{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:05:16Z","timestamp":1791925516736,"version":"4.3.4"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2013disease and genotype\u2013phenotype links (sex-adjusted). MDR evaluated high-order gene\u2013environment interactions using 10-fold cross-validation and balanced accuracy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>rs2972607 was significantly associated with HDL-C, lymphocytes, platelet indices, AST\/ALT, UCB, and 5\u2032-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\u2009=\u20092.07; <jats:italic>P<\/jats:italic>\u2009=\u20090.007). MDR identified a statistical hub comprising rs2972607\u2009+\u2009glucose\u2009+<jats:sans-serif>\u2009TyG\u2009<\/jats:sans-serif>+<jats:sans-serif>\u2009WBC\u2009<\/jats:sans-serif>+<jats:sans-serif>\u2009HDL<\/jats:sans-serif>-C (Training Bal.Acc.CV\u2009=\u20090.996; Testing Bal.Acc.CV\u2009=\u20090.606; CV consistency\u2009=<jats:sans-serif>\u200910<\/jats:sans-serif>\/10). These patterns align with C5L2's established roles in lipid\/glucose handling and complement-driven inflammation<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>C5L2 polymorphisms, particularly rs2972607, are modest but consistent contributors to T2DM\u2013associated CHD and integrate with lipid, platelet, and inflammatory markers, highlighting a potential role in immune\u2013metabolic 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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2025.1629294","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:51:30Z","timestamp":1759297890000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["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 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