Genotypic variation in DPP4 modulates sensitivity to pharmacologic DPPIV inhibition

Dipeptidyl peptidase IV (DPPIV) is a membrane‐associated serine protease that cleaves dipeptides from the amino terminus of peptides with an X‐Pro (or X‐Ala) motif, including the incretin, glucagon‐like peptide 1 (GLP‐1). Pharmacological inhibition of DPPIV improves glucose homeostasis in Type 2 diabetics by inhibiting the degradation of GLP‐1. We hypothesized that genetic variation in DPP4 modulates sensitivity to pharmacological inhibition of DPPIV. Previously, we reported 7 single nucleotide polymorphisms (SNPs) associated with DPPIV activity and/or antigen levels. We have now genotyped 19 subjects with metabolic syndrome who participated in a prospective, randomized, double‐blind, placebo‐controlled parallel group crossover study. Subjects were randomized to receive the DPPIV inhibitor sitagliptin (100 mg/day) or placebo for 5 days. Sitagliptin decreased DPPIV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo, P ≤0.001). 3 of the 7 DPP4 SNPs associated with sitagliptin‐induced decreases in DPPIV activity. For example, sitagliptin reduced DPPIV activity to greater extent in individuals heterozygous at rs1861978 [13.57±0.41, 8.44±0.89, and 14.44±1.34 nmol/ml/min for G/G (n=2), G/T (n=9) and T/T (n=8) (P<0.001 for G/T versus others)]. There was no difference in DPPIV activity during placebo treatment [28.67±2.12, 26.41±3.64, and 31.71±3.83 nmol/ml/min in G/G, G/T and T/T]. In addition, the haplotype, rs12469968‐rs873826‐rs6733162, which we have previously reported to associate with ACE inhibitor‐associated angioedema, also associates with sitagliptin‐induced decreases in DPPIV activity (P<0.005). In conclusion, DPP4 genetic variation modifies the response to pharmacological DPPIV inhibition.