Research article

Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study

Holger Kirsten^1,2,3 , Elisabeth Petit-Teixeira⁴ , Markus Scholz⁵ , Dirk Hasenclever⁵ , Helene Hantmann² , Dirk Heider⁶ , Ulf Wagner⁷ , Ulrich Sack^2,8 , Vitor Hugo Teixeira^4,9 , Bernard Prum¹⁰ , Jana Burkhardt¹ , Céline Pierlot⁴ , Frank Emmrich^2,3,8 , François Cornelis^4,11,12 and Peter Ahnert^1,3,5

¹  Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany

²  Translational Centre for Regenerative Medicine, University of Leipzig, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany

³  Fraunhofer Institute for Cell Therapy and Immunology IZI, Perlickstr. 1, 04103 Leipzig, Germany

⁴  GenHotel-EA3886, Evry-Paris VII Universities, 2 rue Gaston Crémieux, 91057 Evry-Genopole cedex, France

⁵  Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany

⁶  Health Economics Research Unit, Department of Psychiatry, University of Leipzig, Liebigstr. 26, 04103 Leipzig, Germany

⁷  Medical Clinic and Polyclinic IV, University Hospital Leipzig, Liebigstr. 22, 04103 Leipzig, Germany

⁸  Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany

⁹  Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal

¹⁰  Statistics and Genome laboratory, La genopole, 523 place des Terrasses, 91000 Evry, France

¹¹  Hôpital Sud Francilien, 59 Boulevard Henri Dunant, 91106 Corbeil-Essonnes cedex, France

¹²  Hôpital Lariboisière, AP-HP, 2 rue Ambroise – Paré, 75475, Paris cedex 10, France

author email corresponding author email

Arthritis Research & Therapy 2009, 11:R60doi:10.1186/ar2683

Published:	1 May 2009

Abstract

Introduction

The gene MICA encodes the protein major histocompatibility complex class I polypeptide-related sequence A. It is expressed in synovium of patients with rheumatoid arthritis (RA) and its implication in autoimmunity is discussed. We analyzed the association of genetic variants of MICA with susceptibility to RA.

Methods

Initially, 300 French Caucasian individuals belonging to 100 RA trio families were studied. An additional 100 independent RA trio families and a German Caucasian case-control cohort (90/182 individuals) were available for replication. As MICA is situated in proximity to known risk alleles of the HLA-DRB1 locus, our analysis accounted for linkage disequilibrium either by analyzing the subgroup consisting of parents not carrying HLA-DRB1 risk alleles with transmission disequilibrium test (TDT) or by implementing a regression model including all available data. Analysis included a microsatellite polymorphism (GCT)n and single-nucleotide polymorphisms (SNPs) rs3763288 and rs1051794.

Results

In contrast to the other investigated polymorphisms, the non-synonymously coding SNP MICA-250 (rs1051794, Lys196Glu) was strongly associated in the first family cohort (TDT: P = 0.014; regression model: odds ratio [OR] 0.46, 95% confidence interval [CI] 0.25 to 0.82, P = 0.007). Although the replication family sample showed only a trend, combined family data remained consistent with the hypothesis of MICA-250 association independent from shared epitope (SE) alleles (TDT: P = 0.027; regression model: OR 0.56, 95% CI 0.38 to 0.83, P = 0.003). We also replicated the protective association of MICA-250A within a German Caucasian cohort (OR 0.31, 95% CI 0.1 to 0.7, P = 0.005; regression model: OR 0.6, 95% CI 0.37 to 0.96, P = 0.032). We showed complete linkage disequilibrium of MICA-250 (D' = 1, r²= 1) with the functional MICA variant rs1051792 (D' = 1, r²= 1). As rs1051792 confers differential allelic affinity of MICA to the receptor NKG2D, this provides a possible functional explanation for the observed association.

Conclusions

We present evidence for linkage and association of MICA-250 (rs1051794) with RA independent of known HLA-DRB1 risk alleles, suggesting MICA as an RA susceptibility gene. However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.