Anti-integrin αvß6 antibody in Takayasu arteritis patients with or without ulcerative colitis.

Background: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvß6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvß6 Ab and TAK, considering the risk HLA alleles. Methods: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvß6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation. Results: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvß6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10-8). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvß6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189). Conclusions: The prevalence of anti-integrin αvß6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvß6 Ab production would be minimal.

Fine Mapping of the Major Histocompatibility Complex Region and Association of the HLA-B*52:01 Allele With Cervical Cancer in Japanese Women.

Importance: Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. Objective: To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. Design, Setting, and Participants: This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020. Main Outcomes and Measures: Loci within the MHC region associated with CC risk, and the direction and size of association. Results: A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10-10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population-specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue-based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10-9). Conclusions and Relevance: The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.

Takayasu Arteritis: Recent Developments.

PURPOSE OF REVIEW: Takayasu arteritis (TA) is a granulomatous inflammatory disorder that affects large vessels, especially aorta and its proximal branches. Its diagnosis can be extremely challenging due to the non-specificity of the systemic inflammatory manifestations during the early phase of the disease and usually follows an insidious clinical course until the emergence of vascular ischemic complications. RECENT FINDINGS: Its pathogenesis has been better delineated in recent years, especially the role of HLA-B*52 allele in certain ethnic groups, as well as the use of biological therapy, and surgical revascularization. Recent findings are discussed in depth. Clinical and epidemiological aspects of TA, recent developments in pathogenesis, and therapy are presented.

Full-length sequencing of the HLA region identified a novel allele, HLA-B*52:70.

One nucleotide substitution at position 276 of HLA-B*52:01:01 results in a novel allele, HLA-B*52:70.

Epidemiology of Takayasu arteritis.

Takayasu arteritis (TA), a granulomatous large vessel vasculitis involves mostly the aorta and its proximal branches and occurs most commonly in young females. The data on the epidemiology of TA is limited, probably due to the rarity of the disease. Although the disease has a worldwide distribution, it is generally thought to be much more common among Asian populations. The incidences of TA were estimated to be 1-2 per million in Japan and 2.2 per million in Kuwait. Recent epidemiologic studies suggest that TA is being increasingly recognized in Europe with reported incidence estimates varying from 0.4 to 1.5 per million. The highest ever prevalence of TA at 40 per million was estimated in Japan and the lowest ever one at 0.9 per million in US. The reported prevalences in the European populations vary between the ranges of 4.7 per million and 33 per million. These variations between the studies may be derived from geographical and genetic differences between the populations, but also may be due to the methodological differences.

Identification of the novel HLA-B*52:01:27 allele by polymerase chain reaction sequence-based typing.

HLA-B*52:01:27 differs from HLA-B*52:01:01 by a single nucleotide substitution at position 681 C>T.

Full-length sequence of 2 HLA-B alleles, B*52:01:01:01 and B*52:01:02:01, identified by cloning and sequencing.

Full-length sequence of HLA-B*52:01:01:01 and B*52:01:02:01, identified by cloning and sequencing in Chinese donors.

Relationship of HLA-B*51 and HLA-B*52 alleles and TNF-α-308A/G polymorphism with susceptibility to Takayasu arteritis: a meta-analysis.

We performed a meta-analysis to determine whether combined evidence shows an association between HLA-B*51 and HLA-B*52 alleles and TNF-α-308A/G polymorphism and the susceptibility to Takayasu arteritis (TA). Relevant articles dated November 2015 were acquired from the PubMed, Embase and Cochrane databases. The number of genotypes and/or alleles for HLA-B*51 and HLA-B*52 alleles and TNF-α-308 A/G polymorphism in cases and control subjects was extracted, and statistical analysis was conducted using STATA 11.2 software. We included 20 studies with 1864 TA patients and 6973 controls. The HLA-B*52 allele was found to be associated with TA (pooled OR 3.91, 95 % CI 3.22-4.74, P < 0.0001). The meta-analysis of TNF-α-308 A/G polymorphism for the A allele vs. G allele (P = 0.006) and AA + AG vs. GG (P = 0.023) revealed a significant association with TA. However, we did not find that the HLA-B*51 allele was associated with TA. This meta-analysis demonstrated that the HLA-B*52 allele and TNF-α-308 A/G polymorphism may contribute to TA susceptibility.

Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment.

BACKGROUND: We aimed to investigate the effects of immunosuppressive and biological agents on refractory Takayasu arteritis (TA) patients resistant to or dependent on glucocorticoids. METHODS: Forty-four consecutive TA patients were enrolled, and the clinical characteristics and effectiveness of the immunosuppressive and biological agents in achieving and maintaining remission among glucocorticoid-resistant or glucocorticoid-dependent patients were investigated. RESULTS: Fifteen patients showed favorable response to the initial glucocorticoid treatment, and 29 patients exhibited resistance to initial glucocorticoid treatment or relapsed with tapering glucocorticoid. Of the 29 patients, 5 responded to additional glucocorticoid treatment, and 22 of the remaining 24 glucocorticoid-resistant or glucocorticoid-dependent patients were prescribed immunosuppressive agents. Methotrexate was the most commonly used in these patients as the first-line treatment. In total, 10 patients maintained remission using immunosuppressive agents, with the effectiveness of each agent about 20%. The only significant difference between patients who were and were not able to achieve and maintain remission with immunosuppressive agents was the presence of the HLA-B52 allele (p<0.0001). Biological agents were administered to 6 patients refractory to immunosuppressive agents. All patients were administered tumor necrosis factor (TNF) inhibitors as the first-line treatment, and 3 patients maintained remission. Anti-interleukin-6 receptor antibody was administered to 2 patients who were resistant to the TNF inhibitors, and 1 patient achieved and maintained remission. CONCLUSION: In our cohort, 64% of the glucocorticoid-resistant or glucocorticoid-dependent patients maintained remission through a combined treatment with glucocorticoid, immunosuppressive agents, and/or biological agents. The combined use of immunosuppressive and biological agents appears to be a promising treatment option for achieving and maintaining remission in refractory TA patients.

The Severity of Takayasu Arteritis Is Associated with the HLA-B52 Allele in Japanese Patients.

Takayasu arteritis (TA) is a type of vasculitis that affects the large elastic arteries, specifically the aorta and its main branches. It has been reported that TA occurred most frequently in Nagasaki Prefecture, the western area in Japan. We retrospectively collected the information of 34 patients with TA, diagnosed using the American College of Rheumatology 1990 criteria for the classification of TA, from the medical records of Nagasaki University Hospital from 2003 to 2015, and we investigated the clinical characteristics of these TA patients. Among the 35 patients, 25 patients were examined for the existence of the HLA-B52 allele that has been reported to influence TA susceptibility. Seventeen patients (68.0%) of the 25 patients were HLA-B52-allele-positive, which was defined as the state of having at least one HLA-B52 allele. There was a significant difference in the rate of smokers: HLA-B52-allele-positive: six patients (35.3%) vs. HLA-B52-allele-negative: 0 (0.0%). The C-reactive protein level in the HLA-B52-positive patients (9.0 ± 6.4 mg/dL) was significantly higher than that in the HLA-B52-negative patients (3.2 ± 3.9 mg/dL). All HLA-B52-allele-positive patients were found to be active according to Kerr's criteria. The HLA-B52-positive patients' initial prednisolone dosage (37.7 ± 8.6 mg/day) was significantly higher than that of the HLA-B52-allele-negative patients (23.1 ± 13.1 mg/day). Thus, the HLA-B52 allele is associated with the disease activity and the steroid requirements of TA patients. Furthermore, our present findings have revealed for the first time that the HLA-B52 allele and smoking might be associated with the onset of TA.

A new HLA-B allele, B*52:44, sequenced in a Chinese individual.

One nucleotide replacement in codon 154 (GAG>GAT) of HLA-B*52:01:01:01 results in a novel allele formation, HLA-B*52:44.

MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset.

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.

HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn's disease.

BACKGROUND & AIMS: There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohn's disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined. METHODS: We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD. RESULTS: The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 × 10⁻7°; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw*1202-B*5201-DRB1*1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 × 10⁻³³; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 × 10⁻²¹; OR = 2.65), but reduces risk for CD (P = 1.1 × 10⁻7; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 × 10⁻¹9 and P = 7.2 × 10⁻5, respectively). CONCLUSIONS: The HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population.