The effect of the brain-type natriuretic peptide single-nucleotide polymorphism rs198389 on test characteristics of common assays.

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. PATIENTS AND 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.
CONCLUSION: 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.