medwireNews: Individuals who carry a familial hypercholesterolemia (FH) genetic variant are almost three times more likely to develop coronary heart disease (CHD) than noncarriers, even when their low-density lipoprotein cholesterol (LDL-C) level is only moderately elevated, US researchers report.
Yiyi Zhang (Columbia University Medical Center, New York) and co-investigators say their findings “suggest that genetic testing for FH has the potential to refine risk stratification beyond LDL-C alone and, with early treatment, could reduce cumulative exposure to high LDL-C and subsequently reduce excess CHD deaths.”
Their study included 21,426 individuals (mean age 52 years; 56% women) with no pre-existing CHD from six US population-based studies.
All participants underwent whole genome sequencing, which identified an FH variant in LDLR, APOB, or PCSK9 in 0.1% of 11,794 individuals with normal LDL-C (<130 mg/dL), 0.3% of 8295 individuals with moderate LDL-C elevation (130–189 mg/dL), and 2.5% of 1337 with severe LDL-C elevation (≥190 mg/dL).
During a median 18 years of follow-up, there were 1444 incident CHD events among participants with moderately elevated LDL-C and 315 events among those with severely elevated LDL-C.
Using Cox proportional hazards models, the researchers calculated that individuals with moderately elevated LDL-C who carried an FH variant were a significant 2.9 times more likely to develop CHD during follow-up than their noncarrier counterparts, after adjustment for race, ethnicity, sex, smoking status, BMI, high-density lipoprotein cholesterol, systolic blood pressure, diabetes, and use of lipid-lowering or antihypertensive medications.
The corresponding risk increase was a significant 2.6-fold for people with severely elevated LDL-C.
The risks remained significantly elevated, but slightly attenuated, with further adjustment for baseline LDL-C level, but lost statistical significance when the team also accounted for cumulative past LDL-C exposure.
Therefore, “[t]he 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,” Zhang et al remark.
They estimate that among 73.7 million US adults aged 20 years and older with no history of CHD and an LDL-C level of 130 mg/dL or higher, more than 417,000 carry an FH variant. With moderately elevated LDL-C, these individuals were projected to experience more than 12,000 excess CHD deaths relative to people without an FH variant. The excess mortality would be 15,000 in those with severely elevated LDL-C and the excess deaths translate to a mean of 1.6 and 1.5 future life years lost, respectively.
Writing in JAMA Cardiology, Zhang and co-authors conclude: “Further research is needed to assess the incremental value of adding genetic testing to traditional phenotypic FH screening.”
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