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Genetic Factors Influencing B-type Natriuretic Peptide Mediated Production of Cyclic Guanosine Mono Phosphate and Blood Pressure Effects in Heart Failure Patients

      Background

      Natriuretic peptides (NP) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which is partially genetic in origin. We explored genetic determinants of BNP-mediated cyclic guanosine monophosphate (cGMP) production and blood pressure changes.

      Methods

      HF patients (n=135) participating in two studies received recombinant human BNP (nesiritide) at standard doses and plasma cGMP levels were measured at baseline and during infusion (at 2 or 24 hours). Secondary endpoint of change in blood pressure (BP) was also examined. Genomic DNA was genotyped for 119 single nucleotide polymorphisms (SNP) in four candidate genes (Natriuretic peptide receptor 1 [NPR1], NPR2, NPR3, and Membrane metallo-endopeptidase [MME, aka NEP]). We tested the association of each genotype with the change in plasma cGMP (ΔcGMP) using linear regression adjusted for race and the use of bolus. We also performed gene-based association tests for each candidate. Inference for ΔBP was tested similarly.

      Results

      Participant mean age was 65 years, 35% were female, and 60% were non-white. Change in cGMP varied substantially across the cohort (range -13 to +43, Q1 +3.5, Q3 +10.8). Clinical and demographic factors were not associated with ΔcGMP except for race (p=0.019). Of the four candidate genes, gene-based testing for association of ΔcGMP was significant only for MME (p=0.04). Upon individual SNP testing adjusted for race and bolus use, 3 loci in MME were associated with ΔcGMP: rs9864287 (p=0.007), rs9829347 (p=0.001), and rs1836914 (p=0.007). The strongest of these was rs9829347 with false discovery rate of 0.11. These variants were not associated with changes in BP (all p>0.05). Another loci in MME (rs16824656) showed association with BP change (p=0.001) but not cGMP (p=0.3).

      Conclusion

      The pharmacodynamic effects of BNP vary substantially in HF patients, differs by self-identified race, and is associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans; additional studies are warranted.
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