Cardiovascular risk among individuals with and without a genetic mutation for familial hypercholesterolemia: A long-term study

Background Patients with Familial hypercholesterolemia (FH) are exposed to elevated LDL-C levels from early life. Whether FH independently increases risk of atherosclerotic cardiovascular disease (ASCVD) remains uncertain. Objective To compare the risk of developing ASCVD between individuals with and without FH mutations across different levels of LDL-C. Methods A registry-based, cohort study including patients genetically tested for FH from 1991-2023. Exposure was genetic mutation in the LDL, APOB or PCSK-9 genes within the different LDL groups LDL-C <5 mmol/L, LDL-C 5-7 mmol/L and LDL-C >7 mmol/L. ASCVD was defined as composite major adverse cardiac events (MACE) comprising of myocardial infarction, cardiovascular death, angina pectoris and stroke. Adjusted cox proportional hazards model was used. Results The study included 2,327 patients, comprising of 958 with FH mutation and 1,369 without. Mean follow-up time was 13.9 ± 9.8 years. LDL-C was significantly associated with risk of future ASCVD with a multivariable adjusted HR of 1.17 (95%CI: 1.13-1.22, p <0.001) per 1 mmol/L increase in LDL-C. No significant difference in risk of MACE was found between those with versus without a genetic FH mutation (LDL-C <5 mmol/L HR 0.91 (95%CI: 0.48;1.74), LDL-C 5-7 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. Conclusion 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.