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.

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; 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.