Genetic and Non-Genetic Factors Influencing Pharmacokinetics of B-type Natriuretic Peptide


      Natriuretic peptides (NP) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partially genetic in origin. We explored genetic and non-genetic contributions to BNP inactivation.


      Chronic HF patients (n=95) received recombinant human BNP (nesiritide) at standard doses and BNP levels were measured at baseline, 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single nucleotide polymorphisms (SNP) in two candidate genes (Membrane Metallo Endopeptidase [MME] and Natriuretic Peptide Receptor 3 [NPR3]). We tested the association of patient characteristics and genotype with 5 pharmacokinetic (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype association with all 5 PK parameters simultaneously.


      Participant mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs. reduced) was associated with PK (p<0.01), while renal function, race, gender, age, and BMI and were not (p=NS). Two SNPs in MME (rs989692, rs6798179) and two in NPR3 (rs6880564, rs2062708) also had associations with PK (each p<0.05).


      Rates of inactivation of BNP varies greatly in HF patients, differs by HF type, and possibly by MME and/or NPR3 genotype. Additional study is warranted.
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