Familial Hypercholesterolemia May Double Coronary Heart Disease Risk in Moderately Elevated LDL-C

Having familial hypercholesterolemia (FH) may double an individual’s risk of coronary heart disease (CHD) even if their low-density lipoprotein cholesterol (LDL-C) is only moderately elevated, according to a new study published in JAMA Cardiology.

“The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without,” the authors said. “Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.”

FH is a genetic condition that often leads to severely high LDL-C and high risk of premature CHD, with moderately elevated LDL-C defined as 130-189 mg/dL and severely elevated defined as 190 mg/dL or greater. However, the effect of FH on CHD risk for those with only moderately elevated LDL-C has not been well established.

Familial hypercholesterolemia questionnaire | Image credit: Richelle – stock.adobe.com

To assess this, the pooled cohort study included 21,426 individuals without preexisting CHD from 6 US cohort studies: the Atherosclerosis Risk in Communities study, the Coronary Artery Risk Development in Young Adults study, the Cardiovascular Health Study, the Framingham Heart Study Offspring cohort, the Jackson Heart Study, and the Multi-Ethnic Study of Atherosclerosis. Data spanned from 1971 to 2018, with a median (IQR) follow-up duration of 18 (13-28) years. The mean (SD) patient age was 52.1 (15.5) years, 56.2% were female, and the cohort was mostly White (64.2%).

Among the included individuals, 63 had a FH variant. The authors noted this small number as a limitation as it prohibited them from stratifying by subgroups by race or sex in analyses, and from examining potential interactions in relevant areas. Of this group, 22 had moderately elevated LDL-C, 33 had severely elevated LDL-C, and the other 8 had levels below 130 mg/dL. Additionally, those with an FH variant exhibited elevated LDL-C levels from early adulthood compared with matched individuals without a variant, despite having similar LDL-C levels in middle age.

Over the follow-up period, there were 1444 incident CHD events among those with moderately elevated LDL-C at baseline, and 315 events among those with severely elevated LDL-C at baseline.

Compared with individuals without the FH variant, the authors found that those with the variant and moderately elevated LDL-C were 2.9 times more likely to develop CHD (95% CI, 1.4-6.0), and 2.6 times more likely if they had the variant and severely elevated LDL-C (95% CI, 1.4-4.9). However, the association between FH variants and CHD slightly weakened after adjusting for baseline LDL-C level and became statistically insignificant after adjusting for cumulative past LDL-C exposure.

According to the authors, among the estimated 73.7 million US adults aged 20 and older without a history of CHD and with an untreated LDL-C level of 130 mg/dL or higher, over 417,000 individuals carry an FH variant. In patients with untreated moderately elevated LDL-C, those with an FH variant were projected to experience approximately 28,000 excess lifetime CHD events and 12,000 excess CHD deaths compared with those without the variant. Additionally, for individuals with untreated severely high LDL-C, those with an FH variant were projected to experience around 54,000 excess lifetime CHD events and 15,000 excess CHD deaths compared with those without the variant. These excess deaths correspond to an average of 1.6 future life years lost for individuals with an FH variant compared with those without, across both LDL-C groups.

“The increased CHD risk associated with FH variants appeared to be largely explained by the substantially higher lifetime cumulative LDL-C exposure in individuals with an FH variant compared with those without, suggesting that FH variants may provide incremental risk insights when only the baseline LDL-C is known, but not if cumulative past LDL-C exposure is known,” the authors concluded. “Further research is needed to assess the incremental value of adding genetic testing to traditional phenotypic FH screening.”

Reference

Zhang Y, Dron JS, Bellows BK, et al. Familial hypercholesterolemia variant and cardiovascular risk in individuals with elevated cholesterol. JAMA Cardiol. Published online January 31, 2024. doi:10.1001/jamacardio.2023.5366