AnNPPBPromoter Polymorphism Associated With Elevated N-Terminal pro-B-Type Natriuretic Peptide and Lower Blood Pressure, Hypertension, and Mortality.
BACKGROUND
Elevated B-type natriuretic peptide (BNP) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the BNP gene (NPPB), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N-terminal pro-BNP (NT-proBNP) levels and outcomes.


RESULTS
A total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45-64 years; 1987-1989), with follow-up visits occurring every 3 years (visit 2-visit 4, 1990-1999), followed by visit 5 (2011-2013). NT-proBNP levels were measured at visits 2, 4, and 5. At visit 2, the GG genotype (frequency 18%) was associated with a 41% higher mean plasma level of NT-proBNP compared with the AA genotype (frequency 34%), with intermediate values observed in AGs (P=4.2×10-52). The GG genotype was associated with reduced systolic blood pressure (-1.6 mm Hg,P=0.006), diastolic blood pressure (-1 mm Hg,P=0.003), antihypertension medication use (odds ratio, 0.85; 95% CI, 0.74-0.97 [P=0.02]), and hypertension (odds ratio, 0.81; 95% CI, 0.72-0.92 [P=0.002]) compared with the AA genotype with intermediate values in AGs. These relationships persisted throughout subsequent visits. After a median follow-up of 23 years, there were 4031 deaths. With and without covariate adjustment, the GG genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78-0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61-0.92), and increased residual lifespan of 8 months from 50 years of age (P=0.02) versus AAs.


CONCLUSIONS
The rs198389 G allele in theNPPBpromoter is associated with elevated levels of NT-proBNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.|Division of Cardiovascular Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, MA.
Sara B
SB
Seidelmann
Departments of Pharmacy and Medicine, University of Wisconsin-Madison, Madison, WI.
Orly
O
Vardeny
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
Brian
B
Claggett
Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, TX.
Bing
B
Yu
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
Amil M
AM
Shah
Methodist DeBakey Heart Center, Baylor College of Medicine, Houston, TX.
Christie M
CM
Ballantyne
The Johns Hopkins Institute for Clinical and Translational Research, Baltimore, MD.
Elizabeth
E
Selvin
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
Calum A
CA
MacRae
Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, TX.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
Eric
E
Boerwinkle
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA ssolomon@bwh.harvard.edu.
Scott D
SD
Solomon
D001741:Black or African American / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics*; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008136:Longevity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000235:genetics*; D016017:Odds Ratio; D010446:Peptide Fragments / Q000097:blood*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States; D015854:Up-Regulation; D044465:White People / Q000235:genetics
D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain

NPPB
; N‐terminal pro–B‐type; blood pressure; hypertension; mortality; natriuretic peptide; polymorphism; rs198389; single nucleotide polymorphism