Abstract
OBJECTIVES: The impact of the genetic risk for RA on resultant disease phenotype in RA is incompletely understood. Using individual genetic variants associated with RA and a polygenic score (PGS), we hypothesized that those with higher genetic risk for RA would demonstrate a more severe disease course.
METHODS: We genotyped participants from the Veterans Affairs RA registry (VARA), a prospective cohort of RA. We evaluated associations between PTPN22 R620W genotype, HLA-DRB1 shared epitope (SE; 0, 1, or 2 copies of a high-risk HLA allele), and a non-HLA PGS with RA disease activity scores and disease characteristics using linear and logistic regression, adjusted for sex, age, and principal components of population structure.
RESULTS: Among 2557 VARA participants, 50 (2%) were homozygous for PTPN22 R620W, and 1603 (62%) had a PGS greater than the 50th percentile when compared with a reference population. PTPN22 R620W, SE, and the PGS were strongly associated with seropositivity (PGS OR = 1.41, 95% CI 1.26-1.58, P < 0.001). At enrolment, compared with those with no R620W alleles, those with two alleles had higher disease activity [CDAI β = 6.10, 95% CI 1.23-10.97, P = 0.014]; no difference was observed for those with one R620W allele or SE. PGS was not significantly associated with disease activity.
CONCLUSION: Genetic variation renders heterogeneous associations with disease activity and phenotype in RA. Individual genetic variants and pathway-specific genetic risk associated with RA may be more informative than the pooled genetic risk in understanding disease phenotype and disease activity.