Identifying the genetic association between rheumatoid arthritis and the risk of pulmonary arterial hypertension

Abstract

Epidemiological and observational studies have indicated an association between rheumatoid arthritis (RA) and pulmonary arterial hypertension (PAH). However, consistent conclusions have not been reached due to various limitations. In order to determine whether RA and PAH are causally related, we conducted a Mendelian randomization (MR) study with two samples. Data for overall RA (13,621 cases and 262,844 controls), seropositive RA (5103 cases and 402,554 controls), seronegative RA (4192 cases and 311,210 controls), and PAH (248 cases and 289,117 controls) derived from the FinnGen consortium. The inverse variance weighted, along with four other effective methodologies, were employed to comprehensively infer the causal relationships between RA and PAH. To assess the estimation's robustness, a number of sensitivity studies were performed. Causal genetic association was found between seropositive RA and decreased risk of PAH (odds ratio (OR) = 0.812, 95% confidence interval (CI) = 0.687-0.959, p = 0.042), while no causal relationship was found between overall RA or seronegative RA and PAH (OR = 0.871, 95% CI = 0.645-1.175, p = 0.548; OR = 0.791, 95%CI = 0.471-1.328, p = 0.374, respectively). We are the first to use MR analysis to explore the causal relationship between RA and PAH, revealing a decreased risk of PAH in individuals with seropositive RA. Key Points • There is a notable genetic association between seropositive RA and a decreased risk of developing PAH. • No significant association was observed between overall RA or seronegative RA and the risk of PAH. • RA represents a heterogeneous disease, with its seropositive or seronegative forms exhibiting distinct genetic characteristics.

Keywords: FinnGen; Mendelian randomization; Pulmonary arterial hypertension; Rheumatoid arthritis; Seropositive.