Only a small percentage of people with very high cholesterol can attribute their condition to a genetic mutation related to familial hypercholesterolemia (FH); however, individuals with these mutations face a high risk of developing early-onset coronary artery disease (CAD), according to a study presented April 3 at ACC.16 in Chicago and published simultaneously in the Journal of the American College of Cardiology.

The study, led by Amit V. Khera, MD, is the largest gene sequencing analysis to date focused on individuals with very high cholesterol. The researchers analyzed gene sequences of three FH genes: low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) – in twelve distinct cohorts including more than 26,000 participants in order to determine the diagnostic yield of gene sequencing to identify a FH mutation in individuals with severe hypercholesterolemia and the clinical impact of a FH mutation with regard to CAD risk within all levels of  low-density-lipoprotein cholesterol (LDL-C).

In the final cohort, 8,577 control patients who were free of CAD. While 430 participants had LDL-C >e;190 mg/dl, only eight of them (1.9 percent) carried a FH mutation. Among 11,908 participants from 5 prospective cohorts, 956 had LDL-C >e;190 mg/dl, but only 16 (1.7 percent) carried a FH mutation. Regardless of LDL-C levels, risk of early-onset CAD was higher among those with a FH mutation compared to those without. People with LDL-C >e;190 mg/dl and no FH mutation had a six times greater risk of early-onset CAD than those with LDL-C >130 mg/dl. However, those with LDL-C >e; 190 mg/dl and a FH mutation had a 22 times higher risk of developing early-onset CAD. People with a FH mutation faced a substantially increased CAD risk even if their cholesterol level was only mildly elevated.

According to the authors, one of the reasons for the increased risk is due to the fact that those with a FH mutation have elevated cholesterol levels from the time they are born, leading to a cumulative exposure of LDL-C over their lifetime. These results raise the question of whether all individuals with a high LDL should be screened for these mutations.

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

Keywords: ACC Annual Scientific Session, Apolipoproteins B, Cholesterol, LDL, Coronary Artery Disease, Hyperlipoproteinemia Type II, Mutation, Missense, Mutation, Nutrition Surveys

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