title: Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients.
abstract: Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. Upon individual SNP testing, two loci in MME were associated with ΔcGMP; another (rs16824656) showed association with BP change. In summary, the pharmacodynamic effects of BNP vary substantially in HF patients and are associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans.
authors.affiliation: Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI, USA. dlanfea1@hfhs.org.|Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA. dlanfea1@hfhs.org.|Center for Health Policy and Health Services Research, Henry Ford Hospital, Detroit, MI, USA. dlanfea1@hfhs.org.
authors.forename: David E
authors.initials: DE
authors.lastname: Lanfear
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Raza
authors.initials: R
authors.lastname: Abbas
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Ricoung
authors.initials: R
authors.lastname: She
authors.affiliation: Center for Health Policy and Health Services Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Badri
authors.initials: B
authors.lastname: Padhukasahasram
authors.affiliation: Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI, USA.|Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.affiliation: Spectrum Health System, Grand Rapids, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Langholz
authors.affiliation: Heart and Vascular Institute and Center for Clinical Genomics, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.|Center for Health Policy and Health Services Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: L Keoki
authors.initials: LK
authors.lastname: Williams
authors.affiliation: Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI, USA.|Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.affiliation: Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Chow
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006157:Guanosine Monophosphate / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000235:genetics*; D015260:Neprilysin / Q000008:administration & dosage / Q000235:genetics*; D010597:Pharmacogenetics; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D020097:Natriuretic Peptide, Brain; D006157:Guanosine Monophosphate; D015260:Neprilysin
keywords: Drug metabolism; Genetic polymorphisms; Heart failure; Natriuretic peptide; Pharmacogenetics