Abstract 18134: Phenome-wide Study of Electronic Medical Record Data Reveals Novel Association of Natriuretic Peptide A Genetic Variant With Rheumatoid Arthritis

Abstract

Introduction: Phenome-wide association studies (PheWAS) using electronic medical record (EMR)-linked biobanks have been used not only to identify and replicate known associations of genetic variants with disease phenotypes but have also resulted in the discovery of potentially novel genotype-phenotype relationships. The natriuretic peptide (NP) system plays an important role in a broad range of disease processes including cardiovascular and inflammatory diseases. We hypothesized that performing a PheWAS using previously known functional genetic variants of the NP system may result in novel disease associations that could provide mechanistic insights in an unbiased manner. Methods: We scanned for associations between 9 single-nucleotide polymorphisms (SNPs) in the NP system and 27 EMR-derived chronic disease phenotypes in 3,025 individuals participating in a case-control study of peripheral arterial disease. The EMR phenotypes were identified using two or more ICD-9-CM diagnosis codes based on the AHRQ Clinical Classifications Software (CCS). The relationship of SNPs and phenotypes were modeled using logistic regression adjusting for gender. Results: We identified rs5065, a SNP located in the stop codon of exon 3 of the NPPA gene, to be the strongest associated SNP with rheumatoid arthritis (RA) (OR=0.78, p=0.0008, q-value=0.11). The SNP leads to the extension of atrial natriuretic peptide (ANP) by 2 additional arginines at the C terminus. Cardiovascular disease is known to be the leading cause of death in patients with RA and ANP plays an important immunomodulatory role by inhibiting inducible nitric oxide synthase, reducing TNF-α production and attenuating prostaglandin E2 production in macrophages. Circulating NPs have been used to screen for occult cardiac disease and are associated with mortality in RA. This study demonstrates for the first time the importance of the relationship between genetic variation in the NP system and RA. Conclusions: PheWAS was successfully used as a tool to identify a novel association of functional genetic variation in the NPPA gene with RA. The observation is hypothesis generating and further replication studies are required to determine the role of rs5065 in cardiovascular outcomes of RA.