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MICA, a gene contributing strong susceptibility to ankylosing spondylitis
  1. Xiaodong Zhou1,
  2. Jiucun Wang2,
  3. Hejian Zou3,
  4. Michael M Ward4,
  5. Michael H Weisman5,
  6. Maribel G Espitia1,
  7. Xiangjun Xiao6,
  8. Effie Petersdorf7,
  9. Emmanuel Mignot8,
  10. Javier Martin9,
  11. Lianne S Gensler10,
  12. Paul Scheet6,
  13. John D Reveille1
  1. 1Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, Houston, Texas, USA
  2. 2Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
  3. 3Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
  4. 4NIAMS, Bethesda, Maryland, USA
  5. 5Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
  6. 6Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  7. 7Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine and Division of Oncology, University of Washington, Seattle, Washington, USA
  8. 8Department of Psychiatry, Stanford University, School of Medicine, Stanford, California, USA
  9. 9The Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Armilla, Granada, Spain
  10. 10Division of Rheumatology, The University of California, San Francisco, USA
  1. Correspondence to Professor Xiaodong Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB5270, Houston, TX 77030, USA; Xiaodong.zhou{at}uth.tmc.edu

Abstract

Objective The human major histocompatibility complex class I chain-related gene A (MICA) controls the immune process by balancing activities of  natural killer cells, γδ T cells and αβ CD8 T cells, and immunosuppressive CD4 T cells. MICA is located near HLA-B on chromosome 6. Recent genomewide association studies indicate that genes most strongly linked to ankylosing spondylitis (AS) susceptibility come from the region containing HLA-B and MICA. While HLA-B27 is a well-known risk genetic marker for AS, the potential effect of linkage disequilibrium (LD) shields any associations of genes around HLA-B with AS. The aim of this study was to investigate a novel independent genetic association of MICA to AS.

Methods We examined 1543 AS patients and 1539 controls from two ethnic populations by sequencing MICA and genotyping HLA-B alleles. Initially, 1070 AS patients and 1003 controls of European ancestry were used as a discovery cohort, followed by a confirmation cohort of 473 Han Chinese AS patients and 536 controls. We performed a stratified analysis based on HLA-B27 carrier status. We also conducted logistic regression with a formal interaction term.

Results Sequencing of MICA identified that MICA*007:01 is a significant risk allele for AS in both Caucasian and Han Chinese populations, and that MICA*019 is a major risk allele in Chinese AS patients. Conditional analysis of MICA alleles on HLA-B27 that unshielded LD effect confirmed associations of the MICA alleles with AS.

Conclusions Parallel with HLA-B27, MICA confers strong susceptibility to AS in US white and Han Chinese populations.

  • Ankylosing Spondylitis
  • Gene Polymorphism
  • Inflammation

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