Cardiometabolic disease risk: the joint role of the UCP1, UCP2, UCP3, and FTO gene variants.

Cardiometabolic diseases (CMDs) impose a significant global health burden. Although CMDs rarely occur in isolation, most genetic studies have examined individual conditions separately, overlooking shared pathogenic pathways that link them into a continuous cardiometabolic continuum. Moreover, population-specific data for Eastern and Central Europe are scarce, and combined effects of variants in key metabolism-related genes, such as UCP1-UCP3 and FTO, have not been studied within cardiometabolic continuum. In this study, we investigated individual and combinatorial effects of UCP1-UCP3, and FTO variants on risk of CMDs as a continuum in Central Russian and Polish populations. We identified novel risk-increasing combinations: minor alleles of UCP2 c.-866G>A and UCP3 c.-55C>T; and minor alleles of UCP3 c.-55C>T and FTO c.46_23525T>A with wild alleles of four UCP1 and two UCP2 variants. Protective effects were observed for two novel combinations: minor allele of FTO c.46_23525T>A with wild alleles of all studied UCPs variants; and minor allele of UCP2 c.-866G>A with wild allele of UCP2 p.Ala55Val. The FTO variant showed context-dependent effects, shifting from risk to protection depending on genetic background. Increased age, BMI, WtHR, and BF% were also significant predictors, with sex-specific differences. Predictive quality of models integrating genetic and non-genetic factors (AUC up to 0.97) further underscore the potential value of this approach. In silico analysis suggested these variants exhibit regulatory functions across various tissues, which potentially involved in CMD pathogenesis. This is the first study to demonstrate combinatorial UCP1-UCP3 and FTO effects on risk of CMDs as a continuum in Central Russian and Polish populations.