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Open Access Highly Accessed Research article

Negative association of the chemokine receptor CCR5 d32 polymorphism with systemic inflammatory response, extra-articular symptoms and joint erosion in rheumatoid arthritis

Manuela Rossol1*, Matthias Pierer1, Sybille Arnold1, Gernot Keyßer2, Harald Burkhardt3, Christoph Baerwald1 and Ulf Wagner1

Author Affiliations

1 Division of Rheumatology, Department of Internal Medicine II, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany

2 Department of Internal Medicine I, University of Halle/Saale, Ernst-Grube-Straße 40, 06120 Halle/Saale, Germany

3 Division of Rheumatology, Department of Internal Medicine II, Johann Wolfgang Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

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Arthritis Research & Therapy 2009, 11:R91  doi:10.1186/ar2733

Published: 18 June 2009

Abstract

Introduction

Chemokines and their receptors control immune cell migration during infections as well as in autoimmune responses. A 32 bp deletion in the gene of the chemokine receptor CCR5 confers protection against HIV infection, but has also been reported to decrease susceptibility to rheumatoid arthritis (RA). The influence of this deletion variant on the clinical course of this autoimmune disease was investigated.

Methods

Genotyping for CCR5d32 was performed by PCR and subsequent electrophoretic fragment length determination. For the clinical analysis, the following extra-articular manifestations of RA were documented by the rheumatologist following the patient: presence of rheumatoid nodules, major organ vasculitis, pulmonary fibrosis, serositis or a Raynaud's syndrome. All documented CRP levels were analyzed retrospectively, and the last available hand and feet radiographs were analyzed with regards to the presence or absence of erosive disease.

Results

Analysis of the CCR5 polymorphism in 503 RA patients and in 459 age-matched healthy controls revealed a significantly decreased disease susceptibility for carriers of the CCR5d32 deletion (Odds ratio 0.67, P = 0.0437). Within the RA patient cohort, CCR5d32 was significantly less frequent in patients with extra-articular manifestations compared with those with limited, articular disease (13.2% versus 22.8%, P = 0.0374). In addition, the deletion was associated with significantly lower average CRP levels over time (median 8.85 vs. median 14.1, P = 0.0041) and had a protective effect against the development of erosive disease (OR = 0.40, P = 0.0047). Intriguingly, homozygosity for the RA associated DNASE2 -1066 G allele had an additive effect on the disease susceptibility conferred by the wt allele of CCR5 (OR = 2.24, P = 0.0051 for carrier of both RA associated alleles)

Conclusions

The presence of CCR5d32 significantly influenced disease susceptibility to and clinical course of RA in a German study population. The protective effect of this deletion, which has been described to lead to a decreased receptor expression in heterozygous patients, underlines the importance of chemokines in the pathogenesis of RA.