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Multicenter Study
. 2013 Mar;65(3):571-81.
doi: 10.1002/art.37801.

Associations of autoantibodies, autoimmune risk alleles, and clinical diagnoses from the electronic medical records in rheumatoid arthritis cases and non-rheumatoid arthritis controls

Katherine P Liao  1 , Fina Kurreeman, Gang Li, Grant Duclos, Shawn Murphy, Raul Guzman, Tianxi Cai, Namrata Gupta, Vivian Gainer, Peter Schur, Jing Cui, Joshua C Denny, Peter Szolovits, Susanne Churchill, Isaac Kohane, Elizabeth W Karlson, Robert M Plenge
Affiliations
Multicenter Study

Associations of autoantibodies, autoimmune risk alleles, and clinical diagnoses from the electronic medical records in rheumatoid arthritis cases and non-rheumatoid arthritis controls

Katherine P Liao et al. Arthritis Rheum. 2013 Mar.

Abstract

Objective: The significance of non-rheumatoid arthritis (RA) autoantibodies in patients with RA is unclear. The aim of this study was to assess associations of autoantibodies with autoimmune risk alleles and with clinical diagnoses from the electronic medical records (EMRs) among RA cases and non-RA controls.

Methods: Data on 1,290 RA cases and 1,236 non-RA controls of European genetic ancestry were obtained from the EMRs of 2 large academic centers. The levels of anti-citrullinated protein antibodies (ACPAs), antinuclear antibodies (ANAs), anti-tissue transglutaminase antibodies (AGTAs), and anti-thyroid peroxidase (anti-TPO) antibodies were measured. All subjects were genotyped for autoimmune risk alleles, and the association between number of autoimmune risk alleles present and number of types of autoantibodies present was studied. A phenome-wide association study (PheWAS) was conducted to study potential associations between autoantibodies and clinical diagnoses among RA cases and non-RA controls.

Results: The mean ages were 60.7 years in RA cases and 64.6 years in non-RA controls. The proportion of female subjects was 79% in each group. The prevalence of ACPAs and ANAs was higher in RA cases compared to controls (each P < 0.0001); there were no differences in the prevalence of anti-TPO antibodies and AGTAs. Carriage of higher numbers of autoimmune risk alleles was associated with increasing numbers of autoantibody types in RA cases (P = 2.1 × 10(-5)) and non-RA controls (P = 5.0 × 10(-3)). From the PheWAS, the presence of ANAs was significantly associated with a diagnosis of Sjögren's/sicca syndrome in RA cases.

Conclusion: The increased frequency of autoantibodies in RA cases and non-RA controls was associated with the number of autoimmune risk alleles carried by an individual. PheWAS of EMR data, with linkage to laboratory data obtained from blood samples, provide a novel method to test for the clinical significance of biomarkers in disease.

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Figures

Figure 1
Figure 1
(A) Distribution of autoantibodies (ACPA, ANA, anti-TPO) among RA cases of EU ancestry; (B) Distribution of autoantibodies (ACPA*, ANA, anti-TPO) among non-RA controls of EU ancestry. Anti-tTG (not shown), RA cases: 14 subjects (1.1%); non-RA controls: 8 subjects (0.6%). [*ACPA checked in n=202 controls with prevalence of 0.5%].
Figure 2
Figure 2
Comparison of autoantibody presence between (A) RA cases and non-RA controls, and (B) ACPA positive compared to ACPA negative RA cases (adjusted by age, gender and health care utilization; European ancestry).
Figure 3
Figure 3
Distribution of disease specific genetic risk scores and associated autoantibodies among RA cases (European ancestry, n=1265). (A) Distribution of RA GRS among ACPA positive and ACPA negative RA cases, (B) Distribution of the SLE GRS among ANA positive and ANA negative RA cases, (C) Distribution of the celiac GRS among anti-tTG positive and anti-tTG negative RA cases, (D) Distribution of AI GRS with increasing count of autoantibodies in RA cases (ANA, anti-TPO or anti-tTG).
Figure 4
Figure 4
ANA positivity in RA cases compared to non-RA controls among individuals with similar numbers of SLE risk alleles (SLE GRS categorized by tertiles from lowest, tertile 1 to highest, tertile 3; ORs adjusted by age, gender, and health care utilizationin subjects of European ancestry).
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