Rheumatology (Oxford, England) · 2026
Heterogeneity in the association of genetic risk for RA and resultant RA phenotypes.
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Riley Thomas R, Wheeler Austin M, England Bryant R, Cannon Grant W, Sauer Brian, Kunkel Gary A, Wysham Katherine D, Wallace Beth I, Monach Paul A, Reimold Andreas, Kerr Gail S, Smith Isaac D, Richards John Steuart, Lee Iris, Thiele Geoffrey M, Xiao Rui, Damrauer Scott M, Levin Michael G, George Michael D, Mikuls Ted R, Baker Joshua F
Аннотация
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.
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.