Frequency Of HLA-DRB1 Research Articles

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors.

Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

Typing of HLA-A, -B and DRB1 antigens in clinical practice in patients of the Rostov population for early diagnosis of rheumatoid arthritis

Objective: a retrospective analysis of the results obtained by typing HLA-A, -B antigens and HLA DRB1 allele groups in patients with rheumatoid arthritis (RA) in the Rostov population.Materials and methods: typing of patients with rheumatic inflammatory diseases who were on inpatient treatment in the rheumatology department of the SBI “OKB No. 2” was carried out in the LITT SBI RO "BTS" in 2019-2020. 41 patients (9 men, 32 women, median age — 42 years) were diagnosed with RA. All patients were typed by HLA-DRB1 alleles by real-time polymerase chain reaction with DNA-TECH reagents (Russia). To isolate DNA, a set of Sample-Rapid-Genetics was used by NPO DNA Technology LLC. 39 patients were typed аccording to HLA-A, -B. Typing was carried out by a standard lymphocytotoxic test with DILEN reagents (Czech Republic). Lymphocytes were isolated in a density gradient of “Lympholot”, DILEN company. The control group consisted of healthy residents of the Rostov population (donors of the hematopoietic stem cell registry).Results: a retrospective analysis showed that HLA DRB1*04 occurs in 46.3% of the Rostov population with RA, in 61.1% of the seropositive RA group (control — 20%). There was a decrease in the frequency of HLA DRB1*13 (9.7%) compared to the control (24.4%).Conclusions: the high level of reliability (p<0.001) of the increase in the frequency of HLA DRB1*04 alleles confirms their associative relationship with RA in the Rostov population. A decrease in the frequency of HLA DRB1*13 indicates the protective function of these alleles in RA. Typing results are important for early diagnosis of RA.

The HLA profile and genetic affinities of three primitive Tamil-speaking endogamous groups: Kallars of Thanjavur, Piramalai Kallar and Vanniyar

BackgroundThe present study was aimed to study the frequencies of HLA-DRB1/-DQB1 alleles and haplotypes of three endogamous groups of Tamil Nadu state, South India. PCR-SSP typing of HLA-DRB1 and -DQB1 alleles were performed on 111 Kallars of Thanjavur, 80 Piramalai Kallar of Madurai and 119 Vanniyar. Genetic distances, neighbor-joining phylogenetic dendrograms and correspondence analysis have been performed.ResultsThe HLA class II alleles, DRB1*07 (25.2%), DRB1*15 (15.7%), DRB1*14 (11.7%) and DRB1*12 (9.90%) among Kallars of Thanjavur; DRB1*15 (28.7%), DRB1*04 (15.6%), DRB1*10 (14.3%), DRB1*13 (11.2%) and DRB1*03 (9.37%) among Piamalai Kallar and DRB1*15 (24.7%), DRB1*04 (15.9%), DRB1*07 (11.7%), DRB1*12 (11.3%) and DRB1*10 (10.0%) among Vanniyar were more frequent. Similarly, alleles DQB1*06 (31.0%), DQB1*02 (26.5%) and DQB1*05 (24.7%) among Kallars of Thanjavur; DQB1*05 (32.5%), DQB1*06 (31.8%), DQB1*02 (16.2%) and DQB1*03:02 (12.5%) among Piramalai Kallar and DQB1*05 (52.9%), DQB1*06 (22.6%) and DQB1*02 (11.3%) among Vanniyar were more frequent. We genotyped the two most frequent two-locus haplotypes, such as DRB1*15-DQB1*06 and DRB1*07-DQB1*02 for HLA-A/-B/–C alleles to identify the 5-locus extended haplotypes to extrapolate global affinities. We identified a number of five locus extended haplotypes among south Indian population with stronger global affinities. Further, we identified the presence of a highly unique extended haplotypes such as A*11-B*35-C*12-DRB1*07-DQB1*02 (HF:0.1458) in Kallars of Thanjavur, A*03-B*35-C*04-DRB1*15-DQB1*06 (HF:0.1833) in Piramalai Kallar and A*03-B*07-C*07-DRB1*15-DQB1*06 (HF: 0.1800) in Kallars of Thanjavur and (HF: 0.1081) in Vanniyar population.ConclusionsAllele distribution and haplotype analysis have demonstrated that the Kallars of Thanjavur, Piramalai Kallar and Vanniyar populations shared HLA alleles with other ethnic and other Indian populations, while showing population specific haplotypes. Analysis of population-specific distribution of HLA alleles is proved to be important in finding out the relatedness of the ethnic groups across continents. The extensive polymorphism of the HLA system also has useful application in the study of the origin, evolution and migration patterns of human populations.

S1202 Drug-Induced Liver Injury (DILI) Ascribed to Non-Steroidal Anti-inflammatory Drugs (NSAIDs) in the USA: An Update With Genetic Correlations From the U.S. Drug-Induced Liver Injury Network (DILIN)

Introduction: NSAIDs are widely used throughout the world, mainly for management of chronic inflammatory and painful conditions. NSAIDs rarely cause idiosyncratic, non-dose dependent liver injury. Recent evidence from the US DILIN, as well as elsewhere, implicates host immune responses as central to pathogenesis of such idiosyncratic DILI. Previously, we reported the US DILIN experience with NSAID DILI for 2004-2013.1 Aim: To update our clinical experience and report on HLA and other genetic factors recently described as important in idiosyncratic DILI. Methods: The US DILIN, begun in 2004; is comprised of clinical sites [currently 7 in number], a data coordinating center, and the NIDDK. We enroll subjects with suspected DILI and follow them for at least 6 months.2 We adjudicate causality both with RUCAM, and RECAM3 and by a Delphic approach4 and grade severity from mild to fatal or requiring liver transplant.5 Between Sep 2004 and Mar 2022, we enrolled 2,626 subjects and adjudicated causality at 6 months in 2,498. Following adjudication, we identified 55 [41 (75%) women] as definitely [ >95%], highly likely [75-95%], or probably [51-74% likely] due to NSAIDs. Results: Diclofenac was the causative drug in 29/55 [53%] of cases, followed by celecoxib [7], ibuprofen [5], etodolac and meloxicam [4 each]. Median latency was 51 d. With the notable exceptions of meloxicam and oxaprozin [n=2], the type of liver injury was hepatocellular with median R 15-25. 4 subjects died within 6 mo of onset, and 2 others [1 each due to diclofenac and celecoxib] required liver transplants. 7 had chronic DILI at 6+ mo. HLA DRB1*03:01 was more frequent in those with NSAID DILI than in matched controls, and 6/10 had the ancestral AI extended haplotype. The likelihood of carrying the DRB1*04:03 allele increased with causality score confidence and with more severe DILI [p =0.006]. Conclusion: NSAID DILI is relatively rare in the US. The most common cause is diclofenac, which, if prescribed, should carry with it special warnings of risk and close observation, as in the package insert. The increased frequencies of HLA DRB1*03:01, an HLA type known to be associated with SLE and other auto-immune disorders, and the extended ancestral AI haplotype, suggests that immune-mediated responses are of central importance in pathogenesis.

Predisposition of HLA-DRB1*04:01/*15 heterozygous genotypes to Japanese mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease characterized by the production of anti-U1 ribonucleoprotein antibodies and systemic symptoms similar to those of some other autoimmune diseases. HLA-DRB1 polymorphisms are important genetic risk factors for MCTD, but precise associations of DRB1 genotypes with MCTD have not been reported in Japanese people. Genotyping of HLA-DRB1 and -DQB1 was performed in Japanese MCTD patients (n = 116) and controls (n = 413). Associations of specific allele carriers and genotype frequencies with MCTD were analyzed.The following alleles were found to be associated with predisposition to MCTD: HLA-DRB1*04:01 (P = 8.66 × 10–6, Pc = 0.0003, odds ratio [OR] 7.96, 95% confidence interval [CI] 3.13‒20.24) and DRB1*09:01 (P = 0.0189, Pc = 0.5468, OR 1.73, 95% CI 1.12‒2.67). In contrast, the carrier frequency of the DRB1*13:02 allele (P = 0.0032, Pc = 0.0929, OR 0.28, 95% CI 0.11‒0.72) was lower in MCTD patients than in controls. The frequencies of heterozygosity for HLA-DRB1*04:01/*15 (P = 1.88 × 10–7, OR 81.54, 95% CI 4.74‒1402.63) and DRB1*09:01/*15 (P = 0.0061, OR 2.94, 95% CI 1.38‒6.25) were also higher in MCTD patients. Haplotype and logistic regression analyses suggested a predisposing role for HLA-DRB1*04:01, DQB1*03:03, and a protective role for DRB1*13:02. Increased frequencies of HLA-DRB1*04:01/*15 and DRB1*09:01/*15 heterozygous genotypes were found in Japanese MCTD patients.

HLA analysis of immune checkpoint inhibitor-induced and idiopathic isolated ACTH deficiency.

Isolated adrenocorticotropic hormone deficiency is a rare disease; however, since immune check point inhibitors (ICIs) have become widely used, many more cases have been reported. In this study, we compared the human leukocyte antigen (HLA) signatures between ICI-induced isolated adrenocorticotropic hormone deficiency (IAD) and idiopathic IAD (IIAD). Clinical features and HLA frequencies were compared among 13 patients with ICI-induced IAD, 8 patients with IIAD, and healthy controls. HLA frequencies of healthy controls were adopted from a HLA database of Japanese population. Age and body mass index were higher, while the rate of weight loss was lower, in patients with ICI-induced IAD than in those with IIAD. No HLA alleles had a significantly higher frequency in patients with ICI-induced IAD than in healthy controls, whereas the frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02, and DQB1*03:03 were significantly higher in patients with IIAD than in healthy controls. ICI-induced IAD and IIAD were different in terms of HLA frequencies. There were no specific HLAs related to ICI-induced IAD, whereas several HLAs in strong linkage disequilibrium were associated with IIAD. This might suggest that the two diseases have different pathological mechanisms. HLAs unique to IIAD may be helpful in predicting its pathophysiology.

Association of Human Leukocyte Antigen Genotypes with Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine-Induced Subacute Thyroiditis.

Background: Despite mass vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced subacute thyroiditis (SAT) is rarely seen as a complication. The reason why some individuals are susceptible to developing vaccine-induced SAT is not known. SAT develops in genetically predisposed individuals who carry specific human leukocyte antigen (HLA) haplotypes. It is unknown whether specific HLA alleles are associated with SARS-CoV-2 vaccine-induced SAT. Objective: This study compared the HLA profiles of patients with SARS-CoV-2 vaccine-induced SAT to controls, to assess whether there is an association between specific HLA genotypes and development of SAT. The relationship between HLA genotypes and the clinical course of SARS-CoV-2 vaccine-induced SAT was also evaluated. Methods: A case-control study was conducted in a Turkish tertiary care center. Fourteen patients with SARS-CoV-2 vaccine-induced SAT and 100 healthy controls were included. HLA-A, HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 frequencies were analyzed by next-generation sequencing. Results: The frequencies of HLA-B*35 and HLA-C*04 alleles were significantly higher in SARS-CoV-2 vaccine-induced SAT cohort when compared with controls (HLA-B*35: 13 [93%] vs. 40 [40%], p < 0.001; HLA-C*04: 13 [93%] vs. 43 [43%], p < 0.001, respectively). More severe thyrotoxicosis was seen in patients having HLA-B*35 and HLA-C*04 homozygous alleles (free thyroxine: 4.47 ng/dL [3.77-5.18] vs. 1.41 ng/dL [1.22-2.63], p = 0.048). Inflammation tended to be more severe in homozygous patients (C-reactive protein: 28.2 mg/dL [13.6-42.9] vs. 4.8 [1.2-10.5], p = 0.07). Conclusions: The frequencies of HLA-B*35 and HLA-C*04 alleles were higher in SARS-CoV-2 vaccine-induced SAT compared with controls. Homozygosity for HLA-B*35 and HLA-C*04 was associated with thyrotoxicosis and a greater inflammatory reaction. Our findings should be confirmed in studies of other populations.

Assessment of Human Leukocyte Antigen Differences between Smokers with Reinke's Edema and Those with Laryngeal Cancer.

The present study aimed to assess human leukocyte antigen (HLA) typing differences between smokers with Reinke's edema and those with laryngeal squamous cell carcinoma (SCC). The HLA class I, II alleles were examined in 76 unrelated Iranian patients using low-resolution polymerase chain reaction with the sequence-specific primer (PCR-SSP) method. The frequency of the HLA-A*36 allele and HLA-B*35 was significantly higher in patients with SCC. The frequency of HLA-DRB1*01 alleles in Reinke's edema was significantly higher, as compared to that in others. In the volunteer group, HLA-DRB1*13 and HLA-DRB1*15 were significantly higher. As evidenced by the obtained results, HLA-A*36 was significantly higher in SCC, as compared to that in volunteers and Reinke's edema patients. It can be concluded that being positive for HLA-A*36 increases the chance of SCC by three times. This result should be further investigated in cohort studies conducted on larger samples. Furthermore, HLA-A*24 was significantly higher in the volunteer group, as compared to that in other groups. The HLADRB1*01 was remarkably higher in Reinke's edema, as compared to that in SCC.

Helicobacter pylori infection and disease severity in multiple sclerosis patients: Is there a link with HLA alleles?

Backgrounds: Environmental factors such as bacterial infections, as well as genetic factors—in particular the human leukocyte antigen (HLA) alleles—have been implicated in the etiology of multiple sclerosis (MS). This study aims to explore the relationship between Helicobacter pylori infection, HLA alleles, and disease severity in Iranian MS patients. Methods: The study population comprised 125 MS patients and 153 ethnically matched healthy controls. Stool antigen test was used to detect H. pylori, and the expanded disability status scale (EDSS) scores were assessed in the patients. HLA-DRB1 and DQB1 alleles and haplotypes were determined in both the patients and the controls. The relationships between H pylori infection, HLA alleles, and EDSS were also analyzed. Results: HLA-DRB1*15 and DQB1*06 alleles families and the DRB1*15~DQB1*06 haplotype were significantly more frequent in MS patients, whereas HLA-DRB1*14 and DRB1*14~DQB1*05 haplotype were less frequent. Of the 125 MS patients, 38 were diagnosed with active H. pylori infection. We found lower frequencies of HLA-DRB1*15 (P = .08) and DRB1*16 (P = .05) alleles and a higher frequency of DQB1*02 (P = .06) in the H. pylori-positive patients. HLA-DRB1*07 was more prevalent in patients with EDSS≤3.0 (P = .06). More severe MS cases (EDSS&gt;3.0) were linked to H pylori positivity (P = .02), disease chronicity (P = .001), receiving non-steroidal anti-inflammatory drugs (P = .02), and female gender (P = .05). Conclusion: These preliminary findings suggest a link between H. pylori infection and the severity of MS H. pylori-positive patients regardless of the type of HLA carriage.

Association of HLA-DRB1 and -DQB1 Alleles with Susceptibility to IgA Nephropathy in Korean Patients.

BackgroundAssociations between IgA nephropathy (IgAN) and HLA-DRB1 and -DQB1 alleles have been reported in several ethnic groups. We investigated the association of HLA-DRB1 and -DQB1 alleles with the predisposition for IgAN and disease progression to end-stage kidney disease (ESKD) in Korean patients.MethodsWe analyzed HLA-DRB1 and -DQB1 genotypes in 399 IgAN patients between January 2000 and January 2019 using a LIFECODES sequence-specific oligonucleotide (SSO) typing kit (Immucor, Stamford, CT, USA) or a LABType SSO Typing Test (One Lambda, Canoga Park, CA, USA). Alleles with a significant difference in two-digit resolution were further analyzed using in-house sequence-based typing and sequence-specific primer PCR. As controls, 613 healthy hematopoietic stem cell donors were included. Kidney survival was analyzed in 281 IgAN patients with available clinical and laboratory data using Cox regression analysis. Where needed, P-values were adjusted using Bonferroni correction.ResultsThe allele frequencies of HLA-DRB1*0405 (corrected P [Pc]<0.001), -DQB1*0401 (Pc=0.048), and -DQB1*0302 (Pc=0.021) were significantly higher in IgAN patients than in controls, whereas those of HLA-DRB1*0701, -DRB1*1501, -DQB1*0202, and -DQB1*0602 (Pc<0.001 for all) were significantly lower in IgAN patients than in controls. The allele frequency of HLA-DQB1*0503 (Pc=0.016) was significantly lower in the ESKD group than in the non-ESKD group; however, there was no significant difference for ESKD progression between these groups.ConclusionsWe report novel associations of HLA-DRB1*1501, DQB1*0202, -DQB1*0302, and -DQB1*0401 with IgAN. Further studies of HLA alleles associated with IgAN progression in a larger cohort and in various ethnic groups are needed.

Differential HLA Association of GAD65 and IA2 Autoantibodies in North Indian Type 1 Diabetes Patients.

The human leucocyte antigen (HLA) association with type 1 diabetes (T1D) is well known but there are limited studies investigating the association between β-cell autoantibodies and HLA genes. We evaluated the prevalence of GAD65 and IA-2 autoantibodies (GADA and IA2A) in 252 T1D patients from North India and investigated the genetic association of GADA and IA2A with HLA class I and class II genes/haplotypes. GADA and IA2A were detected in 50.79% and 15.87% of T1D patients, respectively, while only 8.73% had both GADA and IA2A. HLA-DRB1∗03 was observed to be significantly higher in GADA+ T1D patients as compared to GADA– (91.41% vs. 66.13%, Bonferroni-corrected P (Pc) = 1.11 × 10−5; OR = 5.45; 95% CI: 2.67-11.08). Similarly, HLA-DQB1∗02 was found to be significantly increased in GADA+ patients (94.53%, Pc = 2.19 × 10−5; OR = 6.27; 95% CI: 2.7-14.49) as compared to GADA– (73.39%). The frequencies of HLA-DRB1∗04 and DQB1∗03 were increased in IA2A+ patients (45.0% and 52.5%, respectively) as compared to that in IA2A– (25.94% and 33.96%, respectively). Further, the frequency of DRB1∗03-DQB1∗02 haplotype was found to be significantly increased in GADA+ T1D patients as compared to GADA- (60.55% vs. 41.94%, P = 3.94 × 10−5; OR = 2.13; 95%CI = 1.49-3.03). Similarly, HLA-DRB1∗04-DQB1∗03 haplotype was found to be significantly increased in IA2A+ T1D patients compared to IA2A– patients (22.5% vs. 12.97%; P = 0.041; OR = 1.95; 95%CI = 1.08-3.52). None of the HLA class I genes (HLA-A, B, and Cw) was found to be associated with GADA or IA2A in people with T1D. Our findings suggest that HLA-DRB1∗03/DQB1∗02 and HLA-DRB1∗04/DQB1∗03 might play an important role in the development of GADA and IA2A, respectively.

The Copy Number of Disease-Associated HLA Alleles Predicts the Response to Immunosuppressive Therapy in Acquired Aplastic Anemia

In immune-mediated acquired aplastic anemia (AA), the presence of an HLA allele, which is highly overrepresented or lost due to somatic mutations, may represent a specific immune pathophysiology and a clinical manifestation. HLA-B*14:02 is one of the most overrepresented class I alleles in AA and is also frequently affected by a somatic loss of expression; the inherited B*14:02 genotype was correlated with high-risk clonal evolution in two independent cohorts in the U.S. (Babushok DV et al. Blood Adv 2017; Zaimoku Y et al. manuscript in preparation). In contrast, HLA-B*14:02 is virtually absent in Japanese, in whom somatic mutations of AA have frequently been detected in HLA-B*40:02, B*54:01, and A*02:06, and occasionally in A*02:01, A*02:07, A*31:01, B*13:01, B*40:01, B*40:03, B*44:03, B*55:02, and B*56:01 (Mizumaki H et al. Haematologica 2021). A class II allele HLA-DRB1*15 is highly overrepresented in AA across various ethnic groups, including those in the U.S. and Japanese. This retrospective study in the Japanese population aimed to explore the clinical significance of disease-associated non-B*14:02 HLA class I and II alleles in AA.A total of 423 enrolled patients with AA (very severe [n = 81], severe [n = 266], transfusion dependent non-severe [n = 76]; median age 60 [range, 1-86] years) had undergone genotyping for HLA-A, HLA-B, HLA-C, and HLA-DRB1 at 2-field resolution. The HLA allele frequencies in these patients were compared to those in a Japanese HLA haplotype dataset (n = 19183; Ikeda N et al. Tissue Antigens 2016).The most overrepresented allele in AA was HLA-DRB1*15:02, followed by DRB1*15:01, B*40:02, and A*02:06 (Table); DRB1*13:02 and B*44:03, which are in linkage disequilibrium, were markedly underrepresented, consistent with a well-known protective role of DRB1*13 against autoimmune diseases. HLA-DRB1*15:02 was also significantly correlated with age and its frequency among patients aged <50 years was below the level of the control group (Figure A). Frequencies of HLA-DRB1*15:01, B*40:02, and A*02:06 were increased in both older and younger groups. HLA-A*31:01 and A*02:01 found to be enriched in young patients instead of DRB1*15:02 (Figure B); B*13:01, B*55:02, and B*56:01 showed a similar tendency for an early onset. HLA-B*40:02 was correlated with disease severity and was especially overrepresented in very severe AA (Figure C).The overall response rate to anti-thymocyte globulin-based immunosuppressive therapy at 6 months was 63% (139 of 220 treated and evaluable patients). A trend for a higher response was observed in patients harboring mutation-related HLA-B alleles (except for minor alleles B*13:01, B*40:03, and B*55:02) and the highly overrepresented or protective HLA-DRB1 alleles, but not in the HLA-A alleles (Figure D). A multivariate logistic regression revealed that the combination of the presence of any favorable alleles in HLA-B (odds ratio 3.6, P < 0.0001) or in HLA-DRB1 (odds ratio 2.3, P = 0.00085) was significantly and independently associated with a hematologic response; the tendencies for a lower or higher response in very severe disease and the presence of paroxysmal nocturnal hemoglobinuria clone did not reach statistical significance. Further, there was likely an additive effect when two favorable alleles coexisted in HLA-B or HLA-DRB1 (Figure E); the copy number of the favorable HLA-B and HLA-DRB1 alleles stratified the response rate to four groups: three or four copies, 95% (19 of 20); two copies, 72% (61 of 85); one copy, 59% (50 of 85); and zero copy, 30% (9 of 30). Only eight patients displayed clonal evolution to monosomy 7, myelodysplastic syndrome, or acute myeloid leukemia after immunosuppression without significant overrepresentation or underrepresentation of the pathogenic HLA alleles.Using a large dataset of homogeneous Japanese population with high-resolution HLA typing, we revealed, for the first time, a strong relationship between disease-associated (overrepresented, inactivated, or protecting) HLA alleles and the responsiveness to immunosuppressive therapy. [Display omitted] DisclosuresTakamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Yamazaki: Novartis Pharma: Honoraria; Kyowa Kirin: Honoraria; Kyowa Kirin: Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding.

HLA-DRB1 alleles as predisposing and resisting factor in women suffering from vulvovaginal candidiasis

BackgroundVulvovaginal candidiasis (VVC) is a vaginal mucosal infection that usually affects women in their reproductive age. When the signs of VVC persist on a daily basis or last for a long time and repeat at least three times per year, the disease is considered chronic and recurrent. ObjectiveThe purpose of this study was to evaluate the frequency of HLA-DRB1 alleles in patients with recurrent vulvovaginal candidiasis (RVVC). Study design120 patients with RVVC and 136 age-matched healthy controls underwent low-resolution HLA-DRB typing performed using the polymerase chain reaction-sequence-specific primers (PCR-SSP) technique. ResultsIn the present work, we studied different genes that encode HLA-DRB (HLA-DRB1 / HLA-DRB3 / HLA-DRB4 / HLA-DRB5) and showed that HLA-DRB1×14, found in 25% of the patients. In the present study, the significant frequency of HLA-DRB1×10 in the control group suggests a resistant role of this allele to RVVC infections ConclusionsIn the HLA-DRB region, the DRB1×14 allele showed a higher frequency in the patients with RVVC than in the controls. Moreover, the higher frequency of DRB1×10 observed in the controls than in the patients with RVVC. These results demonstrate the HLA-DRB1 alleles are in relation with both susceptibility and immunity factors in RVVC infection and possible susceptible role of HLA-DRB1×14

HLA-DRB1 and DQB1 genetic susceptibility to pemphigus vulgaris and pemphigus foliaceus in Vietnamese patients

Pemphigus is a group of rare, lifethreatening bullous autoimmune diseases that affect the skin and mucous membranes and are associated with high morbidity and morbidity. HLA class II genes, particularly HLA-DRB1 and HLA-DQB1, play roles in pemphigus. The aim of this paper is to investigate the susceptibility of HLA class II DRB1 and DQB1 alleles in Vietnamese patients with pemphigus vulgaris (PV) or pemphigus foliaceus (PF). The study enrolled 31 participants (22 with PV, 9 with PF) with diagnoses confirmed by clinical manifestations, histopathology, and direct immunofluorescence from November 2019 to June 2020. The HLA polymorphisms were determined by Sanger sequencing. The HLA-DRB1 and HLA-DQB1 profiles of the 101 healthy individuals in the control group have been published previously. The frequencies of HLA-DRB1*14, DRB1*13:07, DRB1*04:04, DRB1*03:02, DQB1*02:02, and DQB1*05:03 were significantly higher, whereas those of DRB1*09:01, DRB1*12:02, DQB1*03:03, DQB1*05:01, and DQB1*06:01 were significantly lower, in the PV group than in the controls. The frequencies of DRB1*14:54, DRB1*13:07, and HLA-DQB1*03:02 were significantly higher in the PF group than in the controls. Alleles HLA-DRB1*14:54, DRB1*14:04, DRB1*14:03, DRB1*14:01, DRB1*14:12, DRB1*13:07, DRB1*04:04, DRB1*03:02, DQB1*02:02, and DQB1*05:03 were associated with an increased risk of PV, whereas alleles DRB1*09:01, DRB1*12:02, DQB1*03:03, DQB1*05:01, and DQB1*06:01 might protect against PV. In PF, DRB1*14:54, DRB1*13:07, and HLA-DQB1*03:02 are promising susceptibility alleles.

HLA-DRB1*04 may predict the severity of disease in a group of Iranian COVID-19 patients

Human leukocyte antigen (HLA) genes with extreme diversity can make a contribution for individual variations to the immune response against SARS-COV-2 infection. This study aimed to explore the distributions of HLA class II alleles frequencies and their relations with disease severity in a group of Iranian COVID-19 patients. This prospective and case-control study was conducted on 144 COVID-19 patients including 46 cases with moderate form, 54 cases with severe and 44 cases with critical disease. HLA-DRB1 and -DQB1 allele families were determined by PCR-SSP method and compared between three groups of the patients and in comparison to 153 ethnic-matched healthy controls. The patients group showed lower frequencies of HLA-DRB1*15 (OR = 0.57, P = 0.06), DRB1*15 ~ DQB1*05 haplotype (P = 0.04) and DRB1*15/DRB1*04 genotype (P = 0.04) in compare with healthy controls. Moderate COVID-19 patients had higher frequencies of HLA-DRB1*04 (P = 0.03), HLA-DRB1*10 (P = 0.05) and DRB1*04/DRB1*11 genotype (P = 0.01). Also, a higher significantly frequency of HLA-DRB1*03 allele group was observed in the critical patients versus controls (P = 0.01). Multiple logistic regression analysis revealed that the presence of DRB1*04 allele group was negatively associated with development of severe and critical disease (OR: 0.289, P = 0.005). Our results indicate a possible contribution of some HLA class II alleles in disease severity and clinical features of COVID-19 disease.

Abstract 799: Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers

Abstract Female carriers of germline BRCA1 mutation almost inevitably develop breast cancer (BC). However, the age of BRCA1-associated cancer onset varies widely. We hypothesize that age-related penetrance of BRCA1 mutations may depend on the inherited variability in the host immune system. We utilized high-throughput HLA-typing to describe 10 classical HLA class I/II loci for 90 young (&amp;lt;38 y.o.) and 73 elderly (&amp;gt;57 y.o.) BRCA1-mutated BC patients. 39% of young females were homozygous for two or more HLA-II loci; this was significantly higher than in the “elderly” cohort [OR = 3.23; p = 0.002]. In contrast, women who harboured identical alleles at HLA-B locus (class I) had increased chances to stay tumour-free to their older ages [OR = 3.02; p = 0.077]. Allele HLA-DBR1*11:03/04 was overtly overrepresented in elderly BRCA1-driven BC [11% vs. 3%, p = 0.006]. The frequencies of HLA-DRB1*01:01 and HLA-DQB1*05 were significantly higher in group of “young” patients [p = 0.020 and p = 0.011, correspondently]. The tumour immunogenicity was analyzed in early-onset and late-onset BC patients through the evaluation of the intratumoral density of cytotoxic T-lymphocytes (TILs) with anti-CD8 IHC staining. 5/10 carcinomas arisen in young BRCA1-carriers were classified as a “hot” phenotype with a high density of TILs across the tumour. Inversely, the BC developed in “elderly” women was characterized by the reduced levels of TILs. Conclusions: 1) the limited repertoire of HLA peptides caused by the homozygosity for HLA II loci may increase susceptibility to BC in BRCA1-carriers and manifest by early disease onset; 2) tumours from “elderly” BRCA1-associated patients have reduced levels of lymphocytic infiltration compared to “young” patients. The research is supported by RSF grant #19-15-00207 Citation Format: Ekaterina ShKuligina, Alexandr A. Romanko, Tatjana Jankevic, Aleksandr S. Martianov, Tatyana N. Sokolova, Alexandr O. Ivantsov, Evgeny N. Imyanitov. Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 799.

Evaluation of HLA class I and HLA class II allele profile and its relationship with clinical features in patients with alopecia areata: a case–control study

Background Alopecia areata (AA) is an autoimmune disease where autoimmune dysregulations along with genetic susceptibility are hypothesized to play a role in pathogenesis. Objective The aim of this study in to evaluate HLA-A, HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 profile and its relationship with clinical features in AA patients. Materials and methods Ninety-eight patients with AA and 100 healthy controls were included in the study. HLA-A, HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 frequencies were analyzed using polymerase chain reaction-sequence specific primers (PCR-SSP). Results HLA-B*39 and HLA-HLA-DRB1*15 allele frequencies were increased (p = .022 and p = .023, respectively), HLA-A*11 and HLA-B*35 frequencies were decreased (p = .006 and p = .014, respectively) in AA patients. HLA-B*13 and HLA-DRB1*11 were associated with poor prognostic factors. A class I allele, HLA-B*13 was associated with recurrence (p = .023) and presence of nevus flammeus (p = .022), while the class II allele HLA-DRB1*11 was associated with widespread hair loss (diffuse or universal alopecia) (p = .026), presence of ophiasis (p = .049) and juvenile onset (p = .018). Conclusion Belonging to two different classes of HLA family, HLA-B*13 and HLA-DRB1*11 alleles identified separate set of risk factors. In addition to increasing the risk of AA, HLA alleles may affect the prognosis of the disease.

Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population.

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA.

The influence of HLA genotype on the severity of COVID-19 infection.

The impact of COVID‐19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in HLA genes might influence this variation. Using next generation sequencing, we analysed the class I and class II classical HLA genes of 147 individuals of European descent experiencing variable clinical outcomes following COVID‐19 infection. Forty‐nine of these patients were admitted to hospital with severe respiratory disease. They had no significant pre‐existing comorbidities. We compared the results to those obtained from a group of 69 asymptomatic hospital workers who evidence of COVID exposure based on blood antibody testing. Allele frequencies in both the severe and asymptomatic groups were compared to local and national healthy controls with adjustments made for age and sex. With the inclusion of hospital staff who had reported localised symptoms only (limited to loss of smell/taste, n = 13) or systemic symptoms not requiring hospital treatment (n = 16), we carried out ordinal logistic regression modelling to determine the relative influence of age, BMI, sex and the presence of specific HLA genes on symptomatology. We found a significant difference in the allele frequency of HLA‐DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% vs. 16.7%, P = .003 after adjustment for age and sex). There was a significantly lower frequency of the haplotype DQA1*01:01‐DQB1*05:01‐DRB1*01:01 in the asymptomatic group compared to the background population (P = .007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID‐19 observed in the cohorts. These alleles are found in greater frequencies in the North Western European population. This regional study provides evidence that HLA genotype influences clinical outcome in COVID‐19 infection. Validation studies must take account of the complex genetic architecture of the immune system across different geographies and ethnicities.

HLA-DRB1 polymorphism in recurrent pregnancy loss: New evidence for an association to HLA-DRB1*07

Many cases of recurrent pregnancy loss (RPL) defined as ≥3 consecutive pregnancy losses are suggested to be caused by an aberrant maternal immune response against the fetus or trophoblast. Human leukocyte antigen (HLA)–DRB1 and -DQB1 polymorphisms are associated with most autoimmune disorders and studies of HLA-DBB1 polymorphism in RPL patients are thus relevant. In previous studies, the HLA-DRB1*03 allele was found with increased prevalence in RPL patients.We wanted to clarify whether HLA-DRB1 alleles indeed were associated with RPL among women of Caucasian descent. A total of 1078 women with unexplained RPL and 2066 bone marrow donors were HLA-DRB1-typed and subsets were also HLA-DQB1 typed.All patients were initially HLA-DRB1-typed by DNA-based low-resolution techniques and subsets of patients and all controls were typed by high-resolution techniques.Among patients, the HLA-DRB1*07 allele frequency was significantly increased compared with controls; OR 1.29 (95 % CI 1.09−1.52), p < 0.0025; after correction for multiple comparisons pc = 0.031. The HLA-DRB1*07/*07 genotype was highly increased in patients with RPL compared with controls: OR 2.27 (1.31−3.93), p = 0.0027. The frequency of the HLA-DRB1*07 phenotype in RPL patients had increased significantly (p = 0.002) in three studies from our group published 1994–2021. The allele frequency of HLA-DRB1*03 was not increased in RPL patients compared with controls; OR 0.96 (0.83−1.12).In conclusion, the previous association between HLA-DRB1*03 and RPL could not be confirmed in our study whereas an association to HLA-DRB1*07 was detected for the first time. Since the latter association is a new finding, it should be confirmed in future studies.