Genetic Risk and Longitudinal Disease Activity in Systemic Lupus Erythematosus Using Targeted Maximum Likelihood Estimation

Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprised of 41 established SLE variants and clinically important disease activity as measured by the validated systemic lupus activity questionnaire (SLAQ) in a multi-ethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (> 4.0) for individuals with a high GRS compared to those with a low GRS across nine timepoints after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking, and education, as well as time-dependent confounding of missing visits. Individual SNP analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across timepoints 8 and 9 after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors.