C5L2 Gene Polymorphisms and Their Functional Interaction with Metabolic-Inflammatory Networks in T2DM-Associated CHD: Insights from an Integrative Genetic and Clinical Analysis in a Chinese Population

Mengjia LiuFen LiuAbulaiti DilihumaerJuan YangYating WangMeng YeTaotao JiaYing Gao^*

• First Affiliated Hospital of Xinjiang Medical University, Urumqi, China

Abstract Background: Comorbid type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) represent a major clinical burden, driven by overlapping metabolic and inflammatory mechanisms. Genetic factors are increasingly recognized as contributors to individual susceptibility, yet the specific variants influencing T2DM-associated CHD remain incompletely defined. Complement 5a receptor 2 (C5L2) serves as a receptor for acylation-stimulating protein (ASP) and C5a, regulating glucose uptake, triglyceride clearance, lipid metabolism, and immune signaling, and has been implicated in both pro- and anti-inflammatory pathways. This study investigates whether C5L2 polymorphisms are associated with T2DM-CHD and integrate with metabolic and inflammatory markers in the Han Chinese population from Xinjiang. Methods: A hospital-based case-control study was conducted involving 951 adult participants (206 with T2DM and CHD, and 745 controls), who were genotyped for two single-nucleotide polymorphisms (SNPs), C5L2 rs2972607 and rs8112962, using improved multiplex ligation detection reaction methods. Clinical, hematologic, and biochemical traits were measured. Logistic regression assessed genotype–disease and genotype–phenotype links (sex-adjusted). MDR evaluated high-order gene–environment interactions using 10-fold cross-validation and balanced accuracy. Results: rs2972607 was significantly associated with HDL-C, lymphocytes, platelet indices, AST/ALT, UCB, and 5′-NT; rs8112962 was associated with monocytes and HDL-C. Sex-stratified analyses confirmed associations between HDL-C and UCB in both sexes; platelet effects were stronger in females. In multivariable models, rs2972607 remained a modest but significant independent predictor (OR = 2.07; P = 0.007). MDR identified a statistical hub comprising rs2972607 + glucose + TyG + WBC + HDL-C (Training Bal.Acc.CV = 0.996; Testing Bal.Acc.CV = 0.606; CV consistency = 10/10). These patterns align with C5L2’s established roles in lipid/glucose handling and complement-driven inflammation Conclusions: C5L2 polymorphisms, particularly rs2972607, are modest but consistent contributors to T2DM–associated CHD and integrate with lipid, platelet, and inflammatory markers, highlighting a potential role in immune–metabolic interplay. While our findings are observational and hypothesis-generating, they are biologically plausible and align with established C5L2 biology, suggesting that integrating C5L2 genotyping with biochemical profiling may refine individualized risk prediction and guide future mechanistic studies.