Not So Rare, FH Is Truly Risky Lipid Disorder

–Not all elevated is LDL is equally dangerous

CHICAGO — Familial hypercholesterolemia (FH), a condition that has long been overshadowed by more common cardiovascular diagnoses, has now found the spotlight in the big tent as a hot and even controversial topic.

The new interest is driven by important advances in understanding the genetics of the disease and, of course, the availability of PCSK9 inhibitors, which many believe may offer the best therapeutic option for many FH patients.

A study presented at the American College of Cardiology meeting here and published simultaneously in the Journal of the American College of Cardiology provided important new information about FH frequency and impact.

Amit Khera, MD (Massachusetts General Hospital and the Broad Institute) and colleagues, found that only about 2% of people who have very high LDL levels (190 mg dL or higher) had a FH mutation. They speculated that the elevated LDL levels in the remaining population was due to other genetic or environmental causes.

But confirmed FH mutation has a significant clinical implication: the risk for people with FH was much higher than for those without FH, even if the LDL level was the same.

According to the analysis, among people with LDL levels over 190 the increase in risk of coronary artery disease was increased 6-fold in people without an FH mutation compared with a much larger 22-fold increase in those with an FH mutation.

“One of the reasons for this increased risk is that if you have a mutation, your cholesterol is elevated from the time of birth,” said Khera, at an ACC press release. “We think it is the cumulative exposure to LDL over the course of your lifetime that is the important factor here.”

“Our findings suggest that if you performed widespread genetic screening of all individuals with very high LDL cholesterol, your yield would likely be low, but for the people who do have the mutations, the results could be quite meaningful,” he said. “This knowledge would be relevant not only to people with familial hypercholesterolemia mutations but to their relatives as well.”

“Many clinicians assume that patients with LDL above 190 have a familial hypercholesterolemia mutation as the major driver,” Khera said. “But there are a lot of other causes that can lead to this very high LDL, such as poor diet, lack of exercise and a variety of common genetic variants that each have a small impact on cholesterol but can add up to a big impact when they occur together.”

The researchers analyzed genetic data from more than 26,000 people who participated in various research studies. They defined FH as known mutations in 3 genes, LDLR, APOB and PCSK9. They did not look for or characterize other genes, though this area is being explored in ongoing studies.

This is the first study to attempt a precise assessment of the prevalence of classic FH mutations in people with high cholesterol levels. The rate found in the study is far lower than had been generally assumed beforehand. Genetic studies have now identified hundreds of mutations of additional genes not specifically tied to the LDL receptor that may also play a role in cardiovascular disease. This “polygenic” FH, alone or in combination with lifestyle factors, likely explains the underlying cause for the vast majority of cases of LDL elevation.

The authors estimated that about 14 million US adults have LDL levels over 190, 412,000 of these have FH.

“This debunks the notion that the vast majority of people with high LDL levels have FH,” said Fred Masoudi, MD, of the University of Colorado, at the ACC press conference. “At this point I would not recommend routine genetic testing because its effectiveness and cost effectiveness have not been measured.”

Khera agreed that it was too early to recommend widespread genetic testing in people with very high cholesterol levels. “Clinical criteria work pretty well,” he said at the press conference. “Does the incremental cost of genetic testing improve? That’s an open question.”

But Khera and many others don’t reject genetic testing entirely. Sekar Kathiresan, MD, of Massachusetts General Hospital, who was the senior author of the paper said in an interview that genetic testing can be very valuable in some people with elevated LDL levels, especially young people with high LDL levels who might not qualify for statin therapy because of their low level of calculated risk.

The current cost of genetic testing outside is more than $1,000 in clinical practice.

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