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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,  r   2  = 1) with the functional  MICA  variant rs1051792 (D' = 1,  r   2  = 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.

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