Background/Purpose: C-reactive protein (CRP) is often used as a biomarker for disease activity in patients with rheumatoid arthritis (RA). We evaluated whether rs1205, a common genetic variant in CRP previously associated with lower CRP, impacts disease activity assessment in patients with RA, including the disease activity score-28 with CRP (DAS28(CRP)). We hypothesized that patients with this variant would have lower CRP and DAS28(CRP).

Methods: Participants from 3 observational cohorts were evaluated: the United Kingdom Biobank (UKB), the Veterans Affairs RA registry (VARA), and the FORWARD Databank RA cohort. All participants from UKB were included, regardless of a diagnosis of RA; a subgroup of participants with ≥1 ICD-10 code for RA (ICD-10 M06.9*) was identified. Participants were directly genotyped for rs1205. Population structure was estimated using principal component analysis. The effect of rs1205 genotype (CC, CT, or TT) on log-adjusted serum CRP and disease activity metrics were assessed using linear regression adjusted for sex, age, and 6 principal components of population structure in each cohort.  Regression coefficients from UKB were used to create a corrected CRP and DAS28(CRP) within FORWARD and VARA. Finally, reclassification to an abnormal CRP ( >0.8 mg/dl) and between DAS28(CRP) disease activity states were determined.

Results: Among 488,377 participants from UKB, 214,153 (44.0%) were heterozygous and 52,055 (10.7%) were homozygous for rs1205 T. Those in UKB with the TT and CT genotype had a lower log-adjusted CRP compared to the CC genotype [Β TT genotype: -0.371 (95% CI -0.381, -0.360), p< 0.001; Β CT genotype: -0.173 (95% CI -0.179, -0.167), p< 0.001]; this was similar in participants with an ICD-10 code for RA.In 2597 VARA participants, 1107 were heterozygous (42.6%) and 269 (10.4%) were homozygous for the rs1205 T allele. Those with the TT and CT genotypes had a significantly lower log-adjusted CRP compared to the CC genotype (Table 1). The DAS28(CRP) was significantly lower in the TT genotype compared to the CC genotype [Β -0.22, (95% CI -0.44, -0.0027), p = 0.047)], but not in the CT genotype. There were no significant differences for other disease activity components or composite scores (Table 1).Among 766 participants from FORWARD, 352 were heterozygous (46.0%) and 82 were homozygous for rs1205 T (10.7%). Individuals with TT had a lower log-adjusted CRP compared to the CC genotype (but not CT); there were no observed differences by genotype in Patient Activity Score-II or patient global assessment.Application of a correction factor derived from UKB was applied in VARA (Fig. 1, Fig. 2). In VARA participants with the TT genotype, 8% were reclassified to an abnormal CRP ( >0.8 mg/dl) and 3% were reclassified from low disease activity to moderate disease activity. With this adjustment in FORWARD, 11 (3.6%) with the CT genotype and 4 (5.9%) with the TT genotype were reclassified as having an elevated CRP.

Conclusion: The rs1205 CT and TT genotype in CRP is associated with lower CRP; the TT genotype is associated with lower DAS28(CRP), but not other components of disease activity. A modified CRP and DAS28(CRP), corrected for genotype, has modest effects on disease activity interpretation and reclassification.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetically-determined-variation-in-c-reactive-protein-impacts-disease-activity-assessment-in-rheumatoid-arthritis/