MHC Class I Chain-related Gene A Research Articles

Association of MICA Gene Polymorphism in Opisthorchis viverrini-Induced Periductal Fibrosis in Northeastern Thais.

Chronic Opisthorchis viverrini (OV) infection is the cause of advanced periductal fibrosis (APF), subsequently leading to cholangiocarcinoma (CCA). Natural killer (NK) cells can kill hepatic stellate cells (HSCs), the initiating cells for fibrosis formation, by using the interaction between the natural killer group 2 member D (NKG2D) receptor and its ligand on the HSCs. This can inhibit the fibrosis formation. Major histocompatibility complex class I chain-related A (MICA) is the ligand of the NKG2D receptor and has highly polymorphic characteristics that are involved in NKG2D binding and NK cell activation. This study aimed to investigate the polymorphism of MICA in OV-induced fibrosis. MICA typing was performed by polymerase chain reaction- sequence specific primer (PCR-SSP) and sequencing in two groups: OV infection without fibrosis (N = 99) and with fibrosis (N = 290). Six alleles were identified and the MICA*010 allele had the highest frequency in both groups. The MICA*00201-02 allele was a protective factor for fibrosis (OR= 0.508, 95%CI= 0.34-0.76, Pc <0.05), while the MICA*019 allele was suggested to be a risk allele for fibrosis (OR=1.95, 95%CI=1.25-3.03, Pc<0.005). In addition, two motifs, glycine (G) at position 14 and glutamine (Q) at position 251, were negatively associated with fibrosis (G14: OR=0.508, 95%CI=0.34-0.76, Pc <0.05 and Q251: OR=0.586, 95%CI=0.41-0.84, Pc <0.05). Moreover, the distribution of the MICA-129 genotype also showed the protective genotype (Pc<0.05, OR=0.319, 95%CI= 0.12-0.54) for fibrosis. The MICA*00201-02 allele encoded all these motifs, and this suggested that it might lead to strong NK cell activation to kill HSCs, subsequently preventing fibrosis formation. This study described initial evidence suggesting that the polymorphism of the MICA gene might be a marker for OV-derived periductal fibrosis.

Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?

Extending long-term allograft survival has been an elusive goal in all solid organ transplantation. Although the causes of allograft loss are varied, antibody-mediated rejection (AMR) remains a significant contributor to late allograft loss despite advances in HLA testing. A subset of kidney transplant recipients has undetectable HLA donor-specific antibodies (DSA) yet has histologic and even molecular features consistent with AMR. A lack of clarity exists on how to classify these patients while long-term effects are largely unknown. A broad panel of antibodies toward multiple endothelial and nonendothelial antigen targets have been associated with allograft dysfunction and injury. In clinical practice, these antibodies are often not measured and rarely found. Complicating this issue, a debate exists about whether detectable non-HLA antibodies are the cause of antibody-mediated injury or only innocent bystanders. To date, one of the most extensively investigated nonclassical HLA targets is the major histocompatibility complex (MHC) class I chain-related gene A (MICA).1,2 Recently published data substantiated the relevance of this antigenic target, renewing the need to look beyond classical HLA to understand AMR.3 Among a retrospective multicenter French cohort of 1356 kidney transplant recipients with a median follow-up of 6.3 y who had MICA and HLA genotyping, mismatching at MICA was independently associated with inferior allograft survival with an HR 2.12, P < 0.001.3 Five-year allograft survival was 96% in the MICA genotype matched patients compared with 88% among the MICA mismatched cohort.3 Other independent factors associated with reduced allograft survival included age of donor and recipient, duration of dialysis, end-stage renal disease caused by nephropathy likely to recur, absence of induction treatment, depleting induction, and HLA-DQ beta 1 mismatch. In this comprehensive study, a subset of patients also had testing for anti-MICA and HLA DSAs. Donor-specific MICA antibodies identified either pretransplant or posttransplant were strongly associated with AMR (HR 3.79, P < 0.001), and the effect appeared to add to the risk of HLA DSA.3 The hazard ratio for AMR among patients with both MICA and HLA preformed DSA was 25.68, P = 0.002.3 The association between MICA antibody and allograft survival was confirmed in an independent validation cohort of 168 patients with biopsy-proven AMR. In the validation cohort, patients with anti-MICA DSA detected at the time of AMR were at higher risk for graft failure. Like the initial cohort, patients with both anti-MICA and HLA DSA had the lowest allograft survival. This large retrospective multicenter trial validates multiple previous studies4 but also provides important clarity about the role of MICA independent of HLA. The retrospective, sequence-based genotyping of recipients and donors for MICA was a major accomplishment and has been lacking from prior studies. This additional and critical step allowed the authors to determine the donor specificity of the MICA antibodies. Most prior studies only evaluated the presence or absence of antibodies, and donor specificity was unknown. These findings are particularly relevant in the era of sensitive donor-specific HLA antibody testing and a renewed interest in the role of HLA whole antigen and eplet matching strategies intended to improve long-term allograft survival. Adding MICA genotyping and DSA testing pretransplant and posttransplant could enhance our ability to predict rejection and personalize immunosuppression. The relevance of the findings extends beyond renal transplant as prior studies have also suggested the role of MICA in heart,5 liver, and lung6 rejection. To understand how MICA can independently result in rejection, it is worthwhile to understand how it differs from classical HLA. Like classical HLA, the MICA gene is part of the MHC class I complex located on chromosome.6 In contrast to classical HLA, the polymorphic MICA molecule is not involved in antigenic peptide presentation and has limited tissue distribution.7 MICA antigens are expressed conditionally on epithelial cells in the gastrointestinal tract, endothelial cells, fibroblasts, monocytes, keratinocytes, and dendritic cells.8 Importantly, MICA is not expressed on resting T or B lymphocytes or upregulated by interferon-gamma. Therefore, traditional T- and B-cell crossmatching does not help with detection.8 MICA molecules play a key role in connecting innate and adaptive immune responses because they activate a C-type lectin-like natural killer (NK) group 2, member D (NKG2D) receptor that is present on NK cells, γδ T cells, and CD8+ αβ T cells.7 The interaction between MICA and the NKG2D receptor leads to antigen-specific cytotoxic T lymphocyte-mediated cytotoxicity, NK cell responses, and cytokine production. Importantly, a major dimorphism exists for MICA alleles (MICA-129) that strongly influences this interaction, and alleles can be classified into one of these two functional groups.8 The authors of the recent study conclude that assessment of MICA matching and antibody detection is warranted to identify patients at elevated risk for rejection. We agree that the findings are valuable and undoubtedly contribute to our understanding of transplant rejection, but widespread MICA genotyping and DSA testing may not be ready for prime time. Several drawbacks warrant additional studies to further bolster the clinical validity and utility of MICA genotyping and antibody testing. First, assay standardization, validation, and appropriate assignment of antibody positivity are key issues to resolve. Notably, the MFI cutoffs to define positivity for HLA and MICA antibodies, respectively, were very low at 500 and 100 MFI in this study. In fact, the positive cutoff of 500 MFI to define HLA antibody positivity is much lower than typically used or recommended and could have affected the results of this study.9 Furthermore, recipient and donor racial and ethnic breakdowns were not provided. Because of the preponderance of extended haplotypes and MICA alleles combined with differences across individuals with disparate backgrounds, a follow-up validation study in a diverse cohort is needed. After addressing the laboratory issues, the community needs to understand when MICA should be obtained and how to interpret the results. Currently, MICA antibody testing is infrequently utilized by only a few transplant centers in select circumstances when searching to explain histological features suggestive of AMR when classical HLA antibody is not present. Widespread MICA genotyping and DSA testing would certainly help to further clarify the role of MICA in transplantation, but unintended consequences must be considered. Reducing access to transplantation by overestimating the risk of MICA mismatch and DSA without further data would be inappropriate. The causes of allograft failure are multifactorial, and DSA is only one of the multiple factors to consider. In conclusion, the evidence is building that the MICA antigen should no longer be ignored in solid organ transplantation. MICA genotype mismatching is associated with reduced kidney allograft survival independent of HLA matching, and future pretransplant workup will likely include MICA genotyping. At the same time, there is, more than ever, a need to standardize, validate, and optimize MICA DSA testing. Thus, it will need to be determined how to use the information by Carapoito and coworkers with the question remaining of how to incorporate the data provided into practice to improve long-term patient outcomes.

MICA Polymorphism and Genetic Predisposition to T1D in Jordanian Patients: A Case-Control Study.

Type 1 diabetes (T1D) is an autoimmune disorder whose etiology includes genetic and environmental factors. The non-classical Major Histocompatibility Complex (MHC) class I chain-related gene A (MICA) gene has been associated with increased susceptibility to T1D as the interaction of MICA to the Natural Killer Group 2D (NK2GD) receptors found on the cell surface of natural killer (NK) cells and T cells is responsible for inducing immune responses. MICA polymorphisms were reported in association with T1D among different ethnic groups. However, data from different populations revealed conflicting results, so the association of MICA polymorphisms with predisposition to T1D remains uncertain. The aim of this sequencing-based study was to identify, for the first time, the possible MICA alleles and/or genotypes that could be associated with T1D susceptibility in the Jordanian population. Polymorphisms in exons 2-4 and the short tandem repeats (STR) in exon 5 of the highly polymorphic MICA gene were analyzed. No evidence for association between T1D and MICA alleles/genotypes was found in this study, except for the MICA*011 allele which was found to be negatively associated with T1D (p = 0.023, OR = 0.125). In conclusion, MICA polymorphisms seem not to be associated with increasing T1D susceptibility in Jordanian patients.

MICA*019 Allele and Soluble MICA as Biomarkers for Ankylosing Spondylitis in Taiwanese.

MICA (major histocompatibility complex class I chain-related gene A) interacts with NKG2D on immune cells to regulate host immune responses. We aimed to determine whether MICA alleles are associated with AS susceptibility in Taiwanese. MICA alleles were determined through haplotype analyses of major MICA coding SNP (cSNP) data from 895 AS patients and 896 normal healthy controls in Taiwan. The distributions of MICA alleles were compared between AS patients and normal healthy controls and among AS patients, stratified by clinical characteristics. ELISA was used to determine soluble MICA (sMICA) levels in serum of AS patients and healthy controls. Stable cell lines expressing four major MICA alleles (MICA*002, MICA*008, MICA*010 and MICA*019) in Taiwanese were used for biological analyses. We found that MICA*019 is the only major MICA allele significantly associated with AS susceptibility (PFDR = 2.25 × 10−115; OR, 14.90; 95% CI, 11.83–18.77) in Taiwanese. In addition, the MICA*019 allele is associated with syndesmophyte formation (PFDR = 0.0017; OR, 1.69; 95% CI, 1.29–2.22) and HLA-B27 positivity (PFDR = 1.45 × 10−33; OR, 28.79; 95% CI, 16.83–49.26) in AS patients. Serum sMICA levels were significantly increased in AS patients as compared to healthy controls. Additionally, MICA*019 homozygous subjects produced the highest levels of sMICA, compared to donors with other genotypes. Furthermore, in vitro experiments revealed that cells expressing MICA*019 produced the highest level of sMICA, as compared to other major MICA alleles. In summary, the MICA*019 allele, producing the highest levels of sMICA, is a significant risk factor for AS and syndesmophyte formation in Taiwanese. Our data indicate that a high level of sMICA is a biomarker for AS.

MICA and KLRK1 genes and their impact in cervical intraepithelial neoplasia development in the southern Brazilian population

Cervical carcinoma and cervical intraepithelial neoplasia (CIN) are associated with persistent infection by oncogenic subtypes of HPV (Human Papillomavirus). Factors linked to immunity, genetics and others like oral contraceptive use, sexual behavior, coinfections with other microorganisms and smoking seem to influence the mechanisms that determine regression or progression to CIN and cervical cancer. We investigated the effect of the MHC class I chain-related gene A (MICA) and Killer Cell Lectin Like receptor K1 (KLRK1) genes on cervical cancer and CIN lesions susceptibility in a group of 195 patients from southern Brazil. There were found a significantly higher number of ex-smokers in the control group (p = 0.005). There were more oral contraceptives (OC) users in the patient group. MICA*008:01/04 allele showed a significant difference between patient and control groups (p = 0.03; OR = 0.63, 95% CI 0.41–0.96), as well as MICA*018:01(p = 0.004, OR = 0.15, 95% CI 0.03–0.64) and MICA*002:01/020 (p = 0.01; OR = 0.60, 95% CI 0.40–0.88). We also analyzed cases and controls according to the MICA-129 genotypes (Met/Val). There was found a difference (p = 0.02) with the Met/Val genotype in a higher frequency in controls and Val/Val and Val/MICA del at a higher frequency in the patient group. For the KLRK1 gene there was no significant difference between groups.

Influence of major histocompatibility complex class I chain-related gene A polymorphisms on cytomegalovirus disease after allogeneic hematopoietic cell transplantation

Objective/BackgroundCytomegalovirus (CMV) infection and disease are common infectious complications after allogeneic hematopoietic cell transplantation (alloHCT). Major histocompatibility complex (MHC) class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity. We hypothesized that MICA polymorphisms may influence CMV infection and disease incidence after alloHCT. MethodsWe conducted a retrospective analysis of 423 adults at the Cleveland Clinic with hematologic malignancies treated with a matched related or unrelated donor alloHCT. CMV cases analyzed included a compositive of instances of viral copy replication above detection limits as well as any biopsy-proven tissue invasive disease episodes. Genotypes at the MICA-129 position have been categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. ResultsIn multivariable analysis, V/V donor MICA-129 genotype was associated with CMV infection and disease (hazard ratio [HR] = 1.40; 95% confidence interval [CI], 1.00–1.96; p = .05), but not MICA mismatch (HR = 1.38; 95% CI, 0.83–2.29; p = .22). There was no association of acute or chronic GVHD with MICA donor–recipient mismatch (HR = 1.05; 95% 95% CI, 0.66–1.68; p = .83 and HR = 0.94; 95% CI, 0.51–1.76; p = .85, respectively) or V/V donor MICA-129 genotypes (HR = 1.02; 95% CI, 0.79–1.31; p = .89 and HR = 0.89; 95% CI, 0.65–1.22; p = .47, respectively). ConclusionThese findings suggest that the donor MICA-129 V/V genotype with weak NKG2D receptor binding affinity is associated with an increased risk of CMV infection and disease after alloHCT.

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

BackgroundPancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk.MethodsMICA alleles and s-MICA levels were measured in 121 pancreatic cancer cases and 419 controls. General linear regression with a log transformation assessed geometric means of 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 associated with MICA alleles.ResultsAfter multivariate adjustment, participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 (95% CI: 1.05–1.74) times greater s-MICA levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% CI: 1.05–3.48).ConclusionsOur study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response.ImpactThese findings provide further evidence at the genetic and molecular level of the important role of MICA in pancreatic cancer development, and may have important implications with regards to pancreatic cancer screening.

Risk Factors for Early Relapse after Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome

Background Relapse is a challenge after allogeneic hematopoietic cell transplantation (alloHCT) in MDS. MHC class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells. There have been conflicting reports in regards to MICA mismatch and relapse after alloHCT in hematologic malignancies (Carapito Blood 2016, Askar BBMT 2017). However, these studies did not assess somatic mutations, which have shown to impact relapse (Coleman NEJM 2017). We first assessed risk factors for relapse within 6 and 12 months after alloHCT. We then assessed for an effect of somatic mutations and MICA dimorphisms on relapse. Methods We conducted a single center, retrospective analysis of adults with MDS who underwent 1st alloHCT with T-cell replete HLA-8/8 matched related (MRD) or unrelated donor (MUD). In addition to cytogenetic risk stratification, a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms of MICA-129 were categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. Results From 2000 - 2017, 128 adult MDS patients met inclusion criteria. Median age at alloHCT was 56 years (range, 20-76). IPSS-R scores at diagnosis included 2% very good, 42% good, 23% intermediate, 19% poor, and 14% very poor risk. 62% had MUDs and 87% had a myeloablative regimen. Among 78 patients with data, donor/recipient MICA mismatch was present in 8% while donor MICA-129 dimorphisms were 49% V/V, 42% M/V, and 9% M/M In multivariable analysis, the presence of at least 1 of these less favorable mutations (ASXL1, DNMT3A, FLT3, KRAS, NRAS, and TP53) was a risk factor for relapse within 6 mos (HR 4.30, CI 1.40-13.3, P=0.011; Figure 1); 6-mo relapse incidence (CI) was 45% (22-65) for those with at least 1 of the above mutations vs. 15% (9-22) for all others. A MRD graft was a risk factor for relapse within 12 mos (HR 2.27, CI 1.12-4.59, P=0.023); 12-mo relapse incidence was 36% (23-50) for those with a MRD vs. 19% (11-28) for MUDs. In a 41-patient subset with both MICA and mutation data, although not significant, patients with both donor V/V dimorphism and at least 1 of these less favorable somatic mutations had higher relapse incidence (40% at 12 mos) than those with only 1 of these adverse factors (28%) or neither factor (9%) (P=0.12; Figure 2). Conclusion The presence of at least 1 of the 6 less favorable somatic mutations in our cohort was associated with a risk of relapse within 6 mos after alloHCT for MDS. Our data suggest an additive effect of both weak NK cell activation and less favorable somatic mutations in increasing the risk of relapse, but was not statistically significant. Future investigation of larger cohorts and mechanistic studies are needed to better assess potential interactions between these two elements and the risk of relapse.

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

BackgroundMHC class I chain-related gene A (MICA) is a polymorphic ligand of the natural killer (NKG2D) receptor on immune effector cells. The activating NKG2D receptor controls immune responses by regulating NK cells, NKT cells and γδ-T cells. Dimorphisms at sequence position 129 of the MICA gene confers varying levels of binding affinity to NKG2D receptor. MICA previously has been associated with post-allogeneic hematopoietic cell transplantation (alloHCT) outcomes including graft-versus-host-disease (GvHD), infection, and relapse. However, it is unclear how MICA interacts with cytogenetic and somatic mutations in regards to these outcomes in acute myeloid leukemia (AML).MethodsWe conducted a single center, retrospective analysis of adult AML patients in first or second complete remission (CR1, CR2), who underwent T-cell replete matched related or unrelated donor alloHCT. Analysis was limited to those who had MICA data available for donors and recipients. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Fine and Gray or Cox regression was used to identify the association of MICA and outcomes with results as hazard ratios (HR) and 95% confidence intervals (CI).ResultsFrom 2000 - 2017, 131 AML patients were identified meeting inclusion criteria. Median age at transplant was 54 years (18-74), with 98% Caucasian. Disease status at transplant included 78% CR1 and 22% CR2. Cytogenetic risk stratification showed 13% of patients as favorable, 56% as intermediate, and 31% as adverse-risk. The five most common somatic mutations were FLT3 (15%), NPM1 (14%), DNMT3A (11%), TET2 (7%), and NRAS (6%). 60% of patients had a related donor. A myeloablative transplant was performed in 84% of patients and 53% had a bone marrow graft source. The most common conditioning regimen used was busulfan/cyclophosphamide (52%). 12% of patients were MICA mismatched with their donor. The distribution of donor MICA-129 polymorphisms were 41% V/V, 53% M/V, and 6% M/M.In univariable analysis, donor-recipient MICA mismatch tended to be associated with a lower risk of infection (HR 0.49, CI 0.23-1.02, P=0.06) and grade 2-4 acute GvHD (HR 0.25, CI 0.06-1.04, P=0.06) but was not associated with other post-transplant outcomes. In multivariable analysis, donor MICA-129 V/V was associated with a higher risk of non-relapse mortality (NRM) (HR 2.02, CI 1.01-4.05, P=0.047) (Figure 1) along with increasing patient age at transplant (HR 1.46, CI 1.10-1.93, p=0.008) and the presence of a TET2 mutation (HR 6.00, CI 1.77-20.3, P=0.004). There were no differences between the V/V and the M/V+M/M cohorts regarding somatic mutational status, cytogenetics and other pre-transplant characteristics and post-transplant outcomes. With a median follow-up of 65 months for both cohorts, 45% vs. 49% of patients remain alive, respectively. The most common causes of death between the V/V and the M/V+M/M cohorts was relapse (38% vs. 62%) and infection (31% vs. 8%), respectively.ConclusionWhile previous studies have demonstrated associations of somatic mutations and cytogenetics with survival outcomes after alloHCT for AML, we observed mutations in TET2 and the V/V donor MICA-129 polymorphism to be independently prognostic for NRM. Mechanistic studies may be considered to assess for possible interactions of TET2 mutations with NK cell alloreactivity. The weaker binding affinity to the NKG2D receptor by the V/V phenotype may diminish immune responses against pathogens that subsequently contribute to higher NRM. These observations may have implications for enhancing patient risk stratification prior to transplant and optimizing donor selection. Future investigation with larger cohorts interrogating pre-transplant AML somatic mutations with MICA polymorphisms on post-transplant outcomes may further elucidate which subsets of patients may benefit most from transplant. [Display omitted] DisclosuresNazha:MEI: Consultancy. Mukherjee:Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; BioPharm Communications: Consultancy; Bristol Myers Squib: Honoraria, Speakers Bureau; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; LEK Consulting: Consultancy, Honoraria; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Advani:Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy; Novartis: Consultancy. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Gerds:Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.

Histone Deacetylase Inhibitors with or without AKT Inhibition Potentially Increase the Efficacy of Daratumumab in Multiple Myeloma By Enhancing the Antibody-Dependent Cell-Mediated and Complement-Dependent Cytotoxicity As Well As Apoptosis

Multiple myeloma (MM) is one of the many types of hematological malignancies, and many novel drugs, including histone deacetylase (HDAC) inhibitors such as panobinostat (pan-HDAC), romidepsin (HDAC1-3-specific), ACY-1215 and ACY-241 (HDAC6-specific) are currently undergoing preclinical and clinical evaluation.Daratumumab, an anti-CD38 monoclonal antibody, is a promising agent showing high activity in relapsed/refractory MM. However, some patients become resistant to daratumumab, partly due to the reduced CD38 expression in MM cells. It was previously shown that panobinostat increased CD38 expression in a time-dependent manner, particularly after 72 h (García et al). In our study, treatment with panobinostat for 24 h did not change the expression of CD38. Moreover, the expression of MHC class I chain-related gene A (MICA) was increased by all the examined HDAC inhibitors following treatment for 24 h (Figure 1). We established luciferase-expressing MM cell lines and examined antibody-dependent cell-mediated cytotoxicity (ADCC) in a luciferase assay. ADCC was enhanced after 24 h-treatment with the examined HDAC inhibitors (Figure 2). These results suggest that induction of MICA plays an important role in the enhancement of ADCC by HDAC inhibitors.Furthermore, HDAC inhibitors decreased the expression of CD55 and CD59. Presumably, CD55 and CD59 inhibit complement activation and suppress complement-dependent cytotoxicity (CDC). We found the possibility of CDC enhancement of daratumumab by HDAC inhibitors in the luciferase assay.CD47 in tumor cells inhibits phagocytosis. Blockade of interaction between CD47 in tumor cells and signal regulatory protein α (SIRP-α) in macrophages increases tumor cell phagocytosis in hematological malignancies. Moreover, the treatment of MM cells with HDAC inhibitors decreased CD47 expression. Thus, the possibility of enhancement of antibody-dependent cellular phagocytosis (ADCP) by daratumumab in these cells was suggested.Ikaros family zinc finger 1 (IKZF1) is a transcription factor and pivotal target of immunomodulatory drugs (IMiDs). IMiDs mediate the binding of IKZF1 to cereblon complex and degrades IKZF1, thereby causing the loss of interferon regulatory factor 4 and MYC expression. A previous report showed that IKZF1 could suppress the transcription of MICA (Fionda et al). Here, we found that MM cells treated with HDAC inhibitors showed downregulated expression of IKZF1 mRNA (Figure 3). These results suggest the possibility that HDAC inhibitors increase MICA expression via inhibition of IKZF1, its negative regulator. IKZF1 could be a novel target of HDAC inhibitors, including panobinostat, romidepsin, ACY-1215 and ACY-241. Furthermore, it was presumed that IKZF1 is suppressed by HDAC inhibitors in a cereblon-independent manner.Afuresertib is an oral AKT inhibitor, which has been clinically tested in patients with advanced hematological malignancies. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against patients with MM in phase I of a clinical trial (Spencer et al). In a proliferation assay, we found that afuresertib combined with HDAC inhibitors showed higher cytotoxicity than that of each agent used singly (Figure 4). The expression of cleaved caspase 3 and caspase 7 was induced more in MM cells treated with a combination of HDAC and AKT inhibitors than in those treated with only one agent. These results suggested that the combination of HDAC and AKT inhibitors strongly induces the apoptosis of MM cells. Moreover, the addition of AKT inhibitors to HDAC inhibitors caused a decrease in CD55, CD59 and CD47 expression.The findings of the present study suggest the possibility that combination therapy with HDAC and AKT inhibitors could overcome drug resistance via multiple action mechanisms. Firstly, HDAC inhibitors could enhance ADCC owing to increased MICA expression, and these may be effective in patients with reduced CD38 expression during daratumumab therapy. Secondly, the possibility of IKZF1 decrease by HDAC inhibitors in a cereblon-independent manner was presumed. Thirdly, a combination of HDAC and AKT inhibitors induced strong apoptosis in MM cells, and it may enhance the CDC and ADCP of daratumumab. These data suggest that the addition of HDAC and AKT inhibitors to daratumumab could be an effective therapy for relapsed/refractory MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Factors for Early Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

BackgroundWhile allogeneic hematopoietic cell transplantation (alloHCT) can be curative for patients with acute myeloid leukemia (AML), relapse remains a significant challenge. Previous work has suggested that disease status at time of transplant and cytogenetics are important predictors of relapse. However, it is unclear if common somatic mutations or dimorphisms of MHC class I chain-related gene A (MICA), a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity, also contribute. Moreover, the mechanisms of early relapse are an area of ongoing investigation. We assessed risk factors for relapse within 6 and 12 months after alloHCT.MethodsWe conducted a single center, retrospective analysis of adults with AML who underwent a first alloHCT. Analysis was restricted to patients with T-cell replete HLA-8/8 matched related or unrelated donor. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Risk factors for early relapse were assessed with Fine and Gray competing risk regression with results as hazard ratios (HR) and 95% confidence intervals (CI).ResultsFrom 2000 - 2017, 319 adult AML patients were identified meeting inclusion criteria. Median age at transplant was 51 years (range, 18-74), with 95% Caucasian. The distribution of low, intermediate, and high HCT-CI scores was 28%, 28%, and 44%, respectively. 75% of patients were transplanted ≤12 months from diagnosis. Disease status at transplant included 48% in first complete remission (CR1), 19% in second CR (CR2), 33% in third CR or relapsed/refractory or untreated (collectively, <CR2). By cytogenetic risk stratification, 13% of patients had favorable, 58% had intermediate, and 29% had adverse-risk cytogenetics. The four most common somatic mutations were FLT3 (12%), NPM1 (10%), DNMT3A (7%), and TET2 (6%). MICA mismatch was present in 10% of patients. The distribution of donor MICA-129 dimorphisms were 44% V/V, 51% M/V, and 5% M/M. 56% of patients had a related donor. A myeloablative transplant was performed in 88% of patients and 63% had a BM graft source. Conditioning with busulfan/cyclophosphamide was used in 56% of patients.In univariable analysis, non-Caucasian race, disease status <CR2, and adverse cytogenetics were risk factors for relapse within 6 months; all but race were also risk factors for relapse within 12 months. None of the somatic mutations assessed, MICA mismatch, nor dimorphisms at the MICA-129 position were identified as risk factors for early relapse. In multivariable analysis, relative to CR1, patients in <CR2 was a risk factor for relapse within 6 months (HR 2.21, CI 1.28-3.82, P=0.005) and 12 months (HR 2.23, CI 1.39-3.58, P<0.001), while patients in CR2 also had higher risk of relapse within 12 months relative to CR1 (HR 2.02, CI 1.10-3.70, P=0.024) (Figures 1A, 1B). In addition, adverse-risk cytogenetics were a risk factor for relapse within 6 months (HR 3.96, CI 1.33-11.8, P=0.013) and 12 months (HR 3.58, CI 1.67-7.68 P=0.001) (Figures 2A, 2B). Relapse incidence estimates (CI) at 6 months were 16% (11-22) CR1, 15% (7-25) CR2, and 33% (24-42) <CR2; estimates were 10% (3-22) for favorable, 17% (12-23) intermediate, and 31 % (22-41) adverse-risk cytogenetics. Relapse incidence estimates at 12 months were 21% (15-28) CR1, 30% (19-41) CR2, and 42% (33-52) <CR2; estimates were 21% (10-36) for favorable, 21% (15-27) intermediate, and 47% (36-57) adverse-risk cytogenetics.ConclusionRelapse after alloHCT for AML remains a challenge. In our study, the strongest risk factors for early relapse after alloHCT remains absence of CR1 disease status at transplant and adverse-risk cytogenetics. We observed no prognostic effect of somatic mutations nor MICA dimorphisms prior to transplant on 6 or 12-month relapse post-transplant. Further interrogation of pre-transplant or post-transplant persistence of somatic mutations in a larger series may better risk stratify subjects who may benefit from more intensive or innovative approaches to prevent post-transplant relapse. DisclosuresNazha:MEI: Consultancy. Advani:Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Carraway:Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; FibroGen: Consultancy; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Majhail:Atara: Honoraria; Incyte: Honoraria; Anthem, Inc.: Consultancy.

Lower protein expression levels of MHC class I chain-related gene A in hepatocellular carcinoma are at high risk of recurrence after surgical resection

MHC class I chain-related gene A (MICA) variants have been associated with hepatocellular carcinoma (HCC). Their association with MICA expression in cancer cells and cancer recurrence is unknown. SNP rs2596542 of MICA was tested in 193 HCC patients with surgical resection. The corresponding MICA expression in the cancer tissue was measured by immunochemistry microarray. Patients with the SNP rs2596542 A allele had significantly lower MICA expression in tumor tissue than did those with the GG genotype (24.7 ± 15.1% vs. 41.5 ± 23.4%, P < 0.001). Patients who had HCC recurrence had significantly lower MICA expression in tumor tissue (34.2 ± 21.8% vs. 24.0 ± 19.8%, P = 0.03). Cox regression analysis revealed that the factors independently predictive of HCC recurrence included low MICA expression (hazard ratio [HR]/95%confidence intervals [CI]: 2.77/1.07–7.14, P = 0.035) and tumor size (HR/CI: 5.22/2.11–12.96, P < 0.001). Compared to patients with tumors <5 cm and MICA expression >30%, patients with either one and both two risk factors had HCC HRs of 9.76 (C.I. 1.27–75.03, P = 0.03) and 27.30 (C.I. 3.46–215.6, P = 0.002), respectively. We concluded that low cellular MICA expressions were at a greater risk of HCC recurrence after curative treatment.

Association Between MICA Gene Variants and the Risk of Hepatitis C Virus-Induced Hepatocellular Cancer in a Sicilian Population Sample.

There are currently no biomarkers that predict hepatocellular carcinoma (HCC) risk in patients with hepatitis C virus (HCV)-related cirrhosis. We investigated the relationships among major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, plasma levels of soluble MICA (sMICA), and HCC risk in patients with HCV-related HCC. One hundred fifty-four HCV-related HCC patients, 93 HCV-related liver cirrhosis (LC) cases, and 244 healthy controls, all sampled from the native Sicilian population, were genotyped using the KASP™ single-nucleotide polymorphism genotyping method. The MICA rs2596542 polymorphism showed that the G/G genotype was significantly more frequent in HCC than control subjects and LC patients (p < 0.005). For MICA rs2596538 polymorphism, the C allele and C/C genotype were significantly more frequent in HCC than in controls and LC cases (p < 0.005), after controlling for potential confounders. These results demonstrate that MICA rs2596542G/G, and particularly the rs2596538C/C polymorphism, are associated with the risk of developing HCV-related HCC in a Sicilian population sample. Importantly, using a machine learning classifier, we found that "age" and either rs2596542 or rs2596538 were important discriminating factors for patients with LC and HCC. Finally, sMICA levels significantly increased during HCV-related liver disease progression, while a significant relationship between both rs2596542 and rs2596538 genotypes and sMICA plasma levels was identified in patients with LC and HCC. In summary, the MICA rs2596538 and rs2596542 variants warrant further research for their clinical validity and utility in relationship to the risk of developing HCV-related HCC in independent populations.

200 - Impact of MHC Class I Chain-Related Gene a (MICA) Mismatch on Umbilical Cord Blood Hematopoietic Cell Transplantation

200 - Impact of MHC Class I Chain-Related Gene a (MICA) Mismatch on Umbilical Cord Blood Hematopoietic Cell Transplantation

514 - Impact of MHC Class I Chain-Related Gene a (MICA) Mismatch on Haploidentical Hematopoietic Cell Transplantation Outcomes

514 - Impact of MHC Class I Chain-Related Gene a (MICA) Mismatch on Haploidentical Hematopoietic Cell Transplantation Outcomes

Influence of MHC Class I Chain-Related Gene Α (MICA) Polymorphisms on Cytomegalovirus Infection after Allogeneic Hematopoietic Cell Transplantation

BackgroundCytomegalovirus (CMV) is a common infectious complication after allogeneic hematopoietic cell transplantation (alloHCT). Efforts to enhance immune reconstitution post-transplant have been pursued to help facilitate clearance of such infections. Assessment of natural killer (NK) cell allo-reactivity with investigation of killer cell immunoglobulin-like receptors has been reported to be associated with protection from CMV infection after alloHCT (Davis ZB et al, BBMT 2015). In addition, the activating NKG2D receptor controls immune responses by regulating NK cells, NKT cells and γδ-T cells. MHC class I chain-related gene A (MICA) is a polymorphic ligand of the NKG2D receptor on these immune effector cells. Given the potential benefit of NK cell allo-reactivity for protection from CMV infection after alloHCT we hypothesized that MICA polymorphisms may influence CMV infection rates after such transplants.MethodsWe conducted a single center, retrospective analysis of allogeneic HCTs for adults with hematologic malignancies in which MICA data were available for donors and recipients. Analysis was restricted to patients with T-cell replete HLA-8/8 matched related or unrelated donor. Fine and Gray regression was used to identify risk factors for CMV infection. The first episode of graft-versus-host-disease (GVHD) was analyzed relative to CMV as a time-dependent covariate. An analysis was performed examining dimorphisms at the MICA-129 position, which previously has been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity.ResultsFrom 2000-2016, 423 alloHCT patients were identified who had MICA data. Diagnoses included 197 AML, 82 MDS, 34 ALL, 34 NHL, 22 CML, 12 CMML, 9 CLL, 9 myelofibrosis, 9 plasma cell myeloma, 9 other leukemias, and 6 Hodgkin lymphoma. High, intermediate, and low co-morbidity index was seen in 42%, 33%, and 25% of patients, respectively. Median age at transplant was 52 years (range, 18-76), with 95% Caucasian. A myeloablative transplant was performed in 80% of patients and 52% had a bone marrow graft source. CMV infection occurred in 141 (33%) of patients at a median time of 46 days post-transplant (range, 0-609 days) with 29 (21%) occurring within 30 days, 108 (77%) within 100 days and 33 (23%) after day 100. Thirty-three (8%) patients were MICA mismatched with their donor. Donor MICA-129 dimorphisms included 203 (48%) V/V, 190 (45%) M/V and 30 (7%) M/M. Baseline donor(d)/recipient(r) CMV serostatus for V/V vs. M/V + M/M cohorts were 25% vs. 28% for d+/r+, 11% vs 9% for d+/r-, 39% vs. 37% for d-/r+, and 25% vs. 26% for d-/r- (P=0.75). In univariate analysis, MICA mismatch was associated with a higher risk of CMV (HR 1.64, CI 1.00-2.69, P=0.049), and V/V donor MICA-129 dimorphism with a marginally higher risk of CMV (HR 1.32, CI 0.85-1.83, P=0.10). In multivariable analysis, MICA mismatch was not associated with CMV infection (HR 1.38, CI 0.83-2.29, P=0.22) while V/V donor MICA-129 dimorphism was associated (HR 1.40, CI 1.00-1.96, P=0.05) (Figure 1). Other significant variables in multivariable analysis were year of transplant (HR 0.95, CI 0.92-0.99 P=0.01), non-Caucasian race (HR 2.15, CI 1.18-3.91, P=0.01), high-risk disease (HR 1.62, CI 1.13-2.32 P=0.008), baseline CMV serostatus (HR 7.51, CI 3.76-15.0, P<0.001 for d+/r+, HR 7.73, CI 3.90-15.3, P<0.001 for d-/r+, both relative to d-/r-), and development of GVHD prior to CMV (HR 2.02, CI 1.37-2.96, P<0.001). There was no association of MICA mismatch with acute (HR 1.05, CI 0.66-1.68, P=0.83) or chronic (HR 0.94, CI 0.51-1.76, P=0.85) GVHD. As compared to the V/M+M/M cohort, patients with V/V donors had a longer interval from diagnosis to transplant (median 8.2 vs 6.2 months, P=0.036) and more often received myeloablative conditioning (P=0.030).ConclusionWe conclude that the donor MICA-129 V/V dimorphism with weak NKG2D receptor binding affinity is associated with increased risk of CMV infection after alloHCT. The presence of at least one M residue encoding allele may confer enhanced NK cell anti-viral reactivity. These observations potentially may have implications in optimizing donor selection. Further investigation of MICA may also help better predict which patients are at higher risk of CMV infection in order to consider intervening sooner with CMV specific therapy or more rapid tapering of immunosuppression. [Display omitted] DisclosuresGerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Majhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy.

MICA diversity and linkage disequilibrium with HLA-B alleles in renal-transplant candidates in southern Brazil.

The major histocompatibility complex (MHC) class I chain-related gene A (MICA) is located centromerically to the human leukocyte antigen (HLA)-B. The short distance between these loci in the MHC indicates the presence of linkage disequilibrium (LD). Similarly to the HLA, the MICA is highly polymorphic, and this polymorphism has not been well documented in different populations. In this study, we estimated the allelic frequencies of MICA and the linkage disequilibrium with HLA-B alleles in 346 renal-transplant candidates in southern Brazil. MICA and HLA were typed using the polymerase chain reaction-sequence-specific primer method (PCR-SSO), combined with the Luminex technology. A total of 19 MICA allele groups were identified. The most frequent allele groups were MICA*008 (21.6%), MICA*002 (17.0%) and MICA*004 (14.8%). The most common haplotypes were MICA*009-B*51 (7.8%), MICA*004-B*44 (6.06%) and MICA*002-B*35 (5.63%). As expected from the proximity of the MICA and HLA-B loci, most haplotypes showed strong LD. Renal patients and healthy subjects in the same region of Brazil showed statistically significant differences in their MICA polymorphisms. The MICA*027 allele group was more frequent in renal patients (Pc = 0.018, OR: 3.421, 95% CI: 1.516–7.722), while the MICA*019 allele group was more frequent in healthy subjects (Pc = 0.001, OR: 0.027, 95% CI: 0.002–0.469). This study provided information on the distribution of MICA polymorphisms and linkage disequilibrium with HLA-B alleles in Brazilian renal-transplant candidates. This information should help to determine the mechanisms of susceptibility to different diseases in patients with chronic kidney disease, and to elucidate the mechanisms involved in allograft rejection associated with MICA polymorphisms in a Brazilian population.

A new MHC-linked susceptibility locus for primary Sjögren's syndrome: MICA.

The association of primary Sjögren's syndrome (pSS) with Major Histocompatibility Complex (MHC) alleles is quintessential of MHC-disease associations. Indeed, although disease associations with classical HLA class I and II alleles/haplotypes are amply documented, further dissection is often prevented by the strong linkage disequilibrium across the entire MHC complex. Here we study the association of pSS, not with HLA genes, but with the non-conventional MHC encoded class I gene, MICA (MHC class I chain-related gene A). MICA is selectively expressed within epithelia, and is the major ligand for the activatory receptor, NKG2D, both attributes relevant to pSS' etiology. MICA-pSS association was studied in two independent (French and UK) cohorts representing a total of 959 cases and 1,043 controls. MICA*008 allele was shown to be significantly associated with pSS (pcor=2.61 × 10-35). A multivariate logistic regression showed that this association was independent of all major known MHC-linked risk loci/alleles, as well as other relevant candidate loci that are in linkage disequilibrium with MICA*008 i.e. HLA-B*08:01, rs3131619 (T), MICB*008, TNF308A, HLA-DRB1*03:01 and HLA-DRB1*15:01 (P = 1.84 × 10-04). Furthermore, independently of the MICA*008 allele, higher levels of soluble MICA proteins were detected in sera of pSS patients compared to healthy controls. This study hence defines MICA as a new, MHC-linked, yet HLA-independent, pSS risk locus and opens a new front in our understanding of the still enigmatic pathophysiology of this disease. The fact that the soluble MICA protein is further amplified in MICA*008 carrying individuals, might also be relevant in other auto-immune diseases and cancer.

MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study

Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA–matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

Interaction Between Polymorphisms of IFN-γ and MICA Correlated with Hepatocellular Carcinoma.

BackgroundWe explored the relationship of interferon--γ (IFN-γ) and MHC class-I chain related gene A (MICA) genes polymorphisms with hepatocellular carcinoma (HCC) risk, and tried to determine whether the interaction existed between these two genes polymorphisms on the basis of HCC.Material/MethodsPolymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the genotypes of the 3 single-nucleotide polymorphisms (SNPs) and to analyze the correlation of each SNP with HCC susceptibility in 120 HCC patients and 124 healthy people. The association strength between the 3 SNPs and HCC is represented with odds ratio (OR) and 95% confidence interval (95% CI). Hardy-Weinberg equilibrium (HWE) was tested by χ2 test in the control group.ResultsGG genotype of IFN-γ rs2069727 polymorphism had apparently different distributions in case and control groups (P<0.05), and might confer increased risk of HCC (OR=3.40, 95%CI=1.23–9.38). Analysis of MICA rs2596542 polymorphism also yielded the same result (OR=2.90, 95%CI=1.10–7.67), as did their risk alleles. Specifically, the interaction between rs2596542 and rs2069705 polymorphisms increased the HCC risk by 1.41 times and between rs2596542 and rs2069727 polymorphisms the increased risk of HCC by 5.56 times.ConclusionsIFN-γ rs2069727 and MICA rs2596542 polymorphisms may be related to the incidence of HCC. Interaction exists between the polymorphisms of IFN-γ and MICA, which may increase risk of HCC.