HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients

Abstract

IntroductionThe revised shared epitope (SE) concept in rheumatoid arthritis (RA) is based on the presence (S) or absence (X) of the SE RAA amino acid motif at positions 72 to 74 of the third hypervariable region of the various human leucocyte antigen (HLA)-DRB1 alleles. The purpose of this study was to investigate SE subtypes on the basis of the American College of Rheumatology 1987 revised criteria for the classification of RA in a cohort of South African RA patients (n = 143) and their association with clinical and circulating biomarkers of disease activity (autoantibodies, acute phase reactants and cytokines).MethodsGenomic DNA was analysed using high-resolution recombinant sequence-specific oligonucleotide PCR typing of the HLA-DRB1 allele. Subtypes of the SE were classified according to the amino acids at positions 72 to 74 for the RAA sequence, and further sub-divided according to the amino acids at positions 70 and 71, which either contribute to (S2, S3P), or negate (S1, S3D) RA susceptibility. Disease activity was assessed on the basis of (1) Disease Activity Score in 28 joints using C-reactive protein (CRP), (2) rheumatoid factor (RF), (3) CRP and (4) serum amyloid A by nephelometry, anticyclic citrullinated peptide antibodies (aCCP) by an immunofluorometric procedure, and cytokines by multiplex bead array technology.ResultsOf the 143 RA patients, 81 (57%) were homozygous (SS) and 50 (35%) were heterozygous (SX) for the SE alleles with significant overexpression of S2 and S3P (respective odds ratios (ORs) 5.3 and 5.8; P < 0.0001), and 12 (8%) were classified as no SE allele (XX). Both the SS and SX groups showed a strong association with aCCP positivity (OR = 10.2 and P = 0.0010, OR = 9.2 and P = 0.0028, respectively) relative to the XX group. Clinical scores and concentrations of the other biomarkers of disease activity (RF, CRP and T helper cell type 1 (Th1), Th2, macrophage and fibroblast cytokines) were also generally higher in the SS group than in the SX and XX groups.ConclusionsRA susceptibility alleles investigated according to revised criteria for the classification of RA were significantly increased in South African RA patients and strongly associated with aCCP in particular as well as with circulating cytokines and disease severity.

Serum Matrix Metalloproteinase-3 in Comparison with Acute Phase Proteins as a Marker of Disease Activity and Radiographic Damage in Early Rheumatoid Arthritis

“…Baseline data was reviewed from 128 patients who were part of the Gauteng Rheumatoid Arthritis Trial (GREAT), a prospective study of early DMARD naive RA patients [27–29]. Patients were recruited from the rheumatology clinics of two tertiary hospitals, Chris Hani Baragwanath Hospital and Steve Biko Academic Hospital, attached to the Universities of the Witwatersrand and Pretoria, South Africa, respectively, and the study was approved by the Research Ethics Committees of the Faculties of Health Sciences of both institutions.…”

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

“…Although smoking is a recognised risk factor for development of RA, probably linked to inappropriate immune activation and production of ACPA, in many settings, particularly in some developing world countries such as South Africa, the majority of ACPA-seropositive/SE allele-positive RA patients do not smoke [89,90]. In this setting, alternative triggering mechanisms of production of ACPA may be implicated.…”

Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans

“…The strong association with the HLA-DRB1 region has been replicated repeatedly (24)(25)(26)(27). Ninety-two percent of black South Africans with RA carry at least one copy of the shared epitope alleles (27) which contrasts with only ~30% in West Africans from Cameroon (28), demonstrating significant heterogeneity within Africans.…”