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

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.