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Genetic mutations, beyond cholesterol levels, are important for predicting CVD
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CHICAGO — Although genetic mutations associated with familial hypercholesterolemia are rarer than previously thought, people with these mutations are at high risk for developing early-onset CAD, according to a new study presented at the American College of Cardiology Scientific Session.
Amit V. Khera, MD, a cardiology fellow at Massachusetts General Hospital, and colleagues first investigated the prevalence of a familial hypercholesterolemia (FH) mutation among people with LDL levels of 190 mg/dl or higher by analyzing data from previous studies. The LDLR, APOB and PCSK9 genes were sequenced in 5,540 participants with CAD, 8,577 participants without CAD and 11,908 participants from prospective cohort studies.
Amit V. Khera
The study was simultaneously published in the Journal of the American College of Cardiology.
Of the 8,577 participants without CAD, 430 had a LDL cholesterol level ≥ 190 mg/dL and only 1.7% of them carried an FH mutation. In addition, the mutation was found in only 1.7% of the prospective cohort participants with elevated LDL.
Khera and colleagues estimated based on National Health and Nutrition Examination Survey data that approximately 2% of people with a LDL level of 190 mg/dL or higher had mutations in any of the three known FH genes. This translates to about 412,000 of approximately 14 million adult Americans with untreated LDL of 190 mg/dL or higher.
“Many clinicians assume that patients with LDL above 190 mg/dL have an [FH] mutation, but there are other causes,” Khera said during a press conference. “Elevated LDL may be due to polygenic and environmental causes instead of [FH].”
Khera and colleagues next evaluated the risk for early onset CAD in people with FH. According to their analysis, those with LDL of at least 190 mg/dL and an FH mutation have a 22-fold higher risk for early-onset CAD (OR = 22.3; 95% CI, 10.7–53.2) compared with the sixfold higher risk (OR = 6; 95% CI, 5.2–6.9) in individuals with LDL 190 mg/dL or higher but no FH mutation. These results demonstrate for the first time that, beyond just measuring an individual’s LDL, knowledge of FH mutation status may be a clinically important predictor of coronary risk.
Khera said that genetic screening might be a useful tool for proactively identifying and treating those with these mutations, especially in younger individuals with high LDL, but acknowledged that there are psychological and ethical issues that need to be addressed before implementation. – by Tracey Romero
References:
Khera AV, et al. Joint ACC/JAMA Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
Khera AV, et al. J am Coll Cardiol. 2016; doi:10.1016/j.jacc.2016.03.520.
Disclosure: The study was funded in part by Merck, Novartis and Pfizer. Khera reports receiving an ACC/Merck Fellowship award and consulting fees from Amarin and Merck. Please see the full study for all other researchers’ relevant financial disclosures.
Perspective
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Karol E. Watson, MD, PhD, FACC
In the cohort the researchers studied — individuals with early-onset coronary disease — and with the genes they sequenced, only 1.9% of the population carried a mutation. But in reality, there are probably other genes or gene clusters that can also cause FH. Because these are not known, the researchers obviously couldn't test for them. Also, the authors didn't have access to any physical exam findings or family history. These are things we always use in addition to LDL level to detect FH.
The authors didn't do any deletion or duplication testing, so they would have missed some FH cases due to that. And a potentially very big issue with this study is that missense mutations were only included if predicted to be deleterious by all five algorithms used or if labeled as pathogenic or likely pathogenic in the database they used.
I am a member of the scientific advisory board of the FH Foundation and we have always known that LDL > 190 is very non-specific, but we think approximately 20% of such patients will actually have FH, not the 1.9% found in this study.
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