Familial Hypercholesterolemia Variants Linked to Coronary Heart Disease Risk

Yiyi Zhang, PhD

Credit: Columbia University

Results from a recent pooled cohort study revealed the presence of familial hypercholesterolemia (FH) variants was associated with an approximate 2-fold higher risk of coronary heart disease (CHD), even with only moderately elevated cholesterol levels.¹

The analysis of ≥21,000 individuals without preexisting CHD, collected from 6 US cohort studies, showed the increased CHD risk primarily resulted from higher cumulative low-density lipoprotein cholesterol (LDL-C) exposure in those with an FH variant.

“In this study, the presence of an FH variant was associated with a higher risk of CHD, even when LDL-C levels were only moderately elevated and was projected to result in a substantial number of excess CHD deaths,” wrote the investigative team, led by Yiyi Zhang, PhD, division of general medicine at the Columbia University Medical Center.

The US Centers for Disease Control and Prevention (CDC) has previously identified FH as a tier 1 genetic condition. The agency indicated a significant public health impact may be made through improved diagnosis and treatment of FH. Although evidence has shown that FH can result in severely high LDL-C and subsequent risk of premature CHD, its effect has not been well-defined in individuals with moderately elevated cholesterol.

Zhang and colleagues aimed to quantify the risk of CHD linked to FH variants among people with moderate (130 – 189 mg/dL) and severe (190 mg/dL) hypercholesterolemia.¹ The investigative team also assessed whether increased CHD risk could be due to greater lifelong exposure to elevated LDL-C in individuals with an FH variant, as well as the population-level effect of FH variants on excess CHD-related mortality in the US population.

The analysis was based on data on 21,426 individuals without preexisting CHD from 6 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). These data were collected from 1971 to 2018, with a median follow-up of 18 years. Cox proportional hazards models were used to assess the risk for incident CHD associated with FH variants.

Participants in the study had a mean age of 52 years and 12,041 (56.2%) were female. Among the study population, 63 had an HF variant, including 22 individuals with moderately elevated LDL-C (0.3%) and 33 with severely elevated LDL-C (2.5%). Those with an FH variant were shown to have a higher LDL-C level starting in early adulthood, compared with matched individuals without a variant with similar LDL-C levels in middle age.

During the follow-up period, a total of 1444 incident CHD events occurred among those with moderately elevated LDL-C, and 315 events occurred among those with severely elevated LDL-C. Upon analysis, the adjusted hazard ratios (HRs) for incident CHD, comparing patients with and without FH variants, were 2.9 (95% CI, 1.4 - 6.0) and 2.6 (95% CI, 1.4 - 4.9) for those with moderately- and severely elevated LDL-C, respectively.

After adjustments were made for time-weighted average LDL-C from baseline, the association with FH variant was slightly attenuated for individuals with both moderately and severely elevated LDL-C. However, investigators noted that the association was considerably attenuated and no longer reached statistical significance after adjustment for cumulative LDL-C exposure from age 20 to the study baseline.

Among a population of 73.7 million adults in the US aged ≥20 years with no CHD history, and LDL-C ≥130 mg/dL, more than 417,000 carry an FH variant. These individuals were projected to experience 12,000 excess deaths in those with moderately elevated LDL-C and 15,000 deaths in those with severely elevated LDL-C, compared with those without an FH variant.

Despite these estimations, Zhang and colleagues indicated the predictive value of FH variants outside of LDL-C, as well as the cost-effectiveness of genetic testing in addition to conventional phenotypic FH screening, has not yet been established.

“Concerns about more limited understanding of FH variant prevalence in minoritized racial and ethnic groups of non-European ancestry, genetic discrimination, cost of genetic counseling, and need for follow-up of false-positive findings also have to be considered before adopting more widespread FH genetic screening,” they wrote.

References

1. _{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}
2. _{Gidding SS, Champagne MA, de Ferranti SD, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association [published correction appears in Circulation. 2015 Dec 22;132(25):e397]. Circulation. 2015;132(22):2167-2192. doi:10.1161/CIR.0000000000000297}