Study demonstrates rarity of familial hypercholesterolemia mutations in individuals with high cholesterol

Only a small fraction of people with very high cholesterol can attribute their condition to a genetic mutation related to familial hypercholesterolemia, but individuals with these mutations face a high risk of developing early-onset coronary artery disease, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

The study, the largest gene sequencing analysis to date focused on individuals with very high cholesterol, demonstrates that familial hypercholesterolemia mutations are likely less common than previous studies had suggested. Despite the rarity of the mutations, however, the study illustrates the serious health consequences of familial hypercholesterolemia mutations, suggesting that genetic screening could help to identify and ward off early cardiovascular disease in affected individuals.

"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," said Amit V. Khera, M.D., a cardiology fellow at Massachusetts General Hospital who performed the research with senior author Sekar Kathiresan, M.D., a Massachusetts General Hospital cardiologist and a geneticist at the Eli and Edythe L. Broad Institute of Harvard and MIT. "This knowledge would be relevant not only to people with familial hypercholesterolemia mutations but to their relatives as well."

The study's first objective was to determine the prevalence of a familial hypercholesterolemia mutation among people with low-density lipoprotein, or LDL, cholesterol levels of 190 mg/dl or higher, a level considered very high.

"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."

Drawing upon genetic information from several large research studies, together representing more than 26,000 people, the team identified individuals with mutations in any of three known familial hypercholesterolemia genes. They found that of people with LDL of 190 or higher, just 2 percent had a familial hypercholesterolemia mutation.

Previous studies had suggested a mutation prevalence upwards of 25 percent, but those studies were limited to people with additional risk factors, such as a family history of high cholesterol, an abnormal physical exam or developing high cholesterol at an early age, in addition to current LDL of 190 or higher. This study is the largest to assess for familial hypercholesterolemia mutations among a broad population of people with elevated cholesterol.

The study's second objective was to examine the health impacts of having a familial hypercholesterolemia mutation, beyond the elevated cholesterol it causes. The researchers focused on early-onset coronary artery disease, or CAD, a condition in which plaque buildup causes the heart's main arteries to become constricted. CAD is considered early-onset when it occurs in men before age 55 or in women before age 65. Very high cholesterol is one of several known risk factors for CAD.

The results show that people with LDL of 190 or higher but no familial hypercholesterolemia mutation have a six times higher risk of early-onset CAD than people with LDL below 130, a level considered average. By contrast, people with LDL of 190 or higher who do have a familial hypercholesterolemia mutation face a 22 times higher risk of early-onset CAD. Although this increased risk is especially pronounced for those with LDL above 190, the study also found that people with a familial hypercholesterolemia mutation faced a substantially increased CAD risk even if their cholesterol level was only mildly elevated.

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

The research team used their genetic sequencing results to estimate that 412,000 of about 14 million adult Americans with an untreated LDL of 190 or higher have a familial hypercholesterolemia mutation.

The study's findings raise the question of whether screening for the mutations in all individuals with a high LDL would be desirable. Khera noted that a major goal of 'precision medicine' is to identify subsets of a population who face an increased disease risk and then design prevention and treatment strategies to address those specific risks. Identifying individuals with high LDL who carry a familial hypercholesterolemia mutation may represent one such opportunity. But while screening for a familial hypercholesterolemia mutation could potentially help doctors and patients work proactively to try to reduce CAD risk, there are a host of psychological and ethical issues to take into consideration before widespread implementation, Khera said.

Limitations of the study are that it focused on patients with early-onset CAD, rather than all CAD patients, and that it defined familial hypercholesterolemia as having a mutation in 1 of 3 genes for the disease: LDLR, APOB and PCSK9; ongoing work may identify additional genes that play an important role. Lastly, authors did not have access to detailed physical exam and family history features of study participants to enable direct comparisons to previous studies.