The genetic determinants of the cardiovascular disease biomarker: N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP)

Background: NT-proBNP is a biomarker of cardiovascular diseases (CVD), especially heart failure. Only one study has estimated the heritability of NT-proBNP, and found it to be significantly heritable. However, multiple studies have tested single nucleotide polymorphism (SNP) associations with NT-proBNP and risk of CVD. Gaining a better understanding of the genetic regulation of NT-proBNP and CVD risk could lead to improved treatment and prevention of CVD, which is of great public health significance. Objective: Estimate the heritability of NT-proBNP, test the genetic association of SNPs in the BNP gene region with NT-proBNP levels and CVD outcomes, and test the association of NT-proBNP with CVD outcomes in the Long Life Family Study (LLFS). Methods: Our study included 4618 participants from the LLFS (mean age 70.5 years, 55.1% female). Genotypes were ascertained by the Human Omni Chip 2.5 v1 (Illumina, CA) and SNPs for this study (N=15) were pulled from the NPPB and NPPA gene regions, which neighbor each other on chromosome 1 and encode for BNP and A-type natriuretic peptide, respectively. We performed all analyses in the Sequential Oligogenic Linkage Analysis (SOLAR) program to account for family relatedness, and adjusted for age, sex, and field center. Full models also included adjustment for BMI, blood pressures, antihypertensive therapy, diabetes, myocardial infarction (MI), atrial fibrillation (AF), and creatinine. Results: Residual heritability of NT-proBNP was 0.22 (p=6 × 10-13) in the full model. In this model, the minor alleles of rs198389 and rs5063 were independently associated with greater NT-proBNP level. NT-proBNP was negatively associated with BMI, blood pressure, AF, and MI. The minor alleles of rs198358, rs198388, and rs632793 were inversely associated with a history of AF, but were not independent of NT-proBNP. However, the minor allele of rs632793 was inversely associated with systolic blood pressure independent of NT-proBNP. Conclusion: In these long-lived families, NT-proBNP is significantly heritable, and rs198389, rs5063, rs198358, rs198388, and rs632793 were found to be associated with either NT-proBNP level or presence of CVD outcomes. This study replicates previous findings that variants in this region (rs198358, rs198388, rs632793) are associated with higher NT-proBNP and are protective against CVD outcomes