Cardiovascular Resilience in Familial Hypercholesterolemia: Genomic Signatures from a Founder Population Highlight IL34 as a Candidate Gene Associated with Event-Free Survival

Background: Familial hypercholesterolemia (FH) is a semi-dominant genetic disorder characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and a markedly increased risk of premature atherosclerotic cardiovascular disease (CVD). Despite this elevated risk, some individuals with FH survive beyond 70 years of age without developing clinical CVD. This study aimed to identify genetic variants associated with protection against cardiovascular events and to uncover mechanisms contributing to this resilience phenotype. Methods: Whole-exome sequencing (WES) was performed in 243 French-Canadian heterozygous FH individuals carrying the pathogenic LDLR c.259T>G (p.Trp87Gly) variant. After stratification by age and cardiovascular event (CVE) status, 35 individuals with premature CVE and 20 individuals aged [≥]70 years who remained free of CVE despite spending several decades in the pre-statin era were selected for comparative analysis. Results: Variant annotation and quality-control validation using Firth logistic regression identified 12 genetic variants potentially associated with cardiovascular resilience. Among these, a stop-gain variant resulting from the single-nucleotide polymorphism rs4985556 in IL34 demonstrated the strongest association with event-free survival (allele frequency in CVE- = 0.25 vs. CVE+ = 0.00; {chi}2 = 19.25; P = 1.15 x 10-5). The IL34 stop-gain variant (c.639C>A [p.Tyr213*]) was associated with a markedly increased likelihood of cardiovascular event-free survival (OR = 20.9; 95% CI, 2.7-2841.7; P = 3.45 x 10-4). Conclusion: These findings identify IL34 as a potential cardiovascular resilience gene and highlight novel genetic determinants that may protect against cardiovascular events despite lifelong exposure to elevated LDL-C levels. In addition to IL34, eleven variants showed strong associations with a CVE-free phenotype and warrant further investigation to elucidate their biological mechanisms and potential relevance for cardiovascular disease prevention.