Cardiovascular risk among individuals with and without a genetic mutation for familial hypercholesterolemia: A...

Patients with familial hypercholesterolemia (FH) are exposed to elevated low-density lipoprotein cholesterol (LDL-C) levels from early life. Whether FH independently increases risk of atherosclerotic cardiovascular disease (ASCVD) remains uncertain.

To compare the risk of developing ASCVD between individuals with and without FH mutations across different levels of LDL-C.

A registry-based cohort study including patients genetically tested for FH from 1991 to 2023. Exposure was genetic mutation in the LDL, APOB, or PCSK-9 genes within the different LDL groups: LDL-C <5 mmol/L, LDL-C 5 to 7 mmol/L, and LDL-C >7 mmol/L. ASCVD was defined as composite major adverse cardiac events (MACE) comprising myocardial infarction, cardiovascular death, angina pectoris, and stroke. An adjusted Cox proportional hazards model was used.

The study included 2327 patients, comprising 958 with FH mutation and 1369 without. Mean follow-up time was 13.9 ± 9.8 years. LDL-C was significantly associated with the risk of future ASCVD, with a multivariable-adjusted hazard ratio (HR) of 1.17 (95%CI: 1.13-1.22, P < .001) per 1 mmol/L increase in LDL-C. No significant difference in risk of MACE was found between those with vs without a genetic FH mutation (LDL-C <5 mmol/L HR 0.91 [95%CI: 0.48;1.74], LDL-C 5 to 7 mmol/L HR 0.91 [95%CI: 0.68;1.21] and LDL-C >7 mmol/L HR 1.13 [95%CI: 0.91;1.41]) using patients without FH as reference.

Genetic FH mutation did not confer additional risk when compared to individuals without an FH mutation but with similar LDL-C levels. These findings suggest that LDL-C levels - rather than FH mutation status - should guide the intensity of lipid-lowering therapy.