Fewer Than 2% of Severe Hypercholesterolemia Cases Related to Familial Hypercholesterolemia

While fewer than 2% of severe hypercholesterolemia cases can be linked to familial hypercholesterolemia mutations, the latter does increase risk for coronary artery disease.

Whole gene analysis of patients from 12 studies found that fewer than 2% of cases of severe hypercholesterolemia could be explained by familial hypercholesterolemia (FH). However these patients have a much higher risk of coronary artery disease (CAD) possibly due to more lifetime exposure.

Amit Khera, MD of the Center for Human Genetic Research and Cardiovascular Research Center at Massachusetts General Hospital in Boston presented the study findings at the 2016 American College of Cardiology Scientific Sessions & Expo (ACC) in Chicago.

The simultaneous publication in the Journal of the American College of Cardiology explains that patients with severe, primary hypercholesterolemia with (LDL) cholesterol ≥190 mg/dL are often assumed to have FH.

FH is associated with dysfunctional clearance of LDL-C particles. Further, it unknown how much FH contributes to severe hypercholesterolemia in the general population and its impact on CAD risk beyond LDL-C levels.

Dr Khera and colleagues performed whole exome sequencing for 3 causative genes (PCSK9, APOB, and LDLR) on 5 prospective cohorts (n=11 908 participants) and 7 case-control cohorts (n=8577 without CAD and n=5540 with CAD).

Among the 5 prospective cohorts, researchers analyzed data from the ARIC (Atherosclerosis Risk in Communities) study (n=5727) and the FHS Offspring study (Framingham Heart Study; n=2714) to estimate the impact of FH status on the cumulative exposure to LDL-C.

Of the patients without CAD (n=8577), a total of 5% (n=430) had LDL-C ≥190 mg/dL with only 1.9% (n=8) carrying the FH mutation (95% confidence interval [CI]: 0.9-3.8%). A similar prevalence of FH was observed in the participants of the prospective cohort studies (1.7%; 95% CI: 1.0-2.8%) and in the 12 combined studies (1.7%).

Compared to the reference group with an LDL-C <130 mg/dL without the FH mutation, the odds of developing CAD were higher in participants with elevated LDL-C of ≥190 mg/dL without FH (odds ratio [OR]: 6.0; 95% CI: 5.2-6.9) and substantially higher in participants with elevated LDL-C of ≥190 mg/dL and the FH mutation (OR: 22.3; 95% CI: 10.7-53.2).

To assess lifetime LDL-C exposure in participants with the FH mutation, the mean LDL-C was compared to the prior study visit LDL-C levels. The investigators found patients with the FH mutation had a 17 mg/dL higher mean LDL-C during the prior visits than non-carriers (95% CI: 5-29, P=.007). 

“At this point, on the basis of this study, I personally would not be perusing genetic testing in patients with severe hypercholesterolemia because the effectiveness and cost-effectiveness of such a strategy at a population level remain unclear,” Frederick Masoudi, MD, chief science advisor, National Cardiovascular Data Registry and professor of medicine at the University of Colorado, told Cardiology Advisor. “This study, however, does seem to inform a further study to determine about the impact of genetic testing on the effectiveness in terms of patient outcomes.”

In an ACC press conference, Dr Khera noted, “Many of us clinicians assume many of these people with very high levels of low-density lipoprotein cholesterol (LDL-C) have an FH mutation. And it turns out that is actually not the case. Only about 2% of these individuals have the FH mutation. And we think the remainders are likely related to either polygenetic or environmental causes.”

Disclosures: The study was funded by multiple grants and Merck, Novartis, and Pfizer. Dr Khera was supported by an ACC/Merck Fellowship and reported consulting fees from Amarin and Merck.


  1. Khera AV, Won H-H, Peloso GM, et al. Presentation 404-12. Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology. April 2-4, 2016; Chicago, IL. 
  2. Khera AV, Won H-H, Peloso GM, Lawson KS. Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016. doi:10.1016/j.jacc.2016.03.520.