Among 243 French-Canadian carriers of the LDLR p.Trp87Gly pathogenic variant, whole-exome sequencing identified a stop-gain mutation in IL34 (rs4985556, p.Tyr213*) as the strongest genomic signal separating individuals who survived beyond age 70 without cardiovascular events from those who suffered premature events. The variant appeared in 25% of event-free survivors versus 0% of premature-event cases, yielding a striking odds ratio of 20.9 — though with a wide confidence interval (2.7–2841.7) reflecting the small comparative cohort of just 55 individuals.
This finding matters because IL34 is a cytokine ligand for CSF1R, the macrophage colony-stimulating factor receptor, positioning it as a plausible regulator of foam-cell formation and atherosclerotic plaque development — a biologically coherent mechanism for cardiovascular resilience even under lifelong LDL elevation. The discovery echoes the broader "resilience genomics" paradigm, where studying outlier survivors can reveal protective biology missed by standard risk-factor research.
However, significant caution is warranted. The sample is tiny, and the confidence interval's upper bound exceeds 2,800 — a statistical artifact of extreme separation in sparse data. The founder-population design, while genetically powerful, limits generalizability to other FH populations. Replication in independent cohorts is essential before any clinical translation is considered. Eleven additional variants also require mechanistic validation. Critically, this is a preprint posted on medRxiv and has not yet undergone peer review, meaning findings and effect estimates may change substantially. Treat this as hypothesis-generating, not practice-changing.
