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01.04.2010 | Research article | Ausgabe 2/2010 Open Access

Arthritis Research & Therapy 2/2010

Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 2/2010
Autoren:
Ann W Morgan, James I Robinson, Philip G Conaghan, Stephen G Martin, Elizabeth MA Hensor, Michael D Morgan, Lori Steiner, Henry A Erlich, Hock-Chye Gooi, Anne Barton, Jane Worthington, Paul Emery, UKRAG Consortium and the YEAR Consortium
Wichtige Hinweise

Competing interests

LS and HAE are employed by Roche Molecular Systems, Inc. (Pleasanton, CA, USA), provider of HLA-DRB1 and PTPN22 genotyping reagents for a subgroup of subjects analysed in the present study. Otherwise the authors declare that they have no competing interests.

Authors' contributions

AWM conceived and designed this study, contributed to the acquisition of data, undertook the statistical analyses, interpreted the data and wrote the manuscript. JIR contributed to the acquisition of data and drafted part of the manuscript. PGC contributed to the acquisition of data and critically reviewed the manuscript. SGM contributed to the acquisition of data and critically reviewed the manuscript. The YEAR Consortium contributed to the acquisition of data. EMAH contributed to the statistical analysis and critically reviewed the manuscript. MDM drafted part of the manuscript. LS developed the multi-locus SNP genotyping platform and critically reviewed the manuscript. HAE developed the multi-locus HLA-DRB1 genotyping platform and critically reviewed the manuscript. H-CG contributed to the acquisition of data and critically reviewed the manuscript. AB contributed to the acquisition of data and critically reviewed the manuscript. The UKRAG Consortium contributed to the acquisition of data and critically reviewed the manuscript. JW contributed to the acquisition of data and critically reviewed the manuscript. PE contributed to the acquisition of data and critically reviewed the manuscript.

Abstract

Introduction

This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort.

Methods

The magnitude of association for each genotype was assessed in 1,046 RA subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. Additional exploratory subanalyses were undertaken in subgroups defined by autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or disease severity (baseline articular erosions, Health Assessment Questionnaire (HAQ) score and swollen joint count (SJC)).

Results

In the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA. The magnitude of association for these loci was increased in those patients who were autoantibody-positive. PTPN22 was associated with autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no evidence of association between these five genetic loci and baseline erosions or SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was significantly associated with baseline HAQ, however, following adjustment for symptom duration (P trend = 0.03).

Conclusions

These findings support the mounting evidence that different genetic loci are associated with autoantibody-positive and autoantibody-negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production. Additional studies with a specific focus on autoantibody-negative RA will be needed to identify the genes predisposing to this RA subgroup. The TRAF1/C5 locus in particular warrants further investigation in RA as a potential disease severity locus.
Literatur
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