PHARMACOGENOMIC ANALYSES IN ASCEND-HF INDICATE INFLUENCE OF NPR3ON NESIRITIDE BLOOD PRESSURE EFFECT
Lanfear DE, Gui H, Hannawi B, Connolly T, Li J, She R, Pereira N, Adams K, Hernandez A, Luzum J, Francke S, Tang WH, and Williams LK. PHARMACOGENOMIC ANALYSES IN ASCEND-HF INDICATE INFLUENCE OF NPR3ON NESIRITIDE BLOOD PRESSURE EFFECT. Journal of the American College of Cardiology 2021; 77(18):840.
Journal of the American College of Cardiology
Background: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized hospitalized HF patients to nesiritide or placebo and found no survival difference, but some data suggests genetic variation may influence nesiritide effect. We explored if genetic factors are associated with treatment effects on blood pressure (BP) in ASCEND-HF.
Methods: A genetic substudy was conducted including 2680 participants (2173 European Ancestry [EA] and 507 African Ancestry [AA]) that underwent genome-wide (GW) genotyping using Axiom Biobank Array (Affymetrix) and imputation via 1000 Genome reference panels. BP change was defined as systolic BP at 0.5 and 1 hour of nesiritide infusion minus baseline. We tested candidate SNPs in four genes of the BNP pathway (NPR1, NPR2, NPR3 and MME) and performed an unbiased GW association study. Linear mixed models, stratified by race, were used to estimate SNP*nesiritide interaction effects on BP change adjusting for SNP, nesiritide, sex, BMI, HTN, and top five genetic principal components. Overall results (both races) were obtained by meta-analysis. Significance was set at 0.0125 and 5.0x10-8 for candidate and GW study, respectively. Analysis of mortality or re-hospitalization was performed for significant SNPs.
Results: Candidate gene analysis showed two SNPs (rs3792761, minor allele frequency (MAF)=0.18 in EA, 0.37 in AA; rs817893, MAF=0.22 in EA, 0.42 in AA) that had significant interactions with nesiritide on BP (β=2.87, p=0.005 for rs3792761; β=2.26, p=0.012 for rs817893). However, these SNPs were not linked to mortality or re-hospitalization (HR=1.09, p=0.26 for rs3792761; HR=1.07, p=0.34 for rs817893). There were no loci meeting GW significance in either ancestral group nor in the meta-analysis, though a few suggestive hits were identified with p<1x10-5.
Conclusion: Our data indicate there could be pharmacogenomic interactions where NPR3 sequence variants modify the impact of BNP infusion. Further investigation to define responders vs. non-responders may be warranted.