Integrative Genetic Analysis of DPP4-Related Variants Reveals Risk Patterns for Type 2 Diabetes and Cardiometabolic...

Hypertension (HTN) and dyslipidemia (DYS) frequently complicate type 2 diabetes mellitus (T2DM), increasing cardiovascular risk. Genetic variation within the DPP4-ABCC8-INSR-IGF1 axis may underlie this clustering.

A total of 444 T2DM patients were stratified into T2DM (n = 256), T2DM with HTN (T2MH, n = 134), and T2DM with HTN and DYS (T2MH-DYS, n = 54). Six single nucleotide polymorphisms (SNPs) were genotyped, and associations were assessed by logistic regression and haplotype analysis with Bonferroni correction.

Clinical profiling showed higher C-reactive protein (CRP) and adrenocorticotropic hormone (ACTH) in T2MH and more severe metabolic derangements in T2MH-DYS. DPP4 rs3788979 was strongly linked to hypertension: CT (adjusted OR = 0.370, P = 0.001) and CC (adjusted OR = 0.424, P = 0.001) were protective versus TT, while in the T2MH vs T2MH-DYS comparison, the same CT and CC genotypes conferred increased dyslipidemia risk (adjusted OR = 5.418, P = 0.001; OR = 5.620, P = 0.002). In the comparison between T2DM and T2MH-DYS, the same genotypes also increase the susceptibility risk. IGF1 rs972936 TC genotype also reduced T2MH risk (adjusted OR = 0.460, P = 0.006). Haplotype analysis identified GAATGT as protective against hypertension (OR = 0.312, P = 0.0014) and GACCGT as a risk haplotype for dyslipidemia (OR = 4.113, P = 0.0021); both remained significant after Bonferroni correction.

Variants within the DPP4 axis influence susceptibility to HTN and DYS in T2DM, with GAATGT and GACCGT emerging as robust haplotype markers. Notably, the risk conferred by DPP4 rs3788979 genotypes was modulated by lipid status: CT/CC were protective against hypertension alone but became risk factors when dyslipidemia co-occurred.