Synergistic effects of NF-κB1 and inflammatory pathway polymorphisms on hypertension and dyslipidemia susceptibility in type 2 diabetes

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BACKGROUND: Type 2 diabetes mellitus (T2DM) patients exhibit a heightened susceptibility to concurrent hypertension (HTN) and dyslipidemia (DYS), conditions that reciprocally exacerbate cardiovascular risks. This study investigated the association between NF-κB1 polymorphism, related inflammatory mediators, and the predisposition to hypertension and dyslipidemia in T2DM patients, along with their correlations with biochemical parameters. METHODS: Genotyping of 452 T2DM patients was performed using SNP-scan high-throughput technology. Analyzed polymorphisms encompassed: NF-κB1-rs4648068, upstream transcriptional regulators (TLR2-rs3804099, TLR4-rs2149356, TLR9-rs352140), and downstream inflammatory mediators (IL6-rs1800796, IL6R-rs2228145, IL10-rs1800872, ICAM1-rs5498 and rs3093030). The cohort was stratified into three clinically defined groups: T2DM-only (T2DM group), T2DM with hypertension (T2MH group), and T2DM with comorbid hypertension and dyslipidemia (T2MH-DYS group). The T2MH and T2MH-DYS groups were further subclassified into Grade I-III according to hypertension staging criteria. Plasma biochemical profiles were systematically evaluated to delineate their associations with NF-κB1 pathway genetic variants. RESULTS: Patients with T2DM complicated by hypertension (T2MH) or hypertension with dyslipidemia (T2MH-DYS) exhibited distinct metabolic and inflammatory profiles. Genetic analyses revealed significant polymorphisms in inflammatory pathway genes (TLR9, TLR2, NF-κB1, IL6R) across subgroups. TLR9 rs352140 CT heterozygotes conferred a 2.8-2.94-fold increased risk of T2MH/T2MH-DYS, while NF-κB1 rs4648068 GG genotype reduced dyslipidemia risk by 64.8% (P = 0.004). Haplotype analysis identified synergistic effects: the TLR9/IL6R/NF-κB1 risk haplotype (G-C-T) increased hypertension risk 3.26-fold (P = 0.00069), and the IL10/TLR4/NF-κB1 protective haplotype (G-T-A) reduced dyslipidemia risk by 82% (P = 0.0063). IL10 rs1800872 TT genotype and TLR4 rs2149356 G allele were linked to dyslipidemia susceptibility in hypertensive diabetics. CONCLUSION: This study establishes that genetic variants in inflammatory pathways (TLR9, NF-κB1, IL6R) synergistically drive hypertension and dyslipidemia risks in T2DM.

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