Despite striking transcriptional activation of cuproptosis and copper-transport genes in atherosclerotic plaque — including SLC31A2 correlating with M1-macrophage infiltration at r = +0.87 and ATP7B inversely at r = −0.73 — genetically predicted expression of 11 cuproptosis/copper genes showed no colocalization-supported causal effect on coronary artery disease (CAD) in a landmark two-sample cis-Mendelian randomization study. The outcome dataset spanned 181,522 CAD cases and over 1.16 million participants. Two genes, MTF1 and DLAT, reached nominal MR significance but failed colocalization, flagged as linkage-disequilibrium confounding rather than causality.
This is a methodologically important null result that deserves serious attention. The cuproptosis field has rapidly generated biomarker and therapeutic target nominations based almost entirely on observational expression data — a pattern that historically produces high rates of clinical translation failure. By applying stringent causal inference tools (cis-eQTLs from eQTLGen's 31,684 individuals plus GTEx tibial artery data, validated through LPL as a positive control), this team demonstrates that plaque enrichment of copper-metabolism genes likely reflects inflammatory microenvironment rather than upstream causal biology. Well-instrumented genes including ATP7B and FDX1 produced precise null estimates, excluding odds ratios above approximately 1.05 per SD — a tight bound. Limitations include European-only ancestry, whole-blood eQTL instruments as proxies for plaque tissue, and the inherent inability of blood-based cis-eQTLs to fully capture arterial gene regulation. As a preprint not yet peer-reviewed, these conclusions require independent validation before influencing therapeutic strategies.
