospital and Harvard Medical School.
Cholesterol is a strong predictor of heart disease and in a previous study, Abecasis, Boehnke, Willer and colleagues had shown that genetic variants that raise LDL cholesterol (low density lipoprotein or so-called bad cholesterol) levels also increase the risk of heart disease. The current study describes the most detailed assessment of the genetics of cholesterol to date, examining genetic variants and cholesterol levels in more than 40,000 individuals.
"An important finding is that several of these genes have multiple different changes that can affect cholesterol," Willer said. For example, in the PCSK9 gene there are common variants that affect about 40 percent of the population and increase LDL by about 3-6 milligrams per deciliter, a fairly small amount. Another variant affects roughly 2 percent of individuals but increases LDL by about 15-30 milligrams per deciliter. Finally, there are extremely rare changes in the same gene that affect fewer than 1 in 1000 people but can increase LDL by well over 100 milligrams per deciliter.
"We think looking at this list of genes in individuals with extremely high cholesterol may clarify a lot of those unexplained cases," Abecasis said.
In the cholesterol study, U-M scientists and collaborators at more than 10 institutions in the U.S. and Europe located 30 genetic variants associated with cholesterol levels, including 11 new ones. Notably, several of the newly implicated genetic variants were also related to the risk of gallstones and certain rare forms of diabetes.
"Each of these genes is a potentially interesting drug target," said Abecasis. Statins, a class of cholesterol lowering drugs used to reduce the risk of heart disease, target the HMGCR gene, one of the genes identified in the study. The other genes identified in the study could lead to entirely new and more effective therapies to manage cholesterol levels and reduce the risk of heart disease. In addition, the genetic changes they identify can also help predict whether each individual will develop high LDL or low HDL.
In the paper studying glucose levels, Abecasis and Boehnke collaborated with researchers across the globe to discover genetic changes strongly associated with a small increase in glucose levels in non-diabetic individuals. They also found the same changes increased the risk of developing diabetes by up to 20 percent.
"Observing an increased risk for diabetes was surprising because the changes in glucose levels were well within the normal range," said Boehnke, who has studied the genetics of diabetes for more than 15 years.
The gene, called the melatonin receptor, helps regulate the circadian clock, among other things. The finding strengthens the association between disrupted sleep patterns and diabetes, Boehnke said.
In the glucose study, scientists looked at the genomes of 36,000 individuals.
University of Michigan
Cholesterol is a strong predictor of heart disease and in a previous study, Abecasis, Boehnke, Willer and colleagues had shown that genetic variants that raise LDL cholesterol (low density lipoprotein or so-called bad cholesterol) levels also increase the risk of heart disease. The current study describes the most detailed assessment of the genetics of cholesterol to date, examining genetic variants and cholesterol levels in more than 40,000 individuals.
"An important finding is that several of these genes have multiple different changes that can affect cholesterol," Willer said. For example, in the PCSK9 gene there are common variants that affect about 40 percent of the population and increase LDL by about 3-6 milligrams per deciliter, a fairly small amount. Another variant affects roughly 2 percent of individuals but increases LDL by about 15-30 milligrams per deciliter. Finally, there are extremely rare changes in the same gene that affect fewer than 1 in 1000 people but can increase LDL by well over 100 milligrams per deciliter.
"We think looking at this list of genes in individuals with extremely high cholesterol may clarify a lot of those unexplained cases," Abecasis said.
In the cholesterol study, U-M scientists and collaborators at more than 10 institutions in the U.S. and Europe located 30 genetic variants associated with cholesterol levels, including 11 new ones. Notably, several of the newly implicated genetic variants were also related to the risk of gallstones and certain rare forms of diabetes.
"Each of these genes is a potentially interesting drug target," said Abecasis. Statins, a class of cholesterol lowering drugs used to reduce the risk of heart disease, target the HMGCR gene, one of the genes identified in the study. The other genes identified in the study could lead to entirely new and more effective therapies to manage cholesterol levels and reduce the risk of heart disease. In addition, the genetic changes they identify can also help predict whether each individual will develop high LDL or low HDL.
In the paper studying glucose levels, Abecasis and Boehnke collaborated with researchers across the globe to discover genetic changes strongly associated with a small increase in glucose levels in non-diabetic individuals. They also found the same changes increased the risk of developing diabetes by up to 20 percent.
"Observing an increased risk for diabetes was surprising because the changes in glucose levels were well within the normal range," said Boehnke, who has studied the genetics of diabetes for more than 15 years.
The gene, called the melatonin receptor, helps regulate the circadian clock, among other things. The finding strengthens the association between disrupted sleep patterns and diabetes, Boehnke said.
In the glucose study, scientists looked at the genomes of 36,000 individuals.
University of Michigan
Glucose Levels Current Events and Glucose Levels News RSSA decade later, lifestyle changes or metformin still lower type 2 diabetes risk
Intensive lifestyle changes aimed at modest weight loss reduced the rate of developing type 2 diabetes by 34 percent compared with placebo in people at high risk for the disease, researchers conclude based on 10 years of data.
Should children undergo surgery without a long period of fasting after feeding?
Blood glucose levels in a lot of patients fed normal liquid food (NLF) and a high calorie diet (HCD) were high.
URI nutritionist finds chewing gum can reduce calorie intake, increase energy expenditure
A nutrition professor at the University of Rhode Island studying the effects of chewing sugar-free gum on weight management has found that it can help to reduce calorie intake and increase energy expenditure.
Healthy neighborhoods may be associated with lower diabetes risk
Individuals living in neighborhoods conducive to physical activity and providing access to healthy foods may have a lower risk of developing type 2 diabetes in a five-year period, according to a report in the October 12 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.
Self monitoring of blood glucose levels helps patients with diabetes
Self-monitoring of blood glucose (SMBG) enables those with diabetes to modify their behavior, adjust their medicine and understand their disease to better manage it.
Is inhaled insulin delivery still a possibility? Why has it been a commercial failure?
The commercial failure of Exubera® (Pfizer, New York, NY), the first inhaled insulin product to come to market, led other companies such as Eli Lilly-Alkermes to halt studies of similar drug delivery in development intended to compete for a share of the lucrative diabetes market.
Postmenopausal women benefit from endurance training as much as younger women
Marilyn Graham was 56 when she signed up for a grueling hour of cycling each morning for 12 weeks, occasionally decked out in a mask, a heart monitor and a bag of intravenous fluid and subjected to needle pricks to obtain blood samples.
Team reveals molecular mechanism underlying a form of diabetes
By investigating a rare and severe form of diabetes in children, University of Iowa researchers have discovered a new molecular mechanism that regulates specialized pancreatic cells and insulin secretion.
Biotransformed blueberry juice fights fat and diabetes
Juice extracted from North American lowbush blueberries, biotransformed with bacteria from the skin of the fruit, holds great promise as an anti-obesity and anti-diabetic agent.
Elevated arginase levels contribute to vascular eye disease such as diabetic retinopathy
Elevated levels of the enzyme arginase contribute to vascular eye damage and Medical College of Georgia researchers say therapies to normalize its levels could halt progression of potentially blinding diseases such as diabetic retinopathy.
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