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

Abstract Background/Introduction Previous studies have suggested an increased risk of cardiovascular disease in patients with FH mutations compared to patients without FH mutations, at equivalent low-density lipoprotein cholesterol (LDL-C) levels. Purpose To determine the difference in prognosis between patients with and without FH mutations at different LDL-C concentrations. Methods All patients genetically tested for FH at a tertiary centre in the Central Denmark Region from 1991 to 2023 were included in this registry-based, cohort. Exposure was a positive genetic test compared to negative genetic test in the LDL, APO-B 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. Primary endpoint was a composite major adverse cardiac event (MACE) comprising myocardial infarction, incident angina pectoris and cardiovascular death. Difference in MACE was estimated using adjusted cox proportional hazards model. Results In total 2,675 patients were genetically tested for FH. The mean participant age was 43 ± 16.6 years, and the mean follow-up time was 14 ± 9.8 years. Among individuals with LDL-C 5 mmol/L, the mean LDL-C was 3.90 ± 0.8 mmol/L in those with the mutation and 3.39 ± 1.0 mmol/L in those without. For individuals with LDL-C levels between 5–7 mmol/L, the mean LDL-C was 5.96 ± 0.6 mmol/L in mutation carriers and 5.88 ± 0.5 mmol/L in non-carriers. Among those with LDL-C 7 mmol/L, the mean LDL-C was 8.56 ± 1.5 mmol/L in individuals with the mutation and 7.83 ± 1.6 mmol/L in those without. LDL-C levels was associated MACE with 1 mmol/L higher LDL-C increasing risk by 17% (HR 1.17 (95%CI:(1.13;1.21))). 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 (Figure 1). Conclusion(s) LDL-C was associated with higher risk of MACE, but no significant difference in MACE was found in patients with FH mutations in comparison to patients without a FH mutation at the same LDL-C concentrations. These results demonstrate that high LDL-C should be managed irrespectively of whether there is genetic FH or not.Genetic mutation and cardiovascular risk