Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure – a Mendelian randomization study in the FINRISK cohort

Abstract

Background Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and in previous studies several single nucleotide polymorphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. Purpose We investigated whether a causal relationship exists between natriuretic peptides and AF as well as HF using a Mendelian randomization approach. Methods N-terminal pro B-type natriuretic peptide (NT-proBNP) (N=6669), B-type natriuretic peptide (BNP) (N=6674) and mid-regional pro atrial natriuretic peptide (MR-proANP) (N=6813) were measured in the FINRISK 1997 cohort. Thirty common SNPs related to NT-proBNP, BNP and MR-proANP were selected from prior studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF separately. Polygenic risk scores (PRS) based on multiple SNPs were used as the genetic instrumental variable in Mendelian randomizations. Results PRS were significantly associated with the three natriuretic peptides. PRS were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation, other than a weak one, is unlikely. Conclusion In our Mendelian randomization approach, based on common genetic variation at the NPPA-NPPB locus, associations of the common polymorphisms with natriuretic peptides and the protein biomarkers themselves with incident disease could be confirmed. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms. Comparison of hazard ratios Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme, German Ministry of Research and Education