Cardiovascular health, heart disease
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Even people with moderately elevated low-density lipoprotein cholesterol (LDL-C) have higher risk of heart disease if they also had a variant for familial hypercholesterolemia (FH), according to new research. The long-term study included over 20,000 patients and reinforces the value of genetic testing for this condition.

The study was published in JAMA Cardiology last week. The lead author was Yiyi Zhang, PhD of Columbia University, but several other institutions were involved, including the Broad Institute of Massachusetts Institute of Technology and Harvard, Harvard Medical School, Massachusetts General Hospital, Mount Sinai, and others.

This study looked at pooled cohort study of 21,426 participants followed up with for a median of 18 years, FH variants were associated with a two-fold higher CHD risk, even among individuals with moderately elevated LDL-C. The increased CHD risk appeared to be largely explained by the substantially higher lifetime cumulative LDL-C exposure in those with an FH variant vs those without.

The findings suggest that genetic testing for FH may help refine risk stratification beyond LDL-C alone.

FH is a genetic disorder that often results in very high levels of LDL-C and high risk of premature coronary heart disease due to lifelong exposure to markedly elevated low-LDL-C levels. It is a tier 1 genetic condition identified by the U.S. Centers for Disease Control and Prevention as having significant potential for public health impact through improved diagnosis and treatment. FH is the most common genetic cause of CVD, affecting one in 250 individuals in the U.S. 

But, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C has not been well studied. And, despite national guideline recommendations of universal cholesterol screening beginning in childhood, a 2017 report estimated 90% of FH cases remain undiagnosed in the U.S. Further, recent evidence suggests undiagnosed FH cases may be associated with worse health outcomes, including a greater risk of premature death compared with diagnosed FH cases.

It’s notable that among patients with severe hypercholesterolemia (LDL-C ≥190 mg/dL), an FH variant is detected in fewer than five percent. And yet, FH gene variants are associated with greater risks of CHD, even when compared to patients without a variant with similar LDL-C levels. Previous studies have also shown that half of individuals with an FH variant may have LDL-C less than 190 mg/dL, suggesting that FH screening based on severely elevated LDL-C alone may miss a considerable number of individuals with an FH variant.

This study was based on data from six population-based prospective cohort studies: the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Cardiovascular Health Study (CHS), the Framingham Heart Study Offspring cohort (FHS-O), the Jackson Heart Study (JHS), and the Multi-Ethnic Study of Atherosclerosis (MESA).

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