Mariaselvam Christina M, Boukouaci Wahid, Charron Dominique, Krishnamoorthy Rajagopal, Tamouza Ryad, Misra Durga P, Negi Vir S
Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
INSERM, UMRS 1160, Saint Louis Hospital, Paris, France.
Int J Rheum Dis. 2018 Mar;21(3):656-663. doi: 10.1111/1756-185X.13138. Epub 2017 Jul 27.
Rheumatoid arthritis (RA) is a clinically heterogeneous chronic inflammatory disorder characterized by synovitis leading to joint destruction. Both genetic and environmental factors are involved in the pathogenesis of RA. Significant dysregulation of NKG2D, an activating receptor of natural killer and certain autoreactive T cells as well as its ligand major histocompatibility complex class I chain-related gene A (MICA) has been implicated in perpetuating the pathology of RA. Since the genetic polymorphism in MICA gene (MICA-129 met/val polymorphism at codon 129) is known to affect its binding affinity to NKG2D, we explored its influence on RA susceptibility and disease severity.
The MICA-129 met/val polymorphism was examined in 270 patients with RA and 232 healthy controls by TaqMan 5'-nuclease assay. Serum soluble MICA (sMICA) was measured in a subset of 89 patients and 80 controls by enzyme-linked immunosorbent assay.
We observed that the frequency of MICA-129 val allele (73% vs. 65%, Pc = 0.006, odds ratio = 1.48, 95% CI = 1.12-1.95) was higher in patients than in controls. sMICA levels were significantly higher in patients with RA than in controls (P < 0.0001). sMICA levels were higher in patients with val/val genotype than in those with met/val or met/met genotype (P = 0.03). The MICA-129 val/val genotype was associated with high titers of sMICA in patients with deforming RA phenotype (P = 0.02), suggesting a role in determination of severity of RA.
MICA-129 val/val genotype, associated with higher levels of circulating sMICA, may influence disease susceptibility and associate with increased severity of RA in south Indian Tamils.
类风湿关节炎（RA）是一种临床异质性慢性炎症性疾病，其特征为滑膜炎导致关节破坏。遗传和环境因素均参与RA的发病机制。自然杀伤细胞和某些自身反应性T细胞的激活受体NKG2D及其配体主要组织相容性复合体I类链相关基因A（MICA）的显著失调与RA病理过程的持续存在有关。由于已知MICA基因中的遗传多态性（第129密码子处的MICA-129 met/val多态性）会影响其与NKG2D的结合亲和力，我们探讨了其对RA易感性和疾病严重程度的影响。
采用TaqMan 5'-核酸酶分析法检测270例RA患者和232例健康对照者的MICA-129 met/val多态性。采用酶联免疫吸附测定法检测89例患者和80例对照者亚组中的血清可溶性MICA（sMICA）。
我们观察到，患者中MICA-129 val等位基因的频率（73%对65%，Pc = 0.006，优势比 = 1.48，95%可信区间 = 1.12 - 1.95）高于对照者。RA患者的sMICA水平显著高于对照者（P < 0.0001）。val/val基因型患者的sMICA水平高于met/val或met/met基因型患者（P = 0.03）。MICA-129 val/val基因型与畸形RA表型患者的高滴度sMICA相关（P = 0.02），提示其在确定RA严重程度中起作用。
与循环sMICA水平较高相关的MICA-129 val/val基因型可能影响疾病易感性，并与印度南部泰米尔人的RA严重程度增加相关。
