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

Kirsten H, Petit-Teixeira E, Scholz M, Hasenclever D, Hantmann H, Heider D, Wagner U, Sack U, Hugo Teixeira V, Prum B, Burkhardt J, Pierlot C, Emmrich F, Cornelis F, Ahnert P - Arthritis Res. Ther. (2009)

Bottom Line: 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).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).However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany. holgerkirsten@web.de

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.

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Location of MICA relative to the HLA-DRB1 locus. Despite a distance of more than one megabase from the rheumatoid arthritis risk factor HLA-DRB1 in the major histocompatibility complex (MHC) class II region, there is considerable linkage disequilibrium between markers in both genes. Therefore, HLA-DRB1 status must be considered for interpretation of genetic association data.
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Figure 1: Location of MICA relative to the HLA-DRB1 locus. Despite a distance of more than one megabase from the rheumatoid arthritis risk factor HLA-DRB1 in the major histocompatibility complex (MHC) class II region, there is considerable linkage disequilibrium between markers in both genes. Therefore, HLA-DRB1 status must be considered for interpretation of genetic association data.

Mentions: MICA is located within the same genomic region as HLA-DRB1 (Figure 1). It encodes the protein major histocompatibility complex class I polypeptide-related sequence A. This protein interacts with the C-type lectin activatory receptor NKG2D (also known as KLRK1) found on natural killer cells, γδ T cells, and certain subgroups of αβ T cells. MICA-NKG2D interaction is believed to be important for eliminating infected or tumorous cells [9]. This interaction is also described to increase inflammatory cytokine production and proliferation of a certain subset of T cells. In consequence, implications in autoimmunity have been discussed [9-12]. MICA is expressed in RA synovium but not in osteoarthritis synovium [12]. Local NKG2D expression is induced by tumor necrosis factor and interleukin-15 [12]. These findings make MICA an interesting candidate gene for association studies in RA.


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

Kirsten H, Petit-Teixeira E, Scholz M, Hasenclever D, Hantmann H, Heider D, Wagner U, Sack U, Hugo Teixeira V, Prum B, Burkhardt J, Pierlot C, Emmrich F, Cornelis F, Ahnert P - Arthritis Res. Ther. (2009)

Location of MICA relative to the HLA-DRB1 locus. Despite a distance of more than one megabase from the rheumatoid arthritis risk factor HLA-DRB1 in the major histocompatibility complex (MHC) class II region, there is considerable linkage disequilibrium between markers in both genes. Therefore, HLA-DRB1 status must be considered for interpretation of genetic association data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2714103&req=5

Figure 1: Location of MICA relative to the HLA-DRB1 locus. Despite a distance of more than one megabase from the rheumatoid arthritis risk factor HLA-DRB1 in the major histocompatibility complex (MHC) class II region, there is considerable linkage disequilibrium between markers in both genes. Therefore, HLA-DRB1 status must be considered for interpretation of genetic association data.
Mentions: MICA is located within the same genomic region as HLA-DRB1 (Figure 1). It encodes the protein major histocompatibility complex class I polypeptide-related sequence A. This protein interacts with the C-type lectin activatory receptor NKG2D (also known as KLRK1) found on natural killer cells, γδ T cells, and certain subgroups of αβ T cells. MICA-NKG2D interaction is believed to be important for eliminating infected or tumorous cells [9]. This interaction is also described to increase inflammatory cytokine production and proliferation of a certain subset of T cells. In consequence, implications in autoimmunity have been discussed [9-12]. MICA is expressed in RA synovium but not in osteoarthritis synovium [12]. Local NKG2D expression is induced by tumor necrosis factor and interleukin-15 [12]. These findings make MICA an interesting candidate gene for association studies in RA.

Bottom Line: 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).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).However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany. holgerkirsten@web.de

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.

Show MeSH
Related in: MedlinePlus