title: The effect of the brain-type natriuretic peptide single-nucleotide polymorphism rs198389 on test characteristics of common assays.
abstract: OBJECTIVE
  To assess in a US general adult population the effect of the functional single-nucleotide polymorphism rs198389 in the promoter region of the gene of brain-type natriuretic peptide (BNP) on 3 commonly used BNP assays, clinical phenotype, disease prevalence, overall survival, and diagnostic test characteristics of BNP as a biomarker.
  
  
  METHODS
  We genotyped for rs198389 in a random sample of the general population (aged ≥ 45 years; n = 1970; enrolled between June 1, 1997, and September 30, 2000) from Olmsted County, Minnesota. Patients were characterized biochemically, clinically, echocardiographically, and regarding BNP molecular forms (2 assays for BNP and 1 assay for amino-terminal proBNP). Median follow-up was 9 years.
  
  
  RESULTS
  Genotype frequencies were in Hardy-Weinberg equilibrium (P = .98): TT genotype, n = 645 (32.7%); TC genotype, n = 983 (49.9%); and CC genotype, n = 342 (17.4%). The C allele independently predicted higher BNP forms (P<.001 for all assays). Genotypes did not differ with regard to clinical and echocardiographic phenotype or overall survival. When previously reported genotype-unadjusted cut points for the detection of left ventricular ejection fraction less than or equal to 40% (n = 37 [1.9%]) and less than or equal to 50% (n = 116 [6.0%]) were used, sensitivity generally increased with the number of C alleles, whereas specificity decreased, both on average by more than 10% for the TT vs CC genotype.
  
  
  CONCLUSIONS
  The C allele of rs198389 is common in the general US population and is associated with higher concentrations of BNP molecular forms but not with cardiovascular phenotype or survival. The C allele confounds the test characteristics of commonly used assays.
authors.affiliation: Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. costello.lisa@mayo.edu
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Costello-Boerrigter
authors.forename: Guido
authors.initials: G
authors.lastname: Boerrigter
authors.forename: Syed
authors.initials: S
authors.lastname: Ameenuddin
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Mahoney
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Slusser
authors.forename: Denise M
authors.initials: DM
authors.lastname: Heublein
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodeheffer
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012680:Sensitivity and Specificity; D014481:United States; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain