MHC Class I related chain A (MICA), Human Leukocyte Antigen (HLA)-DRB1, HLA-DQB1 genotypes in Turkish patients with ulcerative colitis

Introduction

Ulcerative colitis (UC) is an inflammation of intestine which holds the right proximal colonic mucosa from the rectum and is characterized by remissions and exacerbations. The disease is systemic with various extraintestinal involvements (skin, lung, eye, liver, renal, hematologic, and immunologic findings) [1], [2].The definitive diagnosis is confirmed by interventional tests such as colonoscopy and biopsy [3].Several factors (environmental and genetic) associated with the pathogenesis of the disease have been identified their effects on UC is not clear yet [4], [5], [6].

Human Leukocyte Antigen (HLA)-DRB1 and DQB1 antigens in Major histocompatibility complex (MHC) class II genes are involved in peptide presentation to T cell receptors. Inflammatory bowel diseases can lead to the formation of autoreactive T cells [7]. HLA alleles take part in a significant role in the pathogenesis of the inflammatory intestinal diseases. HLA-DRB1*09, DRB1*15:02, DRB1*01:03, DRB1*07:01 and DRB1*13 alleles were related to UC, and the HLA-DRB1*04, DRB1*08, and DQB1*03:01 alleles were reported as effective prophylactics [8], [9], [10], [11], [12], [13], [14], [15], [16].A rare allele HLA-DRB1 *01:03 was associated with patients resistant to medical therapy and/or requiring colectomy [9].

MHC Class I related chain A (MICA) is recognized by αβ CD8 T, γδ T lymphocytes, and natural killer (NK) cells via the NK cell receptor NKG2D [17], [18], [19]. MICA molecules regulate the protective responses of γδ1 T cells and are increased expression in the gastrointestinal epithelium during cellular stress conditions such as bacterial and viral infections [20], [21], [22]. MICA polymorphism affects the binding of NKG2D [23]. MIC expression increase in intestinal epithelial cells was observed in the active phase of celiac disease [24]. Bacterial antigens induce the expression of MICA in the colonic lumen, and MICA gene is important in the development of ulcerative colitis [22], [25]. MICA A6, MICA*007 (A4), MICA A5, and MICA A5.1 alleles were associated with ulcerative colitis [26], [27], [28], [29]. Kamoun et al. [30]showed that no MICA allele significantly increased in IBD groups compared to controls. In ulcerative colitis, A6 was found to be associated with involvement other than the intestine and MICA-A5 was related with the age of onset.

We aimed to determine the HLA-DRB1, -DQB1, and MICA genotypes in patients with UC.

Materials and methods

Results

Eighty-five patients and 100 healthy individuals were included in this study and there are no significant differences between the ages and genders of groups.

HLA-DRB1 genotyping results according to the most frequent allele was DRB1*11 in the patient (21%), and control (30%) groups. The comparison of the patients and control group showed significantly higher DRB1*01 (p:0.022. OR:0.23. CI:0.06–0.8) in the control group and DRB1*14 (p:0.04. OR:2.25. CI:1–5.08). DRB1*15 (p:<0.0001.OR:4.54. CI:2.09–9.88) alleles were higher in the patient group. DRB1*01 (Pc: 0.26), and DRB1*14 (Pc: 0.52) lost their significance with the Bonferroni test (Table 2).

HLA-DQB1 genotyping results according to the most frequent allele was DQB1*03 in the patient (38%), and control (47%) groups. There was no statistically significant result (Table 2).

MICA genotyping results according to the most frequent alleles were MICA*002 (A9) (22%) in the control, and MICA*002 (A9) (16%), MICA*009 (A6) (16%) in the patient groups. MICA*004 (A6) (p:0.0055. OR:2.9. CI:1.3–6.4) alleles were higher in the patient group. The significance was lost by the Bonferroni test (Table 3).

Forty-six patients (54.1%) developed pancolitis, 20 (23.5%) patients developed left-sided colitis, and 19 (22.4%) patients developed distal colitis. MICA*006 (A6) allele was significantly higher in patients with distal colitis however, the inclusion of HLA-DRB1, and DQB1 alleles showed no statistical significance. The significance was lost by the Bonferroni test.

Extraintestinal manifestations developed in 19 patients. No statistically significant difference was detected between extra involvement, and HLA-DRB1, DQB1, MICA alleles.

The most frequent haplotypes were HLA-DRB1*11-DQB1*03 in patients (19%) and control (25%) group. There was no statistically significant.

Discussion

The multifactorial pathogenesis of UC has not yet been fully explained. We aimed to examine HLA-DRB1, HLA-DQB1, and MICA alleles to shed light on the pathogenesis of UC. Being the first study in Turkey, our research will contribute to the literature by providing the results of the Turkish population.

HLA-DRB1 and DQB1 antigens in MHC class II gene can lead to the formation of autoreactive T cells that cause inflammatory bowel diseases.

HLA-DRB1*04 allele was defined as protective for UC on Northern Europeans, Japanese and Iranian populations [9], [14]. Gao F et al. [11] reported that HLA-DRB1*08 allele in Uyghur patients and HLA-DRB1*03 allele in Han patients were negatively associated with ulcerative colitis [33]. DR13 was found to be protective in a previous study with 59 Turkish patients [8]. In the present study we found HLA-DRB1*01 allele low in patients with UC. In healthy controls the frequencies of DRB1*11, DRB1*04 and DRB1*13 of HLA-DRB1 types were found as 30, 14, and 11%, respectively.

Uyar FA et al. [8]showed that HLA-DRB1*1502 was associated allele in Turkish patients with UC. Myung SJ et al. [10] and Ahmad T et al. [9] observed the association of HLA-DR2 and HLADRB1*1502 with UC. Gao F et al. [11] reported that HLA-DRB1*13 allele in Uyghur patients was positively associated with UC. In the present study, we indicated that HLA-DRB1*14 and DRB1*15 alleles higher in patients with UC. Only DRB1*15 allele was identified in the limit of significance by the Bonferroni test. Consistent with the previous studies, DRB1*15 allele is a risk factor for the disease in our society.

HLA-DRB1*0103 allele has been associated with the disease, disease severity and extraintestinal manifestations in various studies [9], [12], [13], [15], [16]. We obtained no results associated with HLA-DRB1*0103 and illness severity and extra intestinal manifestations in our study.

In previous studies, DQB1*03:01 allele was defined as protective. However, no relationship was found between DQB1*03:01, and disease in the present study [9], [14].

The MIC molecules expressed in the gastrointestinal epithelium are known to significantly increase in cellular stress situations such as bacterial or viral infections [21], [22].

Lucas D et al. [34] reported that MICA*008 (A5.1), *002 (A9), *004 (A6), *001 (A4), *009 (A6), and *016 (A5) alleles were significantly higher in healthy controls. In this study, the frequencies of *002 (A9), *009 (A6), and *008 (A5.1) alleles were found to be 22, 21 and 19%, respectively, in healthy controls.

Some studies found MICA A4 in 340 Spanish patients with UC and MICA*129 Val/Met polymorphism alleles as a protector [29], [35]. However, we found no protective alleles in Turkish patients diagnosed with UC.

Sugimura K et al. [26] showed that MICA A6 allele in 83 Japanese patients was positively associated with UC. Previous studies showed that MICA*007 (A4) allele to be associated with UC in United Kingdom and Spanish patients [29], [35]. In the present study, although lost after Bonferroni test, MICA*004 (A6) allele was significantly higher in the patient group. As a result, we suggest that MICA*004 (A6) allele may provide susceptibility to UC in Turkish patients.

Kamoun et al. [30] showed that MICA-A6 was associated with involvement other than the intestine and MICA-A5 was associated with advanced age in UC patients. The study of Fdez-Morera JL et al. [27] in 121 Spanish patients with UC demonstrated that MICA-A5.1 allele was found to increase in patients with distal colitis and MICA-A5 allele was found to increase in patients with the extensive forms. However, no associated alleles were detected in this study.

The limitation of our study was the number of patients. We suggest that the significance lost with the Bonferroni Test will disappear with the increase of the number of patients.

In conclusion, the present study suggests that HLA-DRB1*01 may demonstrate a protective effect against the disease, and HLA-DRB1*15 is associated with UC. Considering the involvement of the disease, the MICA*006 is associated with distal colitis patients. We suggest that the HLA, and MICA genes associated with UC susceptibility can be used as biomarkers in the diagnosis of the disease. The results of this study are the first studies to help the literature on Turkish patients with UC.