MICA Polymorphism Research Articles

The impact of MICB mismatches in unrelated haematopoietic stem cell transplantation.

MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I-related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon-based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA-genes, sub-stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA-matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA-B mismatches have to be accepted.

Impact of donor NKG2D and MICA gene polymorphism on clinical outcomes of adult and paediatric allogeneic cord blood transplantation for malignant diseases.

NKG2D is an activating receptor expressed by natural killer (NK) and CD8+ T cells and activation intensity varies by NKG2D expression level or nature of its ligand. An NKG2D gene polymorphism determines high (HNK1) or low (LNK1) expression. MICA is the most polymorphic NKG2D ligand and stronger effector cell activation associates with methionine rather than valine at residue 129. We investigated correlation between cord blood (CB) NKG2D and MICA genotypes and haematopoietic stem cell (HSC) transplant outcome. We retrospectively studied 267 CB HSC recipients (178 adult and 87 paediatric) who underwent transplant for malignant disease between 2007 and 2018, analysing CB graft DNA for NKG2D and MICA polymorphisms using Sanger sequencing. Multivariate analysis was used to correlate these results with transplant outcomes. In adult patients, LNK1 homozygous CB significantly improved 60-day neutrophil engraftment (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.4-0.9; p = .003). In paediatrics, HNK1 homozygous CB improved 60-day engraftment (HR 0.4; 95% CI 0.2-0.7; p = .003), as did MICA-129 methionine+ CB grafts (HR 1.7 95% CI 1.1-2.6; p = .02). CB NKG2D and MICA genotypes potentially improve CB HSC engraftment. However, results contrast between adult and paediatric recipients and may reflect transplant procedure disparities between cohorts.

Functional MICA Variants Are Differentially Associated with Immune-Mediated Inflammatory Diseases.

As the principal ligand for NKG2D, MICA elicits the recruitment of subsets of T cells and NK cells in innate immunity. MICA gene variants greatly impact the functionality and expression of MICA in humans. The current study evaluated whether MICA polymorphisms distinctively influence the pathogenesis of psoriasis (PSO), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) in Taiwanese subjects. The distributions of MICA alleles and levels of serum soluble NKG2D were compared between healthy controls and patients with PSO, RA, and SLE, respectively. The binding capacities and cell surface densities of MICA alleles were assessed by utilizing stable cell lines expressing four prominent Taiwanese MICA alleles. Our data revealed that MICA*010 was significantly associated with risks for PSO and RA (PFDR = 1.93 × 10-15 and 0.00112, respectively), while MICA*045 was significantly associated with predisposition to SLE (PFDR = 0.0002). On the other hand, MICA*002 was associated with protection against RA development (PFDR = 4.16 × 10-6), while MICA*009 was associated with a low risk for PSO (PFDR = 0.0058). MICA*002 exhibited the highest binding affinity for NKG2D compared to the other MICA alleles. Serum concentrations of soluble MICA were significantly elevated in SLE patients compared to healthy controls (p = 0.01). The lack of cell surface expression of the MICA*010 was caused by its entrapment in the endoplasmic reticulum. As a prevalent risk factor for PSO and RA, MICA*010 is deficient in cell surface expression and is unable to interact with NKG2D. Our study suggests that MICA alleles distinctively contribute to the pathogenesis of PSO, RA, and SLE in Taiwanese people.

Association of MICA and NKG2D genetic variants with disease susceptibility and outcome of anti-TNF therapy in patients with axial spondyloarthritis.

The disruption of the NKG2D-MICA axis can induce an enhanced immune response and promote autoimmune processes during axial spondyloarthritis (axSpA) pathogenesis. We aimed to investigate potential relationships between selected single nucleotide polymorphisms within the MICA and NKG2D genes and disease susceptibility and clinical parameters in axSpA patients treated with TNF inhibitors. Genotyping of MICA rs1051792 and NKG2D rs1154831, rs1049174, and rs2255336 was performed in 163 axSpA patients and 234 healthy controls using a real-time PCR method. MICA rs1051792 A allele was more common in patients than in controls (p<0.0001). Patients with the AA genotype showed greater disease activity score (BASDAI) after three (p=4×10-4) and six (p=0.032) months of treatment compared to G carriers. After three months of therapy with anti-TNFs, the MICA AA homozygosity occurred more often in non-responsive or moderately responsive patients than good responders with the same genotype (p=1×10-4). Additionally, patients bearing the NKG2D rs1154831 CC genotype demonstrated lower BASDAI scores (p=0.035) and were significantly more common among subjects with a good outcome (p=0.004) after six months of treatment. These results suggest that MICA and NKG2D gene polymorphisms may be biomarkers associated with disease susceptibility and clinical outcomes after anti-TNF therapy in axSpA patients and imply a rather less favourable effect of the MICA A and NKG2D G genetic variants.

MICA and NLRP3 gene polymorphisms interact synergistically affecting the risk of ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoinflammatory disease that affects the sacroiliac joints, causing stiffness and pain in the back. MICA is a ligand of the NKG2D receptor, and an increase in its expression affects the immune response in various diseases. NLRP3 is a multiprotein complex that promotes the release of IL-1β, but its role in AS has been minimally explored. The objective of this study was to analyze the association and interaction of polymorphic variants of the MICA and NLRP3 genes in patients with AS. In this case-control study, patients with AS were included and compared with healthy controls of Mexican origin. The polymorphisms rs4349859 and rs116488202 of MICA and rs3806268 and rs10754558 of NLRP3 were genotyped using TaqMan probes. Associations were determined using logistic regression models, while interactions were analyzed by the multifactorial dimensionality reduction (MDR) method. A P value < 0.05 was considered statistically significant. The minor allele of rs4349859 (A) and rs116488202 (T) of MICA polymorphisms showed risk associations with AS (OR = 9.22, 95% CI = 4.26-20.0, P < 0.001; OR = 9.36, 95% CI = 4.17-21.0, P < 0.001), while the minor allele of the rs3806268 (A) polymorphism of NLRP3 was associated with protection (OR = 0.55, 95% CI = 0.33-0.91, P = 0.019). MDR analysis revealed synergistic interactions between the MICA and NLRP3 polymorphisms (P = 0.012). In addition, high- and low-risk genotypes were identified among these variants. The study findings suggest that the MICA rs4349859 A allele and rs116488202 T allele are associated with AS risk. An interaction between MICA and NLRP3 was observed which could increase the genetic risk in AS.

The impact of NKG2A and NKG2D receptors and HLA-E and MICA ligands polymorphisms on post-transplant complications after paediatric allogeneic HSCT: a single-centre experience.

Introduction: Natural Killer cells are the first subpopulation of lymphocytes that reconstitute after allogeneic haematopoietic stem cell transplantation (HSCT). Their activity is regulated by various receptor-ligand interactions, including stimulation of the activating NKG2D receptor by the MICA molecule, and inhibitory NKG2A receptor interacting with the HLA-E. In this study the research effort focused on the effect of selected NKG2A and NKG2D receptors and their ligands (HLA-E and MICA molecules) polymorphisms that may affect the pathomechanisms of post-transplant complications after HSCT in children. Methods: One hundred donor-recipient pairs from a single paediatric transplantation centre were investigated. Altogether six single nucleotide substitutions (NKG2A rs7301582; NKG2D rs1049174, rs1154831; HLA-E rs1264457; MICA rs1051792, rs1063635) were genotyped, and the influence of polymorphisms was analysed on acute and chronic graft-versus-host disease (GvHD), cytomegalovirus (CMV) infection incidence, disease relapse and survival. Results: The distribution of the evaluated polymorphisms did not differ between patients and their donors. The results showed a significant influence of HLA-E rs1264457 polymorphism in patients' HLA-E*01:01 allele, which was associated with increased risk of CMV infection (p = 0.050), especially in children positive for CMV IgG before transplantation (p = 0.001). Furthermore, the effect of HLA-E*01:01 allele on CMV infections was more evident in children above the age of 7 years (p = 0.031). Strong tendencies (0.05 < p < 0.10) towards association with the risk of acute GvHD were also observed for the NKG2A or MICA polymorphisms of the recipients. In addition, NKG2D rs1154831 AA and MICA rs1063635 GG might play a protective role as they were not present in any recipient who died after transplantation. Conclusion: In summary, there is emerging evidence that genotyping results of NKG2 receptors and their ligands, may have prognostic value for the outcome of paediatric allogeneic HSCT, but more extensive studies performed on larger groups of donors and transplant recipients are required to confirm these observations.

HLA class I chain-related MICA and MICB genes polymorphism in healthy individuals from the Bulgarian population

Although human leukocyte antigen (HLA) gene polymorphism has been investigated in many populations around the world, the data on MHC class I chain-related (MIC) genes are still limited. The present study is aimed to analyze the allelic polymorphism of MICA and MICB genes and haplotype associations with HLA-B locus in 132 healthy, unrelated individuals from the Bulgarian population by next generation sequencing (NGS). A total of 36 MICA and 16 MICB alleles were observed with the highest frequency detected for MICA*008:01 (17.1%) and MICB*005:02 (32.4%). Further, two and three-loci haplotype frequencies and pairwise linkage disequilibrium were estimated. Highly significant global linkage disequilibrium was found between either HLA-B and MICA and MICB genes. This is the first study on MICA and MICB allelic polymorphism, linkage disequilibrium, and haplotype polymorphism in the Bulgarian population. These results will allow for better characterization of the genetic heterogeneity of the Bulgarian population and could contribute to further analyses on MICA and MICB clinical significance.

Distribution of MICA alleles and haplotypes associated with HLA-B in Greek population

IntroductionThe Major Histocompatibility Complex Class I-related chain A gene (MICA) is a highly polymorphic functional gene located close to the HLA-B locus. Certain MICA alleles have been related to inflammatory and autoimmune diseases while MICA antibodies have been implicated in organ allograft rejection or graft-versus-host disease (GVHD). AimThe aim of this study was to identify the frequencies of MICA alleles and MICA ~ HLA-B haplotypes in the Greek population since, as far as we know, these data are still limited. MethodsDNA was obtained from 277 unrelated healthy Greek individuals of Caucasian origin, volunteer donors of blood stem cells. HLA-B* and MICA* genotyping was performed by reverse PCR-SSOP. ResultsA total of 18 MICA alleles were defined in the present study. The five most frequent alleles in the Greek population were MICA*008 (24.6%), MICA*009 (22.36%), MICA*018 (16.03%), MICA*002 (8.02%) and MICA*004 (7.17%) which altogether account for 77.8% of all alleles. The most common MICA ~ HLA-B haplotypes were MICA*018 ~ B*18 (12.5%) and MICA*009 ~ B*51(11.5%). ConclusionsThe five most frequent MICA alleles in the Greek population were *008, *009, *018, *002, *004. In other Caucasian populations, two of these alleles (*008, and *004) were observed in similar frequencies. MICA*002 was observed less frequently (8.02%) in the Greek population compared to other Caucasian groups (frequencies > 15%). Also, MICA*009 and MICA*018 had elevated frequencies (above 15%) whereas in other Caucasian populations they were found around 10% or less. These data may be important for the elucidation of the role that MICA polymorphisms play in organ and stem cell transplantation and to identify the relation of certain MICA with susceptibility to specific diseases.

Associations of high-resolution-typing-defined MICA and MICB polymorphisms, and the levels of soluble MICA and MICB with Oral Squamous Cell Carcinoma in Bulgarian patients.

Oral Squamous Cell Carcinoma (OSCC) is a malignancy characterized by an aggressive tumor growth and significant mortality. Clarifying mechanisms responsible for immunomodulation are among the main challenges for the development of personalized approaches for the management of patients with Oral Squamous Cell Carcinoma. The aim of the present study was to analyze the relevance of MICA and MICB to Oral Squamous Cell Carcinoma pathogenesis focusing on allele polymorphisms and the levels of soluble MICA and MICB molecules. 73 patients diagnosed with Oral Squamous Cell Carcinoma and 149 healthy controls from the Bulgarian population were included in the study. MICA and MICB polymorphism was analyzed at high-resolution level using Next-Generation Sequencing. Serum levels of soluble MICA and MICB molecules were measured by ELISA. Our results show significant protective association with MICB*002:01, while relatively rare alleles MICB*018, *019, and *020 were observed with statistically significant increased frequency in Oral Squamous Cell Carcinoma patients compared to controls. Additionally, a predisposing association was observed for MICA*008:01-MICB*019 haplotype. A correlation analysis between functionally relevant MICA polymorphisms and sMICA showed that homozygosity for MICA-A5.1 or 129Val in OSCC patients was associated with significantly higher serum levels of sMICA. This is the first study showing significant associations between MICB alleles and Oral Squamous Cell Carcinoma and suggesting the possible role of MICB in immunosurveillance in Oral Squamous Cell Carcinoma development. Observed correlations between the levels of soluble MICA molecules and functionally relevant polymorphisms might represent a further step toward a better understanding of molecular mechanisms of Oral Squamous Cell Carcinoma and developing strategies for therapeutic targeting harnessing effective immunosurveillance.

Shared epitope and polymorphism of MICA and NKG2D encoding genes in Greek and Polish patients with rheumatoid arthritis.

The present study aimed to analyse and compare the distribution of MICA (rs1051792) and NKG2D/KLRK1 (rs1154831, rs1049174, rs2255336) polymorphisms in 61 Greek and 100 Polish patients with rheumatoid arthritis in relation to the presence of the HLA-DRB1 shared epitope and clinical parameters. Genotyping of selected polymorphism was performed using real-time PCR. HLA-DRB1 shared epitope alleles segregated differently in Greek and Polish patients but in both populations were detected in over 60% of cases. The rs1051792-A variant was more common among SE-positive Polish patients (p = 0.003) while the rs1049174-G allele was more frequently observed in Greeks than in Poles (p < 0.001). Moreover, among Greek patients, the rs1051792-GG homozygotes more frequently presented with anti-CCP antibodies and rheumatoid factor (RF), while carriers of the rs1049174-G variant and rs1154831-CC homozygotes were characterized by lower disease activity scores (p < 0.05 in all cases). These results imply that, in addition to the HLA-DRB1 SE alleles, MICA and NKG2D polymorphisms may also play a role in rheumatoid arthritis.

Germline MICA Polymorphism Is Associated with the Long-Term Outcomes in Patients Undergoing Hepatectomy for Colorectal Liver Metastases

Germline MICA Polymorphism Is Associated with the Long-Term Outcomes in Patients Undergoing Hepatectomy for Colorectal Liver Metastases

Association of MHC Class I Chain-Related Gene a (MICA) Polymorphisms with Allogeneic Hematopoietic Cell Transplantation Outcomes in Acute Myeloid Leukemia

Association of MHC Class I Chain-Related Gene a (MICA) Polymorphisms with Allogeneic Hematopoietic Cell Transplantation Outcomes in Acute Myeloid Leukemia

MICA and NKG2D variants as risk factors in spondyloarthritis: a case\u2013control study

The major histocompatibility complex class I polypeptide-related sequence A (MICA) glycoprotein mediates the activation of the natural killer group 2D receptor (NKG2D) expressed on NK and CD8+ T cells. A methionine or valine at position 129 in exon 3 results in strong (MICA129 met) or weak (MICA129 val) binding to NKG2D. The MICA A5.1 allele causes a premature stop codon. Various NKG2D polymorphisms are associated with low (NKC3 C/C and NKC4 C/C) or high (NKC3 G/G and NKC4 T/T) levels of NK cell cytotoxic activity. In 162 patients with spondyloarthritis (115 with ankylosing spondyloarthritis, 46 with psoriatic arthritis and 1 with reactive arthritis) compared to 124 healthy controls, MICA-129 with methionine allele was more frequent in patients with spondyloarthritis (odds ratio (OR) (95% confidence interval) = 4.84 (2.75‒8.67)), whereas MICA-129 val/val, MICA A5.1 and NKC3 C/C variants were less frequent (OR = 0.20 (0.11‒0.37), 0.15 (0.06‒0.36) and 0.24 (0.13‒0.44), respectively). After adjustment for HLA-B*27 status, only NKC3 C/C remained linked to spondyloarthritis (adjusted OR = 0.14 (0.06‒0.33)). Homozygosity for MICA A5.1 is linked to ankylosing spondyloarthritis, and NKC3 C/C and MICA-129 val/val to psoriatic arthritis. MICA and NKC3 polymorphisms (related to a low NK cell cytotoxic activity) constituted a genetic association with spondyloarthritis.

Host MICA Polymorphism as a Potential Predictive Marker in Response to Chemotherapy for Colorectal Liver Metastases

Background: Understanding the genetic background of a tumor is important to better stratify patient prognosis and select optimal treatment. For colorectal liver metastases (CLM), however, clinically available biomarkers remain limited. Methods: After a comprehensive sequencing of 578 cancer-related genes in 10 patients exhibiting very good/poor responses to chemotherapy, the A5.1 variant of the MICA gene was selected as a potential biomarker for CLM. The clinical relevance of MICA A5.1 was then investigated in 58 patients who underwent CLM resection after chemotherapy. Results: The A5.1 variant was observed in 16 (27.6%) patients examined using direct DNA sequencing, and a very high concordance rate (56/58, 96.6%) for the MICA variant was confirmed between tumor tissues and normal liver parenchyma. A multivariate analysis of 38 patients with no history of treatment with anti-EGFR antibodies confirmed that MICA A5.1 was significantly correlated with an optimal CT morphologic response (OR 11.67; 95% CI 2.08–65.60; p = 0.005) and tended to be correlated with a tumor viability of < 20% after chemotherapy (OR 5.91; 95% CI 0.97–36.02; p = 0.054). MICA A5.1 was also associated with a decreased risk of progression after CLM resection. Conclusion: The MICA A5.1 polymorphism was associated with a better CT morphologic response to chemotherapy and a reduced risk of relapse after CLM resection. Given the high concordance rate in MICA variants between normal liver tissue and CLM, the genetic background of the host could be a new biomarker for CLM.

Abstract 1219: Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study

Abstract Objectives: The immune system has been shown to play an important role in pancreatic cancer. Abnormal cells express the transmembrane major histocompatibility complex class I chain-related gene A (MICA) protein, which is recognized by receptors present on NK and cytotoxic T cells. However, pancreatic tumor cells release MICA protein in soluble form (called s-MICA) from the tumor surface and thus avoid immune surveillance. In our previous study, we showed that a higher serum concentration of the s-MICA protein was associated with increased pancreatic cancer risk. In the current study, we hypothesized that functional variants in the MICA gene are associated with higher circulating s-MICA levels and increased pancreatic cancer risk. We focused on the A5.1 MICA allele, as this allele encodes a MICA protein that is shorter than its normal counterpart and is more easily cleaved from the cell surface. Methods: MICA alleles and s-MICA levels were measured in 116 cases and 492 controls (n=608) in a population-based case-control study in Minnesota. Allele assignments were based on the number of repeat units in the amplified regions of the MICA gene, and s-MICA levels were measured by enzyme-linked immunoabsorbent assay. To address the non-normal distribution of s-MICA levels, general linear regression with a log link was used to assess mean s-MICA levels across MICA alleles. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer after adjustment for age, sex, education, smoking status, alcohol consumption, and diabetes status. The analysis was restricted to Caucasians, who represented 96% of all study participants. Results: 452 participants (74%) possessed at least one copy of the A5.1 allele. After adjustment for confounders, participants with at least one copy of the MICA A5.1 allele were at an increased risk of pancreatic cancer (multivariable OR=2.00, 95% CI: 1.06-3.79), compared to participants who did not possess any A5.1 allele. Participants who had at least one copy of the A5.1 allele had 2.46 (95%CI: 2.36-2.56) times greater mean s-MICA levels than those without the A5.1 allele. These associations were consistent among pancreatic cancer cases and controls. Conclusions: Our study supports the role of the MICA A5.1 allele in impaired immune response, which may increase the risk of pancreatic cancer. Citation Format: Guillaume C. Onyeaghala, John Lane, Nathan Pankratz, Heather H. Nelson, Bharat Thyagarajan, Kristin E. Anderson, Anna E. Prizment. Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1219.

MICB*002 and MICB*014 protect against rheumatoid arthritis, whereas MICA*009 and MICA*A6 are associated with rheumatoid arthritis in a Hainan Han Chinese population

Rheumatoid arthritis (RA) as an inflammatory autoimmune disease affects the synovial joints as well as other organs and tissues. Since aberrant expression of MIC molecules has been observed in RA patient, MIC genotypes might play certain roles in the development of RA. To explore the association of MICA and MICB polymorphisms with RA in a Han Chinese population in Hainan Island, samples from 172 RA and 137 healthy controls were genotyped for MICA and MICB. Our results indicated that MICB*002 and MICB*014 were less frequent in RA patients than in controls (P = 0.000, 0.005) while there were higher percentages of RA patients carrying MICA*009 and MICA*A6 (P = 0.005). Different MIC variants might modulate the autoimmune reaction differently in RA disease and therefore serve as protective or risk factors.

Research on polymorphism of MICA genes in patients with type 1 diabetes mellitus in the Han and Li populations in Hainan province

Objective To investigate the genetic diversity of MICA, and to analyze the correlation between genetic polymorphisms of MICA and T1DM in population of Han and Li nationalities in Hainan province. Methods This study was performed as a case-control study. Fifty-five individuals with T1DM and Fifty-five healthy controls of Han and Li nationalities from Wuzhishan, Lingshui, Qiongzhong, Baisha, Ledong, Changjiang, Dongfang and Haikou regions in Hainan province(35 Male, 20 Female of T1DM of Han; 28 Male, 27 Female of healthy controls of Han; 33 Male, 22 Female of T1DM of Li; 28 Male, 27 Female of healthy controls of Li), were enrolled for the study. MICA allelic variation was analyzed by sequencing-based typing (PCR-SBT). Fisher′s exact test was performed to determine the statistical significance of the distribution and allele frequency of MICA. Results In healthy population, 11 MICA-sequence and 5 MICA-STR alleles were found in Han nationality, while 13 MICA-sequence and 5 MICA-STR alleles were detected in Li nationality. The MICA-sequence allele MICA*008: 01 and the MICA-STR allele MICA-A5 were most frequently observed in Han nationality[30.85%(29/94) and 41.49%(39/94), respectively], while MICA*002: 01 and A4 were the most common in Li nationality [21.57% (22/102)and 36%(36/100), respectively]. Among patients with T1DM, 10 MICA-sequence and 5 MICA-STR alleles were detected in Han, and 9 MICA-sequence and 5 MICA-STR alleles were found in Li. MICA*002: 01 and A9 were most frequently observed in Han [29%(29/100), 29.29%(29/99), respectively] , while MICA*012: 01, MICA*002: 01 and the A4 were the most common in Li [21.15%(22/104), 21.15%(22/104), 38.24%(39/102), respectively]. The allelic frequency of MICA*002: 01, MICA*010, MICA-A5, MICA-A6 and MICA-A9 between the healthy population and T1DM patients of Han nationality(5.32%, 22.34%, 41.49 %, 9.58%, 6.38%, respectively in healthy population; 29%, 7%, 26.26%, 2.02%, 29.29%, respectively in T1DM patients), exist significant difference(χ2 value were 18.799, 9.233, 5.218, 5.197, 16.762, respectively.P value were 0.000, 0.002, 0.025, 0.024, 0.000, respectively. all P 0.05) between the healthy population and T1DM patients of Li nationality. Conclusions The most common MICA alleles were MICA*008: 01 and MICA-A5 in healthy population of Han nationality, while MICA*002: 01 and MICA-A4 in healthy population of Li nationality. MICA*002: 01 and MICA-A9 were high frequency in T1DM patients of Han population, while the MICA*010, MICA-A5 and MICA-A6 were low frequency. There was not any MICA alleles associated with T1DM in Li nationality. (Chin J Lab Med, 2018, 41: 116-121) Key words: MHC class I chain-related gene; Gene polymorphism; Li nationality; Han nationality; Type 1 diabetes mellitus

Impact of MICA and NKG2D polymorphisms in HLA-fully matched related and unrelated hematopoietic stem cell transplantation.

Impact of MICA and NKG2D polymorphisms in HLA-fully matched related and unrelated hematopoietic stem cell transplantation.

Association of MICA-129 polymorphism and circulating soluble MICA level with rheumatoid arthritis in a south Indian Tamil population.

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.

Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% [n = 127]; 9/10, 22.3% [n = 142]; 8/10, 38.2% [n = 60]; MICA-129 mismatched 10/10, 3.9% [n = 54]; 9/10, 10.2% [n = 65]; 8/10, 17.2% [n = 27]). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio [HR], 1.77; confidence interval [CI], 1.22-2.57; P = .003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P = .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup.