Early-Onset Ankylosing Spondylitis Is Associated With a Functional MICA Polymorphism Habiba Amroun, Hachemi Djoudi, Marc Busson, Rachida Allat, Shérif Mohsen El Sherbini, Ivan Sloma, Rajendranath Ramasawmy, Manuel Brun, Nicolas Dulphy, Rajagopal Krishnamoorthy, Antoine Toubert, Dominique Charron, Mohamed Chérif Abbadi, and Ryad Tamouza ABSTRACT: Major histocompatibility complex (MHC) class I chain–related A (MICA) molecules deliver activating signals through the NKG2D receptor expressed on the sur- face of natural killer (NK), CD8 and  T cells, and the MICA gene is polymorphic. The recently described MICA amino acid substitution at position 129 (MICA-129) seems to affect its binding to NKG2D. We investigated whether this dimorphism (MICA-129met [methionine] and MICA-129val [valine]) is associated with susceptibility to ankylosing spon- dylitis (AS) in a cohort of Algerian patients stratified accord- ing to their HLAB27 status and the age of onset of the disease. DNA from 129 patients and 76 healthy individuals were analyzed to determine the HLA-B generic type as well as MICA-129 polymorphism. Statistical analysis revealed: (1) a weaker association between AS and HLA-B27 in Algerians than in that reported for European patients (63% versus 80 –90%), suggesting a possible influence of other genetic/ environmental determinants in the studied population and (2) an association between MICA-129 met/met genotype and juvenile AS (p = 0.02) independent of HLA-B27 status. These data suggest a potential role for a functionally relevant MICA gene polymorphism in autoimmune/inflammatory disease susceptibility. Human Immunology 66, 1057–1061 (2005). © American Society for Histocompatibility and Im- munogenetics, 2005. Published by Elsevier Inc. KEYWORDS: Spondyloarthropathies; early-onset; MICA; polymorphism ABBREVIATIONS AS ankylosing spondylitis HLA human leukocyte antigen MHC major histocompatibility complex MICA MHC) class I chain–related A gene NK natural killer INTRODUCTION Ankylosing spondylitis (AS) belongs to the spondyloar- thropathies group, which also includes reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel diseases, and the so-called undifferentiated spondy- loarthropathies. The development of this complex multi- factorial disease is under the influence of the patient ge- netic background and environmentally related factors [1, 2]. Both can increase susceptibility by affecting the overall reactivity of the immune system. Indeed, even though three to nine loci, involving the worldwide recognized human leukocyte antigen (HLA)-B gene [1], play a sig- nificant role in the disease susceptibility, it is also admitted that reactive arthritis is triggered by gastrointestinal or genitourinary infections from Yersinia salmonella, Campy- lobacter, or Chlamydia [2]. From the Laboratoire d’Immunologie et d’Histocompatibilité CIB-HOB, AP-HP, IUH and INSERM U662, Hôpital Saint-Louis, Paris, France (H.A., M.B., M.E.S., I.S., R.R., M.B., N.D., A.T., D.C., R.T.), Labo- ratoire d’Immunologie, Institut Pasteur d’Algérie, Alger, Algérie (H.A., M.C.A.), Service de Rhumatologie, EHS Douéra, Alger, Algérie (H.D., R.A.), and INSERM U458, Hôpital Robert Debré, Paris, France (R.K.). HA and HD contributed equally to this work and are considered first authors. Address reprint requests to: Dr Ryad Tamouza, Laboratoire d’Immunologie et d’Histocompatibilité, Hôpital Saint Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France. Supported by EUROAS BMH4-CT98-3605 and EUROAS Genomic Bank (QLRI-CT-2002-02276). Grant coordinator: Dr. S. Laoussadi. Received July 8, 2005; accepted September 15, 2005. Human Immunology 66, 1057–1061 (2005) © American Society for Histocompatibility and Immunogenetics, 2005 0198-8859/05/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2005.09.004