Abstract
Dipeptidyl peptidase-4 (DPP4) can influence lipid homeostasis and atherosclerosis progression. We aimed to assess the association of DPP4 gene polymorphisms with hypoalphalipoproteinemia and DPP4 serum levels, in a cohort of Mexican individuals. Five DPP4 polymorphisms (rs12617336, rs12617656, rs1558957, and rs3788979, and rs17574) were genotyped in 748 participants with and 745 without hypoalphalipoproteinemia. The associations were evaluated using logistic regression analyses. Under inheritance models adjusted for confounding variables, the rs12617336 (OR = 0.22, Pheterozygote = 0.001) and rs17574 (OR = 0.78, Padditive = 0.022; OR = 0.73, Pdominant = 0.012; OR = 0.73, Pheterozygote = 0.017; OR = 0.72, Pcodominant1 = 0.014) minor alleles were associated with a low risk of hypoalphalipoproteinemia. After the correction for multiple comparisons, the associations were marginal except the association of the rs12617336 that remaining significant. Additionally, both DPP4 minor alleles were associated with protection for the presence of insulin resistance (IR) (OR = 0.17, Pheterozygote = 0.019 for rs12617336 and OR = 0.75, Padditive = 0.049 for rs17574). The rs12617336 minor allele was also associated with a low risk of hyperinsulinemia (OR = 0.11, Pheterozygote = 0.006). Differences in DPP4 levels were observed in individuals with rs17574 genotypes, the rs17574 GG genotype individuals had the lowest levels. Our data suggest that rs12617336 and rs17574 DPP4 minor alleles could be envisaged as protective genetic markers for hypoalphalipoproteinemia, IR, and hyperinsulinemia. The rs17574 GG genotype was associated with the lowest DPP4 levels.
Highlights
Hyperglycemia, insulin resistance (IR), dyslipidemia, oxidative stress, and inflammation are well-documented risk factors for subclinical atherosclerosis (SA) and cardiovascular disease (CVD)
The rs12617336 and rs17574 minor alleles were associated with a 20–25% risk reduction for the presence of hypoalphalipoproteinemia, a metabolic abnormality that often coexists with obesity
The rs17574 polymorphism, that we report associated with a low risk of hypoalphalipoproteinemia, is located in exon 2 of the gene; the computer analysis that we carried out establishes that the G allele in this position can affect the efficiency of cutting and splicing, modifying the binding affinity for splicing factors SF2ASF1 and SF2ASF2
Summary
Hyperglycemia, insulin resistance (IR), dyslipidemia, oxidative stress, and inflammation are well-documented risk factors for subclinical atherosclerosis (SA) and cardiovascular disease (CVD). Dipeptidyl peptidase-4 (DPP4, known as CD26) is a multifunctional protein expressed in two molecular forms: a soluble form circulating in the plasma, and a membraneanchored form Both forms have peptidase activity and cleave a wide variety of substrates, such as incretins (GLP-1-glucagonlike peptide-1, and GIP-glucose-dependent insulinotropic polypeptide), chemokines, growth factors, and regulatory peptides (Mulvihill and Drucker, 2014). Considering the high prevalence of obesity and comorbidities such as T2DM (Rtveladze et al, 2014) and hypoalphalipoproteinemia in the Mexican population (Hernández-Alcaraz et al, 2020) and that the expression of DPP4 is increased in these abnormalities, the present study aimed to evaluate the association of the DPP4 polymorphisms with the presence of hypoalphalipoproteinemia and with DPP4 levels in a cohort of Mexican individuals. Based on a functional prediction analysis, we decide to study 5 DPP4 polymorphisms (rs12617336, rs12617656, rs1558957, rs3788979, and rs17574) with possible functional consequences and/or with minor allele frequency >5%
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