Association Of HLA Alleles Research Articles

Evaluating the Role of HLA DRB1 Alleles and Oligoclonal Bands in Influencing Clinical Course of Multiple Sclerosis - A Study from the Mangalore Demyelinating Disease Registry.

Background:The possible interaction between genetic and immunological factors in influencing clinical course of multiple sclerosis (MS) has not been studied previously in Indian population.Aim:In this study we evaluated the association of HLA alleles and OCB in affecting clinical course and disability of MS.Methods:Clinical and demographic features of 145 MS patients who had CSF oligoclonal bands (OCB) tested by isoelectric focussing technique were analyzed, disability status estimated, and HLA DRB1 alleles were genotyped.Results:OCBs were positive in 53.8% (78/145) of all MS cases. Patients with CSF OCB had more frequent relapses and an association with HLA DRB1*15. Early disease onset and a high annualized relapse rate was associated with HLA DRB1*03 allele. A relapsing remitting course for MS was seen with HLA DRB1*03 & 15 while a progressive disease was associated with DRB1*01. Presence of both OCB and HLA DRB1*13 was significantly associated with disability in this cohort.Conclusion:The results of our study suggest that an interaction between immunological and genetic factors may influence disease onset, course, and disability in MS.

Frequencies and haplotype associations of non-expressed HLA alleles in ethnically diverse populations on the National Marrow Donor Program’s Be The Match Registry

HLA allele matching is critical to successful bone marrow transplantation between a patient and donor. Non-functional HLA alleles, so called ‘null alleles’, are not well described within a large population of well HLA-typed ethnically diverse individuals despite their impact on donor selection. A retrospective analysis was performed on 833,789 unrelated donors (URDs) in the National Marrow Donor Program’s Be The Match Registry® typed for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 by next-generation DNA sequencing. Results showed that null alleles occur in low frequency (2.30E−04) compared to expressed alleles. Their overall frequency ranged from 6.00E−07 to 9.25E−04 with a median of 1.20E-06. The expected allele associations were commonly observed for HLA-A*24:09N, HLA-B*51:11N, and HLA-C*04:09N; however, associations outside of the expected were also observed. Notably, 82% of the National Marrow Donor Program Registry URDs carrying HLA-A*24:11N showed a different HLA-C allele association, HLA-C*05:01, compared to the allele described by prior published work characterizing German donor populations, HLA-C*04:01. The frequencies of these observed null alleles and linkage disequilibrium information could be invaluable and helpful in guiding the HLA testing decisions.

Risk and Association of HLA Alleles with Methimazole-Induced Cutaneous Adverse Reactions in Chinese Han Population

Methimazole (MMI) is a widely used antithyroid drug, which inhibits thyroid hormone synthesis by interfering with the activity of thyroid peroxidase (Cooper, 2005). However, MMI is sometimes associated with cutaneous adverse drug reactions (cADRs), varying from urticaria and maculopapular eruption to severe reactions such as drug-induced hypersensitivity syndrome (Burch and Cooper, 2015; Ozaki et al., 2005). MMI-induced cADRs cannot always be predicted and sometimes could be life-threatening, requiring or prolonging hospitalization, impeding proper treatment, and increasing treatment costs considerably.

P0083HLA-DRB1*1301-DQB*0603-DRB3*0202 HAPLOTYPE IS INDEPENDENTLY ASSOCIATES WIHT POOR PROGNOSIS IN PLA2R-RELATED MEMBRANOUS NEPHROPAHTY

Abstract Background and Aims The susceptibility of Idiopathic membranous nephropathy (MN) is associated with HLA alleles. We previously found almost all (98.7%) patients with PLA2R-related MN carry either or both of the HLA-DRB1*1501 and DRB3*0202 risk alleles. However, the associations of HLA alleles and renal outcome is not known. Method we investigated the associations between HLA alleles and renal outcome in 392 PLA2R-related MN patients. Results We found that HLA-DRB1*1301 and DQB1*0603, which are in high linkage disequilibrium (R2 = 1.0, D’=1.0), are associated with at least 30% eGFR decline during follow-up (HR 2.2, p<0.001). HLA-DRB1*1301 and DQB1*0603 are not a susceptible HLA allele for PLA2R-related MN. Neither HLA-DRB1*1501 nor DRB3*0202 is associated with renal outcome. After adjusting age, gender and the two susceptible HLA alleles, DRB1*1301 haplotype remains significant associated with renal outcome. Compared those patients with negative DRB1*1301, patients with positive DRB1*1301 showed a similar eGFR level at baseline, but a significant lower eGFR at the last follow up. There were 12 PLA2R-related MN patients with positive DRB1*1301, eight of them (66.7%) showed more than 30% eGFR decline during follow-up. Among the 12 patients carrying DRB1*1301, all (100%) had DRB3*0202, four (33.3%) had DRB1*1501, and none (0%) had DRB1*0301. Linkage disequilibrium analysis showed the susceptible allele DRB3*0202 was highly linked with DRB1*0301 and DRB1*1301, while HLA-DRB1*0301 was not associated with renal outcome. Conclusion HLA-DRB1*1301-DQB*0603-DRB3*0202 haplotype is independently associated with Poor Prognosis in PLA2R-related Membranous.

HLA Alleles Repertoire in Russian CLL Patients

Introduction. Chronic lymphocytic leukemia (CLL) is one of the most common lymphoproliferative diseases in Europe and the USA. The mutational status of the immunoglobulin heavy chain variable region genes (IGHV) has long been known as an important factor for long-term prognosis in CLL. The variety of the rearranged IGHV structure variants in CLL cells is very limited and differs significantly from that in normal B cells. About 30% of all cases of CLL have immunoglobulin receptors with very similar nucleotide sequences. These quasi-identical receptors are called stereotyped. The most common 20 subtypes of stereotyped antigen receptors (SARs) are presented in 12% of all CLL cases. HLA-complex plays a central role in the formation of the immune response. Associations of specific HLA-alleles with different malignant, autoimmune and infectious diseases have been described. However, possible relationship of HLA phenotype to the development of CLL and the association of HLA alleles with disease are not completely understood. Aim. To study the repertoire of HLA alleles in Russian CLL patients with the most common SARs. Patients and methods. The study included 50 CLL patients with the most common IGHV genes and SARs, followed up at the National Research Center for Hematology from 2008 to 2019. Two groups of healthy donors were selected as control - one from Moscow (1507) and other from Eastern Siberia (296). The mutational status of IGHV and the SARs were determined according to European Research Initiative in CLL (ERIC) criteria. HLA-typing in 5 loci (HLA-A, -B, -C, -DRB1, -DQB1) was performed using Luminex 200 system (Luminex, TX, USA) with Lifecodes HLA SSO typing kits (Immucor, CT, USA). HLA frequencies were compared using chi-square test. ARLEQUIN software package, version 3.5 was used for statistical analysis. Results. All patients enrolled in the study had unmutated IGHV genes. In 43 of them, homology with the germline gene was 100%, and in 7 - it was in the range of 98.6-99.7%. IGHV genes of 46 patients (92%) belonged to the 1st family. In 14 (28%) patients CLL#1 SAR, associated with the most aggressive course of the disease, was expressed. Nine patients (18%) each belonged to the CLL#3 and CLL#6 subtypes. The remaining patients expressed CLL#5, 7H, 12 and 28A SARs. No significant differences in the frequency of HLA-A alleles were found between CLL patients and both donor groups. HLA-B*18, HLA-B*52 and HLA-C*12:02 were found significantly more often in CLL patients than in donors. In the DRB1 locus, differences were observed in the two allelic groups. In CLL patients HLA-DRB1*15 was twice more frequent than in healthy donors, HLA-DRB1*13, on the contrary, was twice less frequent. No significant differences were found for DQB1 locus. Most common HLA haplotype frequencies were also calculated. DRB1*15-DQB1*06 haplotype was significantly 2 times more frequent in CLL patients than in donors. Furthermore, A*02-B*07-C*07-DRB1*15-DQB1*06 and A*25-B*18-C*12-DRB1*15-DQB1* 06 were more frequent, but these data were not statistically significant probably due to the small patient sample (Table 1). No significant differences were found between the SAR subtypes of CLL patients in the studied cohort. Discussion. Despite a small sample, we were able to detect 4 predictive and 1 protective HLA allele for CLL patients. Our data disagree with the data of researchers from the United States and France and partially match those obtained by Iranian scientists. This might be explained by two reasons. First, HLA allele frequencies are differ between various populations. Second, we studied a small selected sample - all patients had unmutated IGHV genes, mainly from the same V gene family, and belonged to a cohort with an aggressive course of the disease. Further studies on extended samples of CLL patients are required to assess possible associations of HLA alleles with CLL subtypes and the course of the disease. Disclosures No relevant conflicts of interest to declare.

HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications.

Our understanding of the mechanisms underlying HLA associations with inflammatory arthritis continues to evolve. Disease associations have been refined, and interactions of HLA genotype with other genes and environmental risk factors in determining disease risk have been identified. This Review provides basic information on the genetics and molecular function of HLA molecules, as well as general features of HLA associations with disease. Evidence is discussed regarding the various peptide-dependent and peptide-independent mechanisms by which HLA alleles might contribute to the pathogenesis of three types of inflammatory arthritis: rheumatoid arthritis, spondyloarthritis and systemic juvenile idiopathic arthritis. Also discussed are HLA allelic associations that shed light on the genetic heterogeneity of inflammatory arthritides and on the relationships between adult and paediatric forms of arthritis. Clinical implications range from improved diagnosis and outcome prediction to the possibility of using HLA associations in developing personalized strategies for the treatment and prevention of these diseases.

Genotypic Analysis Revealed Association of HLA Alleles with Clinical Parameters in Bangladeshi Patients with Rheumatoid Arthritis

This study investigated distribution of HLA alleles (HLADRB1*01, *03, *04, *07, HLA-DQB1*0201, *0301/4) in 34 healthy controls and 57 rheumatoid arthritis (RA) patients in a Bangladeshi population and correlated the genotypic frequencies with clinical parameters. Frequency distribution of HLA-DRB1*04 (34%) and HLA-DRB1*01 (32%) were the highest followed by HLA-DQB1*0301/4 (29%) and HLA-DQB1*0201 (26%) in RA patients while HLA-DRB1*03 (12%) had lowest frequency. Plasma level of anti-CCP and rheumatoid factor antibodies confirmed diagnosis of RA patients that varied significantly between patients and healthy controls. Likewise, plasma levels of C-reactive protein, triglycerides, cholesterol, HDL-cholesterol and activities of AST and ALT exhibited significant variation between the two groups. In contrast, the levels of glucose, total protein, uric acid, LDL-cholesterol and plasma activity of ALP in RA patients had no significant deviations from healthy controls. Relationship between HLA genotype frequency and clinical parameters revealed that the mean levels of anti-CCP and rheumatoid factor antibodies were highest in the patients harboring HLA-DRB1*04 allele. These findings underpin the correlation between HLA genotype with clinical markers of RA which are indicative of disease severity. The positive correlation of these markers with certain HLA genes may be used to identify susceptible individuals who are likely to have RA in Bangladeshi population.

Inflammation, Overweight, Obesity and HLA Gene: The Evidence Based on 1.377 Million Healthy Chinese Adults

After obtaining the authorization approval of the journal, the original article entitled HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03: 02 Strongly Associate With BMI: Data From 1.3 Million Healthy Chinese Adults. , published in Diabetes Volume 67, May 2018: 861-871, written by Shen J, Guo T, et al. have been translated into Chinese by us. Background Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. Method HLA genotyping has been carried out in more than 1.377 million healthy adult donors fromthe Chinese Marrow Donor Program (CMDP) for analyze the association of HLA alleles with BMI. Results Total 23 HLA alleles, including 12 low-resolution and 11 highresolution alleles, were significantly associated with BMI. After correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03: 02 provided the strongest associations with BMI (P=6.89×10-10, 1.32×10-9, 1.52×10-9, and 4.45×10-8, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects (Pheterogeneity=0.006 7 and 0.000 58, respectively). Conclusion In summary, the results of this study suggest that specific HLA alleles are associated with higher or lower BMI in human populations and that these alleles may cause alterations in obesity risk through their roles in immune responses. (Chin J Endocrinol Metab, 2018, 34: 968-975)

Correlation analysis between the progression of HIV infection and HLA polymorphism

Objective: To analyze the polymorphisms of human leukocyte differentiation antigens Ⅰ and Ⅱ (HLA-A, B, DRB1) alleles and explore the association between HIV infection and HLA loci, for discovering the distribution of HLA loci in HIV-infected with different disease progression in different parts of Henan Province. Methods: A total of 48 cases of slow progressers and 80 typical progressers in Weishi County, Shangcai County, Xihua County and Xuchang City of Henan Province were studied, and compared with 380 healthy blood donors.For analyzing HLA-A, B, DRB1 alleles and comparing difference among the study subjects, the method of polymerase chain reaction-sequence special oligonucleotide (PCR-SSO) was used. Results: The association of HLA alleles and HIV infection showed that HLA-B*40∶02, HLA-DRB1*04∶05 was significantly more common in healthy people, while HLA-B*15∶18, B*44∶02, B*67∶01 and HLA-DRB1*14∶01 were present in HIV/AIDS.HLA-A*02∶06, HLA-B*13∶02, B*40∶06 in slow progressers were higher than typical progressers from the grouped study, and HLA-B*46∶01 only appeared in the typical progressers. Conclusion: HLA-B*15∶18, B*44∶02, B*67∶01, and HLA-DRB1*14∶01 may be associated with HIV susceptibility.HLA-A*02∶06, HLA-B*13∶02, and B*40∶06 may be associated with delayed disease progression in HIV-infected people, while HLA-B*46∶01 may be associated with accelerated disease progression.

HLA Polymorphism Affects Risk of de novo Mutation of dystrophin Gene and Clinical Severity of Duchenne Muscular Dystrophy in a Southern Chinese Population.

Immune-mediated pathology has been thought to be an important factor contributing to Duchenne muscular dystrophy (DMD). Allele frequencies of certain HLA types are known to differ between patients with dystrophinopathies and healthy controls with low-resolution HLA gene typing data in limit reports. Using Polymerase chain reactionsequence based typing (PCR-SBT) to genotype 64 children with DMD in HLA-A, -B,-C, -DRB1, and -DQB1 locus and 503 healthy controls in HLA-A, -B, -DRB1 locus, this study aimed to investigate associations of specific HLA alleles with, and their possible roles in the development and clinical phenotypic severity of DMD. The χ2 test was used to evaluate the distribution of allele frequencies in HLA-A, -B, -DRB1 locus between the patients and healthy controls. A significantly higher frequency of HLA-B*07:05 was found in children with DMD compared to that in controls (OR = 16.2, 95%CI = 2.9–89.3, P < 0.046). More importantly, significantly higher frequencies of HLA-A*29:01 (OR = 77.308, 95%CI = 6.794–879.731, P < 0.0160) and HLA-B*07:05 (OR = 60.240, 95%CI = 9.637–376.535, P < 2.41*10−3) was found in patients with de novo mutations (n = 14) compared to controls while no difference of HLA alleles frequency ware indicated between patients with inherited mutation and control. The result indicates that HLA alleles is associated with pathogenesis of DMD especially DMD with de novo mutation. We use Vignos scale to estimate the lower limb motor function of patients. The impact of HLA alleles on score of Vignos scale of DMD children was estimated by multiple linear regression. Our study indicates that HLA-A*02:01 may have a dampening effect on the clinical phenotypic severity of DMD, evidenced by the presence of HLA-A*02:01 being associated with lower Vignos score. Our study demonstrates that certain HLA alleles are indeed associated with the pathogenesis and clinical phenotypic severity of DMD.

Investigation of the predisposing factor of pemphigus and its clinical subtype through a genome-wide association and next generation sequence analysis.

Pemphigus is an autoimmune blistering disease with pemphigus vulgaris (PV) and foliaceus (PF) as the two major histological subtypes. Associations with HLA molecules have been suggested, but specific HLA risk variants as well as non-HLA risk variants remain to be discovered. We performed a two-stage genome-wide association study in the Chinese Han population through a genome-wide discovery analysis and follow-up validation analysis in a total number of 210 PV, 159 PF and 2493 healthy controls. HLA imputation as well as high coverage next generation sequencing based HLA genotyping was employed to investigate the association of classical HLA alleles and amino acid change. We have discovered independent novel associations with PF at rs2178077 on 12q24.33, located next to RAN (PPF = 1.57 × 10-9 ) and rs3888722 within the MHC region (P = 6.73 × 10-9 ). For the HLA variants, we confirmed independent genome-wide level risk associations in HLA-DQB1 and HLA-DRB1, with DQB1*05:03 to be the strongest association with PV (P = 8.59 × 10-68 , OR = 31.16) and PF (P = 4.84 × 10-17 , OR = 5.64). In addition, DRB1*14 was demonstrated to be a second independent variants (P = 4.2 × 10-63 , OR = 35.47) for PV, while DRB1*04:06 was demonstrated to be the second independent signal (P = 7.44 × 10-13 , OR = 5.58) for PF. These findings advance our understanding of the genetic basis of pemphigus susceptibility and may offer opportunities for risk prediction and preventive treatment for pemphigus, in particular for PV.

The role of polymorphic ERAP1 in autoinflammatory disease.

Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions

Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, as part of the adaptive immune response. Amongst the associated drugs-allele combinations, anti-HIV drug Abacavir has been shown to be associated with the HLA-B*57:01 allele, and anti-epilepsy drug Carbamazepine with B*15:02, in both cases likely following the altered peptide repertoire model of interaction. Under this model, the drug binds directly to the antigen presentation region, causing different self peptides to be presented, which trigger an unwanted immune response. There is growing interest in searching for evidence supporting this model for other ADRs using bioinformatics techniques. In this study, in silico docking was used to assess the utility and reliability of well-known docking programs when addressing these challenging HLA-drug situations. The overall aim was to address the uncertainty of docking programs giving different results by completing a detailed comparative study of docking software, grounded in the MHC-ligand experimental structural data – for Abacavir and to a lesser extent Carbamazepine - in order to assess their performance. Four docking programs: SwissDock, ROSIE, AutoDock Vina and AutoDockFR, were used to investigate if each software could accurately dock the Abacavir back into the crystal structure for the protein arising from the known risk allele, and if they were able to distinguish between the HLA-associated and non-HLA-associated (control) alleles. The impact of using homology models on the docking performance and how using different parameters, such as including receptor flexibility, affected the docking performance were also investigated to simulate the approach where a crystal structure for a given HLA allele may be unavailable. The programs that were best able to predict the binding position of Abacavir were then used to recreate the docking seen for Carbamazepine with B*15:02 and controls alleles.It was found that the programs investigated were sometimes able to correctly predict the binding mode of Abacavir with B*57:01 but not always. Each of the software packages that were assessed could predict the binding of Abacavir and Carbamazepine within the correct sub-pocket and, with the exception of ROSIE, was able to correctly distinguish between risk and control alleles. We found that docking to homology models could produce poorer quality predictions, especially when sequence differences impact the architecture of predicted binding pockets. Caution must therefore be used as inaccurate structures may lead to erroneous docking predictions. Incorporating receptor flexibility was found to negatively affect the docking performance for the examples investigated. Taken together, our findings help characterise the potential but also the limitations of computational prediction of drug-HLA interactions. These docking techniques should therefore always be used with care and alongside other methods of investigation, in order to be able to draw strong conclusions from the given results.

Association of class II human leukocyte antigen (HLA) alleles with pulmonary sarcoidosis.

Background and objectives: Sarcoidosis is a systemic inflammatory disease of unknown etiology that involves any part of the body, mainly the lungs and thoracic lymph nodes. The clinical presentation is heterogeneous based on the degree and extent of organ involvement. The existence of variable clinical presentations and treatment responses suggest an important role of genetic predisposition. In genetic studies, sarcoidosis was found to be associated with several genes, but the strongest link was with HLA region. The aim of this study was to investigate the association of HLA class II alleles with the extent and course of disease in Turkish patients with sarcoidosis. Methods: The study included 103 patients with sarcoidosis and 100 unrelated healthy controls. HLA-DRB1 and HLA-DQB1 typing was performed by using Polymerase Chain Reaction-Sequence Specific Priming (PCR-SSP) method at low resolution level. Results: HLA-DRB1* and -DQB1* analysis revealed that while the frequency of HLA-DRB1*01 was significantly higher in the control group, HLA-DRB1*13 and -DQB1*06 alleles were more frequent in the sarcoidosis patients. When the patients were grouped based on clinical outcome as remitters and non-remitters, HLA-DRB1*10 allele was only detected in the remitters, whereas the frequency of HLA-DQB1*06 allele was significantly higher in non-remitters. Conclusions: This study supported the association of HLA alleles with sarcoidosis. In a considerably high number of patients with Turkish origin, the frequency of HLA-DRB1*13, -DRB1*10 and HLA-DQB1*06 alleles was significantly associated with increased risk and clinical outcome. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 143-149).

HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03:02 Strongly Associate With BMI: Data From 1.3 Million Healthy Chinese Adults.

Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI (P = 6.89 × 10-10, 1.32 × 10-9, 1.52 × 10-9, and 4.45 × 10-8, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects (Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B, DRB1, and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity.

HLA class II polymorphism in Saudi patients with multiple sclerosis.

Several studies have investigated the association of different HLA antigens with multiple sclerosis (MS). However, only few studies have considered the association of high-resolution HLA type and MS with none yet from Saudi Arabia. The aim of this study was to investigate the association of HLA class II alleles with MS in the Saudi population. We used next-generation sequencing to investigate HLA association with MS. This study was conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia. We found that several HLA-DRB1 and DQB1 alleles were associated with MS. These alleles included HLA-DRB1*15:01 (odds ratio [OR]: 3.01; 95%, confidence interval [CI]: 1.68-5.54; P = .0001), HLA-DQB1*02:01 (OR: 1.76; 95% CI: 1.20-2.58; P = .0022), HLA-DQB1*06:02 (OR: 3.52; 95% CI: 1.87-6.86; P < .0001), and HLA-DQB1*06:03 (OR: 2.42; 95% CI: 1.16-5.25; P = 0.01). Interestingly, HLA-DRB1*15:01 was associated with increased risk of previous relapses. In addition, HLA-DRB1*15:01 and HLA-DQB1*06:02 were found to be associated with lower vitamin D levels. This study provides insights on the association of different HLA alleles with clinical characteristics and outcome of MS among Saudis. These insights can have future implications for the clinical management of MS based on the patient genetic profile.

P267 HLA haplotype structure in an european population

Aim This is a study of the haplotype frequency and distribution in an European population. In order to study the gene structure of HLA haplotypes, these haplotypes must be determined in a large sample from a given population. Diploid combinations of alleles from different loci must be placed in phase with each other. [Two other parallel studies are performed in two other ethnic populations.]. Methods Approximately 6000 samples come from an European collected for disease association. HLA typing is based on Mia Fora next-generation sequencing by Immucor. The following loci are included: A, B, C, DRB1, DRB345, DQA1, DQB1, DPA1 and DPB1. A modification of the EM algorithm was used to determine the haplotypes in the population. Linkage disequilibrium is performed by means of 2 × 2 contingency tables. Results Full 2 × 2 contingency tables, for each pair of variables, with their corresponding chi-square, p value and other measures of correlation are presented for the following pairs of HLA loci or groups of loci: 1) B vs. C, 2) DRB1 vs. DRB345, 3) DQA1 vs. DQB1, 4) DPA1 vs. DPB1, 5) A vs. B-C, 6) DRB1-DRB345 vs. DQA1-DQB1, 7) DPA1-DPB1 vs. DRB1-DRB345-DQA1-DQB1, and 8) A vs. DRB1-DRB345-DQA1-DQB1. Conclusions Results may be biased by the disease association in this project. (The disease in question cannot be disclosed at this time.) Nevertheless, the identity of the haplotype itself will not be affected by this bias. One of the main finding in this study is that, contrary to what is generally believed, NGS does not disclose a hidden abundance of HLA alleles, it rather helps us characterise in full detail alleles we were already familiar with. This study shows the association of HLA alleles with alleles in other loci. The second main finding in this study is that in those cases where more than one genetic variant is represented by a single previously known protein allele, the linkage disequilibrium measures increase significantly when this genetic variants are taken into account individually.

P266 Hla haplotype structure in a population of african origin

Aim This is a study of the haplotype frequency and distribution in a population of African origin. In order to study the gene structure of HLA haplotypes, these haplotypes must be determined in a large sample from a given population. Diploid combinations of alleles from different loci must be placed in phase with each other. [Two other parallel studies are performed in two other ethnic populations.] Methods Approximately 3000 samples come from a population of African origin collected for disease association. HLA typing is based on Mia Fora next-generation sequencing by Immucor. The following loci are included: A, B, C, DRB1, DRB345, DQA1, DQB1, DPA1 and DPB1. A modification of the EM algorithm was used to determine the haplotypes in the population.Linkage disequilibrium is performed by means of 2x2 contingency tables for each pair of alleles or allele groups. Results Full 2x2 contingency tables, for each pair of variables, with their corresponding chi-square, p value and other measures of correlation are presented for the following pairs of HLA loci or groups of loci: 1) B vs C, 2) DRB1 vs DRB345, 3) DQA1 vs DQB1, 4) DPA1 vs DPB1, 5) A vs B-C, 6) DRB1-DRB345 vs DQA1-DQB1, 7) DPA1-DPB1 vs DRB1-DRB345-DQA1-DQB1, and 8) A vs DRB1-DRB345-DQA1-DQB1. Conclusions Results may be biased by the disease association in this project. (The disease in question cannot be disclosed at this time.) Nevertheless, the identity of the haplotype itself will not be affected by this bias. One of the main finding in this study is that, contrary to what is generally believed, NGS does not disclose a hidden abundance of HLA alleles, it rather helps us characterise in full detail alleles we were already familiar with. This study shows the association of HLA alleles with alleles in other loci. The second main finding in this study is that in those cases where more than one genetic variant is represented by a single previously known protein allele, the linkage disequilibrium measures increase significantly when this genetic variants are taken into account individually.

Abstract 1314: Trans-ethnic HLA fine-mapping of the MHC region identified several independent variants influencing susceptibility to lung cancer

Abstract Background: Genetic variants within the major histocompatibility complex (MHC) are associated with lung cancer. However, debate persists about the identity of the true causal variants, in part due to the broad linkage disequilibrium (LD) characteristic of the MHC and to the complexity and cost of complete HLA genotyping. Here, we assessed the role of the MHC in modulating lung cancer risk in Asians and Europeans using a broad set of HLA variants to detect the main alleles and the presence of independent effects elsewhere in this genomic region. Material and methods: Association between the HLA variants and risk of lung cancer was examined in two collections of samples of different ethnicity (18,686 cases / 15,190 controls and 2,324 cases / 1,646 controls of European and Asian ancestry, respectively). Using existing genome-wide SNP data from the lung cancer OncoArray study, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DPA1 and HLA-DPB1, as well as 7,258 SNPs across the MHC. All the analyses were performed assuming an additive genetic model adjusted for sex and principal components as covariates. The study-wide significant threshold was p=6.03 x 10-6. Results: Conditional, haplotype and stratified analyses identified two independent HLA allele effects associated with lung cancer squamous cell carcinoma in Europeans. One is HLA-DQB1*06 that showed a significant protective effect (OR=0.85, 95%CI 0.80-0.90, p=3.05 x10-8). The other effect is attributed to the long ancestral 8.1 haplotype (OR=1.30, 95%CI 1.18-1.42, p=4.78 x10-8), which contains class I and class II HLA alleles (A*0101 - B*0801 - C*0701 - DRB1*0301 - DQB1*0201 - DQA1*0501). In addition, single-amino-acid polymorphisms in HLA-B (at positions 9, 156, 163 and 178) and HLA-DRB1 (at positions 26, 71 and 74) located in peptide-binding grooves, suggest these proteins as possible functional contributors within the haplotype. In Asians, we observed two independent HLA allele effects associated with lung adenocarcinoma : HLA-DQB1*0401 (OR=1.67, 95% CI 1.35-2.05, p=1.59 x10-6), and HLA-DRB1*0701(OR=1.62, 95% CI 1.31-2.01, p=5.48 x10-6) as well as an intronic SNP in HLA-A (rs2256919) (OR=0.75, 95% CI 0.67-0.83, p=1.75 x10-7). Conclusions: We established an association between HLA haplotype 8.1 and squamous lung cancer risk in Europeans. In contrast, in Asians we observed associations only with class II HLA alleles and risk of lung adenocarcinoma. We did not observed shared HLA alleles effects between populations. This ethnic heterogeneity in classical HLA allelic associations with lung cancer may be explained by allele frequency differences between populations and also different exposures that interact with HLA. Furthermore, our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC. Citation Format: Aida Ferreiro-Iglesias, Corina Lesseur, James McKay, Rayjean J. Hung, Christopher I. Amos, Paul Brennan, on behalf of OncoArray consortium. Trans-ethnic HLA fine-mapping of the MHC region identified several independent variants influencing susceptibility to lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2017-1314

Association of HLA alleles (A, B, DRB1) and HIV-1 infection in the Han population of Hubei, China.

The HIV susceptibility and resistance alleles in the HLA genes were determined by investigating the distribution characteristics of the HLA alleles (A, B, and DRB1) in HIV-infected individuals of the Han population in Hubei, and by comparing these alleles with HIV-negative individuals from the same area. A cohort of 424 HIV-1 infected individuals were chosen as study subjects, and 836 HIV-negative healthy subjects from the same area served as the control population. HLA-A, B, and DRB1 allele typing was performed using polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) and polymerase chain reaction-sequencing based typing (PCR-SBT) techniques. Arlequin ver3.0 was used to analyze the allele and haplotype frequencies of HLA-A, B, and DRB 1, whereas Epi Info 7 and SPSS18.0 was used to analyze the differences in the HLA alleles between the HIV-1 positive and HIV-1 negative groups. A*02:03, DRB1*01:01, and DRB1*15:01 alleles and their haplotypes as well as the HLA_Bw4-Bw6 hybrid showed a protective effect on HIV-1 infection. After adjusting for confounding factors such as age and sex, multivariate logistic regression analysis revealed that B*15:02G, DRB1*01:01, and DRB1*15:01 subtypes were the resistance genes of HIV-1 infection, while B*13:01 might increase susceptibility to HIV-1 infection. The correlation between A*02:06 and B*15:01G subtypes and HIV-1 susceptibility was independent of the age and sex of the host. This study demonstrated the influence of genetic factors in humans such as HLA polymorphism on individuals to resist HIV-1 infection. Association studies of HLA polymorphism, susceptibility/resistance to HIV-1 infection, and hosts' genetic background are of significant importance for research on HIV-1 pathogenesis and vaccine design.