BBC: Cholesterol genes 'protect heart'

BBC ^ | Wednesday, 18 June 2008 02:27 UK 01:27 GMT, | BBC Staff

[Ernest_at_the_Beach]

Cholesterol genes 'protect heart'

Cholesterol appears to play a key role in heart disease

A third of the population have genes that could help them in the fight against heart disease, say scientists.

A study of 147,000 patients suggests that certain types of the CETP gene might increase the levels of so-called "good" cholesterol.

UK and Dutch research, published in the Journal of the American Heart Association, found a 5% cut in heart attacks for those with the key types.

A UK geneticist said it could point to drugs which help many more people.

What it does provide are important insights into the 'cause and effect' relationship, and if you understand this better, you can develop drugs which target it Dr Aroon Hingorani University College London

Scientists already know that cutting the levels of "bad" cholesterol in the bloodstream protects your heart, and well-established drugs such as statins aim to do precisely this.

The relationship between the levels of "good", or HDL, cholesterol, and heart health are less clear, although there is some evidence that raising these levels is good for you.

The team from Cambridge and Newcastle universities, and the University of Groningen in the Netherlands, merged the results of almost 100 other studies, involving 147,000 people worldwide.

They looked for the effect of having one of six different variations of the CETP gene.

The most popular three all seemed to carry a modest positive effect, raising HDL cholesterol levels by between 3% and 5%, and people with them were less likely to have a heart attack.

Cause and effect

Professor John Danesh, who led the study, said that the findings added weight to the idea that heart disease could be prevented by raising HDL levels, perhaps by drugs that blocked CETP.

A trial into a drug which raised HDL cholesterol by influencing CETP was abandoned in 2006 due to an increase in heart disease and deaths, but some scientists believe it may still be possible to target the gene effectively and safely.

Professor Peter Weissberg, of the British Heart Foundation, which funded the study, said: "Researchers are questioning whether approaches that raise HDL cholesterol could further prevent heart disease.

"This suggests that it may have benefits, but that more studies are needed to determine how much might be derived."

Dr Aroon Hingorani, a lecturer in genetics from University College London, said that the relatively small decrease in risk meant that the presence of a particular variant of the CETP gene could not help predict with any accuracy the risk of an individual falling prey to heart disease.

She said: "What it does provide are important insights into the 'cause and effect' relationship, and if you understand this better, you can develop drugs which target it."

[Ernest_at_the_Beach]

fyi

[Ernest_at_the_Beach]

fyi

[Palladin]

Statins are very very bad for you.

Just ask Tim Russert.

[isrul]

I don't understand. Did Russert take statins? I'm convinced that if you already have CAD, statins don't really do squat. Lowering cholesterol doesn't help you if the plaque is already there.

[Palladin]

Yes, he was on statins. He exercised. He dieted (not enough). He had a stress test in April and passed with flying colors.

A guy doing everything right, who just drops dead.

Go figure.

[CaliforniaCon]

Didn’t we hear that Russert was diabetic? If so, that’s likely a factor. Early death from heart disease is pretty common in diabetics.

[Palladin]

Oh, I missed that part. That would be a factor.

[CaliforniaCon]

Now I see that Russert was NOT known to have been diabetic so who knows what’s really true?

Regardless, he definitely carried too much weight in upper body which is not good. And he was in a high-stress job for years. Some combo of all of it was undoubtedly the cause.

[neverdem]

thanks, bfl

[isrul]

Clots. They have no way to predict them. And they don’t usually put you on drugs to help prevent them unless you have a drug eluting stent (which creates a risk for clots) or heart attack.

[neverdem]

Didn’t we hear that Russert was diabetic?

A Search for Answers in Russert’s Death

There was an autopsy. I read it in 2 sources, but no diabetes.

[blam]

Gene Variation May Be Why Some Don't Respond To Cholesterol-lowering Drugs

ScienceDaily (Jun. 18, 2008) — A variation in the way the body processes a single protein may explain why some people don't respond well to drugs that lower "bad" cholesterol, according to a report in Circulation: Journal of the American Heart Association.

The gene variation, called alternative splicing, explained 9 percent of the drugs' decreased power to reduce low-density lipoprotein (LDL) in study participants compared to people with the standard processing pathway.

The study is the first to show that a change in a biological process contributes substantially to the effectiveness of cholesterol-lowering drugs known as statins.

"Nine percent is a large number," said Ronald Krauss, M.D., senior author of the study and director of atherosclerosis research at the Children's Hospital Oakland Research Institute in California. "When we look at individual variations in genes affecting cholesterol metabolism, we can usually explain only a few percent of the variability in statin response."

The discovery could lead to improved cholesterol treatment and new therapy for other chronic ailments.

"The implications could go well beyond the efficacy of statins by helping us to understand the differences among individuals in how cholesterol is metabolized," Krauss said.

Simvastatin is one of several statin drugs that can effectively reduce the risk of heart attacks in people with high cholesterol. They work by blocking a key enzyme required for the production of cholesterol called HMGCR. However, all people don't have the same response to statins.

Krauss and his team sought a genetic explanation for this variability. They analyzed differences in how the gene responsible for producing HMGCR was processed -- or spliced -- among more than 900 participants enrolled in the Cholesterol and Pharmacogenetics (CAP) Study. During splicing, some portions of the gene's first product, mRNA, are removed and others are combined. The enzyme that is produced from the normally spliced HMGCR mRNA plays an early and critical role in the body's production of cholesterol, and its activity can be strongly inhibited by statins. The alternatively spliced form, on the other hand, is more resistant to statin inhibition of cholesterol production.

Researchers found that the "alternative splicing" also accounted for 15 percent of the reduced response of apolipoprotein B -- a constituent of LDL -- to simvastatin and 6 percent of the lower triglyceride response to the drug.

Combining factors already known to affect statin response -- age, race and smoking-- with alternative splicing explains 24 percent of the variation in LDL response, 29 percent for apoB and 8 percent for triglycerides, Krauss said. Despite this variability, statins are generally highly effective for prevention and treatment of heart disease, and there is not yet sufficient evidence for using genetic testing in evaluating the degree of benefit that individuals might be expected to achieve from statin treatment.

Marisa Wong Medina, Ph.D., co-author of the study, measured the two forms of spliced mRNA in cell lines grown from lymphocytes in people in a simvastatin clinical trial. The greater the proportion of alternatively spliced copies, the lower the clinical response to the drug.

Deciphering alternative slicing promises other benefits, including a deeper understanding of cholesterol metabolism.

"We know that the pathway leading to cholesterol has many side branches, some of which are involved in inflammation," Krauss said. "Statin treatment is thought to be effective in reducing heart disease risk by blocking production of molecules in the cholesterol synthesis pathway that can lead to both cholesterol buildup and inflammatory reactions in blood vessels."

Understanding the genetic regulation of these effects, and the role of alternative splicing of HMGCR and perhaps other genes in the cholesterol pathway, could lead to the development of new drugs for reducing heart disease risk, researchers said.

Other co-authors are Feng Gao, M.S.; Weiming Ruan, Ph.D.; and Jerome I. Rotter, M.D.

The National Institutes of Health funded the study.

Adapted from materials provided by American Heart Association.

[Ernest_at_the_Beach]

Well,...I am having a personal experience with Vytorin,...did seem to lower the bad Cholesterol numbers,...but gave me a problem with muscle pain...so backed off for a number of weeks ...but noticed other things so I am easing myself back on to a twice a week schedule.

See the Doctor in July and will see how we do...definitely have a problem with clogged pipes...

Will ask him for what's avaiable in the Roto Rooter drug department...

[SunkenCiv]

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[2ndDivisionVet]

Atkins would’ve probably saved his life.

[djf]

“A trial into a drug which raised HDL cholesterol by influencing CETP was abandoned in 2006 due to an increase in heart disease and deaths...”

djf says: “I got an idea! Think I’ll try it”
then a bunch of people kick the bucket...
djf says: Shucks. Didn’t work...”

Modern medicine. Tossing folks around like poker chips.

[ApplegateRanch]

Eat lots of fats. It keeps the corpuscles lubricated, so they can squeeze through the capillaries easily.

[SunkenCiv]

I should do a search on Lionel Tiger and post the link, but I won’t. :’)

[null and void]

Clots. They have no way to predict them. And they don’t usually put you on drugs to help prevent them unless you have a drug eluting stent (which creates a risk for clots) or heart attack.

An aspirin a day keeps the coroner away.