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Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 [EBNA-1, truncated = amino acids (aa) (325–641), peptide = aa(385–420)] and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched control subjects. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 [odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.60–1.88] and EBNA-1, particularly the peptide (OR = 3.13, 95% CI = 2.93–3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to 12× the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g. DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01 , which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defence against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defence against EBV. Last, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility. [ABSTRACT FROM AUTHOR]

Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCAcontrolled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies. [ABSTRACT FROM AUTHOR]

Hyponastic Leaves 1 (HYL1) [also known as Double-stranded RNA-Binding protein 1 (DRB1)] is a double-stranded RNA-binding protein involved in microRNA (miRNA) processing in plants. It is a core component of the Microprocessor complex and enhances the efficiency and precision of miRNA processing by the Dicer-Like 1 protein. In this work, we report a novel function of the HYL1 protein in the transcription of miRNA (MIR) genes. HYL1 colocalizes with RNA polymerase II and affects its distribution along MIR genes. Moreover, proteomic experiments revealed that the HYL1 protein interacts with many transcription factors. Finally, we show that the action of HYL1 is not limited to MIR genes and impacts the expression of many other genes, a majority of which are involved in plastid organization. These discoveries indicate HYL1 as an additional player in gene regulation at the transcriptional level, independent of its role in miRNA biogenesis. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B Virus (HBV) infection affect all social strata of humanity and in the absence of any management, this infection has a different outcome from one infected person to another. This suggests that there are specific individual factors that influence the outcome of the pathology. Sex, immunogenetics and age of contraction of the virus have been cited as factors that influence the evolution of the pathology. In this study, we looked at two alleles of the Human Leucocyte Antigen (HLA) system to measure their possible involvement in the evolution of HBV infection. Method and results: We conducted a cohort study involving 144 individuals spread over 04 distinct stages of infection and then compared allelic frequencies in these populations. A multiplex PCR was conducted and the data obtained was analyzed using R and SPSS software. Our study revealed a predominance of HLA-DRB1*12 in our study population without, however, showing a significant difference between HLA-DRB1*11 and HLA-DRB1*12. The HLA-DRB1*12 proportion was significantly higher in chronic hepatitis B (CHB) and resolved hepatitis B (RHB) compared to cirrhosis and hepatocellular carcinoma (HCC) (p-value = 0,002). Carrying HLA-DRB1*12 has been associated with a low risk of complication of infection (CHB → cirrhosis; OR 0,33 p-value 0,017; RHB → HCC OR 0,13; p-value = 0,00,045) whereas the presence of HLA-DRB1*11 in the absence of HLA-DRB1*12 increased the risk of developing severe liver disease. However, a strong interaction of these alleles with the environment could modulate the infection. Conclusion: Our study shown that HLA-DRB1*12 is the most frequent and it's carriage may be protective in the development of infection. [ABSTRACT FROM AUTHOR]

Activated cytotoxic CD4 T cells (HLA-DR+) play an important role in the control of EBV infection, especially in cells with latency I (EBNA-1). One of the evasion mechanisms of these latency cells is generated by gp42, which, via peripherally binding to the β1 domain of the β chain of MHC class II (HLA-DQ, -DR, and -DP) of the infected B lymphocyte, can block/alter the HLA class II/T-cell receptor (TCR) interaction, and confer an increased level of susceptibility towards the development of EBV-associated autoimmune diseases or cancer in genetically predisposed individuals (HLA-DRB1* and DQB1* alleles). The main developments predisposing the factors of these diseases are: EBV infection; HLA class II risk alleles; sex; and tissue that is infiltrated with EBV-latent cells, forming ectopic lymphoid structures. Therefore, there is a need to identify treatments for eliminating cells with EBV latency, because the current treatments (e.g., antivirals and rituximab) are ineffective. [ABSTRACT FROM AUTHOR]

Background: Associations between IgA nephropathy (IgAN) and HLA-DRB1 and -DQB1 alleles have been reported in several ethnic groups. We investigated the association of HLADRB1 and -DQB1 alleles with the predisposition for IgAN and disease progression to endstage kidney disease (ESKD) in Korean patients. Methods: We 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. Results: The allele frequencies of HLA-DRB1*04:05 (corrected P [Pc]<0.001), -DQB1 *04:01 (Pc =0.048), and -DQB1*03:02 (Pc =0.021) were significantly higher in IgAN patients than in controls, whereas those of HLA-DRB1*07:01, -DRB1*15:01, -DQB1*02:02, and -DQB1*06:02 (Pc <0.001 for all) were significantly lower in IgAN patients than in controls. The allele frequency of HLA-DQB1*05:03 (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. Conclusions: We report novel associations of HLA-DRB1*15:01, DQB1*02:02, -DQB1*03:02, and -DQB1*04:01 with IgAN. Further studies of HLA alleles associated with IgAN progression in a larger cohort and in various ethnic groups are needed. [ABSTRACT FROM AUTHOR]

MHC genes are highly polymorphic as antigen presenting molecules for adaptive immune response in vertebrates. In this study, we evaluated the diversity of dog leukocyte antigen (DLA) class II genes among two Korean breeds, the Sapsaree and the Jindo, and three Chinese native breeds, Tibetan Mastiff, Pug, and Pekingese, and determined their genetic relationships. Sequence-based typing of DLA-DRB1 and DLA-DQB1 was performed in 138 dogs. We identified 27 alleles for DRB1 and 24 for DQB1, including five new alleles. DRB1*015:01 was shared among all five breeds and was a major allele for the Pug, Tibetan Mastiff, and Sapsaree. The observed heterozygosity for the five breeds ranged from 0.67 to 1.00 for DRB1 and from 0.80 to 1.00 for DQB1. A total of 40 DRB1-DQB1 haplotypes, including nine new haplotypes, were identified. Interestingly, most haplotypes (33/40, 82%) were specific to a single breed, and only seven were present in multiple breeds. Haplotype sharing analysis together with previously available data from 109 breeds revealed that compared to within region distances, Asian breeds were more distant than breeds from other regions. As a first report on the analysis of DLA genes of dog breeds in Korean peninsula, our results show that these breeds carry unique DLA class II haplotype lineages. Our results indicate that the diversity and breed specificity of DLA class II genes are much higher among East Asian breeds than among breeds from other regions. [ABSTRACT FROM AUTHOR]

Abstract Background Type 1 Diabetes Mellitus (T1DM) is the autoimmune disorder of destruction of β cells of pancreas, creating insulin deficiency condition, which leads to hyperglycemia, polyuria, polydipsia, ketoacidosis, and other metabolic disorder especially in children. Different genetic aspects and environmental factors are involved in pathophysiology of the disease. About 20 genes are associated with this disease in which the most common is the different combination of haplotype DRB1‐DQA1‐DQB1 present at HLA gene. At HLA‐DQB1, there are some SNPs which are associated with T1DM. In T1DM, there are number of biochemical, serological parameters which show some abnormalities leading to some complications. Methods Samples were subjected to all biochemical and serological techniques to get the measurement of concentration of glucose, lipid profile (cholesterol, triglycerides, and HDL and LDL cholesterol), urea, creatinine, albumin, insulin, anti‐insulin antibodies, C‐peptides, and leptin. All these values were compared with controls values and statistical analysis was also done on these values. At molecular level, two primers set which were allele specific at HLA‐DQB1, were used to amplify the SNPs, homozygous and heterozygous conditions were stated. Results PCR results for the studied population showed that most of samples have heterozygous condition for these SNPs of this allele specific region on HLA‐DQB1. Very few of them have homozygous state for it. Even in the control sample have the same conditions. Conclusion In Pakistan, there is dire need of studies about SNPs and haplotypes related to HLA‐DQB1 which show association with T1DM.

Background: Type 1 Diabetes Mellitus (T1DM) is the autoimmune disorder of destruction of β cells of pancreas, creating insulin deficiency condition, which leads to hyperglycemia, polyuria, polydipsia, ketoacidosis, and other metabolic disorder especially in children. Different genetic aspects and environmental factors are involved in pathophysiology of the disease. About 20 genes are associated with this disease in which the most common is the different combination of haplotype DRB1‐DQA1‐DQB1 present at HLA gene. At HLA‐DQB1, there are some SNPs which are associated with T1DM. In T1DM, there are number of biochemical, serological parameters which show some abnormalities leading to some complications. Methods: Samples were subjected to all biochemical and serological techniques to get the measurement of concentration of glucose, lipid profile (cholesterol, triglycerides, and HDL and LDL cholesterol), urea, creatinine, albumin, insulin, anti‐insulin antibodies, C‐peptides, and leptin. All these values were compared with controls values and statistical analysis was also done on these values. At molecular level, two primers set which were allele specific at HLA‐DQB1, were used to amplify the SNPs, homozygous and heterozygous conditions were stated. Results: PCR results for the studied population showed that most of samples have heterozygous condition for these SNPs of this allele specific region on HLA‐DQB1. Very few of them have homozygous state for it. Even in the control sample have the same conditions. Conclusion: In Pakistan, there is dire need of studies about SNPs and haplotypes related to HLA‐DQB1 which show association with T1DM. [ABSTRACT FROM AUTHOR]

The Colombian population is characterised by a high genetic diversity, secondary to the ethnic mixture arising from colonisation. Unfortunately, few reports are available regarding HLA‐DRB1 and DQB1 diversity in Colombia to date. HLA‐DRB1 and DQB1 diversity was identified in this study using next‐generating sequencing (NGS) on a cohort of Colombian women. Cervical samples taken from 276 women were used for typing DRB1 and DQB1 loci by Illumina MiSeq. Allele and haplotype frequencies were calculated using an expectation‐maximisation algorithm. Hardy‐Weinberg Equilibrium and linkage disequilibrium (LD) between loci were evaluated. Forty‐seven DRB1 alleles and 14 DQB1 alleles were identified. DRB1*04:07:01G and DQB1*03:02:01G alleles occurred most frequently in the target population. Significant LD was found in 44 out of the 144 identified haplotypes, within which DRB1*04:07:01G‐DQB1*03:02:01G occurred most frequently (6.56%). The alleles and haplotypes found with NGS agreed with that found in previous reports involving lower resolution for the Colombian population, and greater genetic variability was found, especially concerning DRB1. Comparing allele and haplotype frequency distribution in the target population to that of other populations denoted HLA system intra‐ and inter‐population diversity. [ABSTRACT FROM AUTHOR]

Aim: To study the major histocompatibility complex (MHC) Class II DRB1 gene polymorphism in Rohilkhandi goat using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and nucleotide sequencing techniques. Materials and Methods: DNA was isolated from 127 Rohilkhandi goats maintained at sheep and goat farm, Indian Veterinary Research Institute, Izatnagar, Bareilly. A 284 bp fragment of exon 2 of DRB1 gene was amplified and digested using BsaI and TaqI restriction enzymes. Population genetic parameters were calculated using Popgene v 1.32 and SAS 9.0. The genotypes were then sequenced using Sanger dideoxy chain termination method and were compared with related breeds/species using MEGA 6.0 and Megalign (DNASTAR) software. Results: TaqI locus showed three and BsaI locus showed two genotypes. Both the loci were found to be in Hardy–Weinberg equilibrium (HWE), however, population genetic parameters suggest that heterozygosity is still maintained in the population at both loci. Percent diversity and divergence matrix, as well as phylogenetic analysis revealed that the MHC Class II DRB1 gene of Rohilkhandi goats was found to be in close cluster with Garole and Scottish blackface sheep breeds as compared to other goat breeds included in the sequence comparison. Conclusion: The PCR-RFLP patterns showed population to be in HWE and absence of one genotype at one locus (BsaI), both the loci showed excess of one or the other homozygote genotype, however, effective number of alleles showed that allelic diversity is present in the population. Sequence comparison of DRB1 gene of Rohilkhandi goat with other sheep and goat breed assigned Rohilkhandi goat in divergence with Jamanupari and Angora goats.

Autoimmune Thyroid Diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), arise by the complex interaction of genes and environmental factors. The aim of present study was to study the susceptible associations of HLA-DRB1* alleles and CTLA4 + 49 AG polymorphism in AITD in south India. AITD patients ( n = 235; HT = 180; GD = 55) and age/sex matched healthy controls (n, 235) were enrolled to type HLA-DRB1* alleles and ‘ CTLA4 + 49 AG’ by PCR-SSP and PCR-RFLP methods respectively. Analysis revealed CTLA4 + 49 ‘GG’ genotype was increased significantly in patients (PL: p = 8.7 × 10 − 8 ; HT: p = 9.3 × 10 − 6 ; GD: p = 0.006). Decreased frequencies of ‘AA’ genotype was observed in patients (PL: p = 9.4 × 10 − 6 ; HT: p = 0.008; GD: p = 9.0 × 10 − 6 ). Increased frequencies were observed for HLA alleles DRB1*12 (PL: p = 1.42 × 10 − 10 ; HT: p = 5.75 × 10 − 8 ; GD: p = 0.002) and DRB1*11 (PL: p = 0.0025; HT: p = 0.013) in patients. Decreased frequencies for alleles DRB1*10 (PL: p = 0.00002; HT: p = 0.018; GD: p = 1.63 × 10 − 5 ) and DRB1*03 (PL: p = 0.003; HT: p = 0.003) were observed, suggesting a protective association. Combinatorial/Synergistic analysis have revealed an increased frequencies for ‘DRB1*11 + AG’ (PL: p = 0.022), ‘DRB1*12 + AG’ (PL: p = 6.1 × 10 − 5 ; HT: p = 0.0001), ‘DRB1*04 + GG’ (PL: p = 0.003; HT: p = 0.008), ‘DRB1*07 + GG’ (PL: p = 0.009; HT: p = 0.014) and ‘DRB1*12 + GG’ (PL: p = 0.005; HT: p = 0.005) in patients. However, the combinations such as ‘DRB1*10 + AA’ (PL: p = 1.8 × 10 − 6 ; HT: p = 0.003) and ‘DRB1*15 + AA’ (PL: p = 0.006; GD: p = 0.011) were decreased in patients showing a protective association. The ‘GG/G’ of CTLA4 + 49AG SNP, HLA-DRB1*11/-DRB1*12 (DR5) alleles and the combinations of DRB1*11/DRB1*12 alleles with AG/GG genotype and DRB1*04/07/12 alleles with GG genotype may act as synergistic manner to confer the strong susceptibility to AITD in south India. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren’s syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E−07, OR = 1.9) and eight with Löfgren’s syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E−12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P

HLA‐DRB1*11:04:21 differs from HLA‐DRB1*11:04:01 by one nucleotide substitution in codon 69 in exon 2. [ABSTRACT FROM AUTHOR]

India harbors a vast diversity of sheep (40 breeds). The study was carried out to assess the genetic diversity of DRB1 and DQA2 locus of the ovar-MHC and their possible association with Peste des petits ruminants (PPR) virus vaccine response in Malpura and Avikalin sheep breeds maintained at an organized institute flock in the semi-arid region of India. Genetic analysis revealed the rich diversity of DRB1 locus with 23 alleles in Malpura and 21 alleles in Avikalin sheep that included 9 new alleles. DQA2 locus also had rich diversity with 19 alleles in Malpura and 20 alleles in Avikalin sheep that included 7 new alleles. At the protein level, high variability alike at the nucleotide level was observed. A marker for footrot susceptibility, DQA2*1101 was absent in both breeds. Genotypic association of DRB1 and DQA2 with PPR vaccine response was statistically non-significant. Vaccine response being a multifactorial (polygenic and influenced by environment) variable, could not show statistically significant association with MHC genotypes in the present study. However, rich genetic diversity of DRB1 and DQA2 gene reflects the importance of this locus for future selection programs. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen--presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA--DRA with tag--SNPs and their relation to HLA--DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren's syndrome. In a joint analysis, seven SNPs were associated with non--Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E--07, OR = 1.9) and eight with Löfgren's syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E--12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA--DRB1 challenged the result interpretation. When the SNPs and HLA--DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA--DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA--DRB1 and/or HLA--DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA--DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA--DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi--population study demonstrates that at least a part of these associations are HLA--DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA--DRB1 associations acted as eQTL for HLA--DRB1 and/or --DRB5, suggesting a role in regulating gene expression. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex system is the most polymorphic gene cluster of the mammal genome. In humans, this is a genomic locus known as the human leukocyte antigen (HLA) system. The HLA encodes mostly immune-associated proteins whose main effect is the presentation of antigens to the immune cells. Thus, it is clear that it is essential for to the proper function of the immune response against pathogens and strongly implicated in the development of autoimmune diseases. Nonetheless, there are hundreds of polymorphisms of HLA- DRB1 which have been associated with different autoimmune disorders as well as with immune response to infection and vaccines. It is possible that the interaction of specific HLA with pathogenic antigens is one of the keys favoring (or protecting) toward the development of an autoimmune disease. In the era of personalized medicine, it would be of great help to build a map of the genomic risk of each individual to evaluate the risk of developing an autoimmune condition. [ABSTRACT FROM AUTHOR]

Objetivos: Identificar biomarcadores de susceptibilidad para AIJ poliarticular y AR de instalación temprana por estudio del polimorfismos de MHC/HLA-DRB1* y PTPN22. Materiales y métodos: Se realizó un estudio de casos y controles con una relación 1:2. Todos los sujetos de investigación y los controles provinieron de una corta anidada perteneciente a un proyecto institucional; 30 pacientes con AIJ y 30 con AR de instalación temprana. Como controles se estudiaron 60 individuos sanos. El ADN se obtuvo por salt- ing out modificado. La tipificación de los alelos MHC/DRB1* se realizó por PCR-SSP y en el polimorfismo (C1858T) del sistema PTPN22 se utilizó PCR-RTq. Resultados: Para AIJ Poliarticular, el alelo DRB1*0404 se asoció con susceptibilidad (OR=10.82; p

In Arabidopsis thaliana, efficient microRNA (miRNA) production requires DICER-LIKE1 (DCL1) with the assistance of a partnering protein, DOUBLE-STRANDED RNA BINDING1 (DRB1) or DRB2. The presence of either of these DRB proteins is crucial to determine the mode of action of a miRNA; i.e. cleavage or translation inhibition. Here we studied the structural determinants for the role of DRB1 and DRB2 in the miRNA pathway. We developed a series of chimeric vectors encoding different functional domains of DRB1 and DRB2, and expressed these in the drb1 mutant background in Arabidopsis under the control of the native DRB1 promoter. Complementation of the drb1 developmental phenotype was used to assess the biological role that each functional domain of DRB1 and DRB2 mediates in the miRNA-guided transcript cleavage pathway. The DRB1 amino acid sequence differs considerably to that of DRB2, and analysis of drb1 transgenic lines revealed that the first dsRNA-binding domains (dsRBD1) of DRB1 and DRB2 are functionally similar; in contrast, the dsRBD2 of DRB1 and DRB2 appear functionally distinct. Our bioinformatic analysis further suggests that the C-terminal domain of DRB2 mediates a functional role in the miRNA pathway, whereas its counterpart in DRB1 is known to be dispensable. Our results provide evidence for the differences between DRB1 and DRB2 proteins in vivo, which may be essential for the selection of the miRNA regulatory mechanisms, and suggest that these features are conserved among land plants.

The major histocompatibility complex (MHC) in sheep, Ovar-Mhc, remains poorly characterized relative to other domestic animals. However, its basic structure is similar to that of other mammals, comprising class I, II and III regions. In this study, the Ovine MHC class II DRB1 and DRB3 genes were amplified by polymerase chain reaction in eight sheep breeds reared in Turkey. Informative restriction fragment length polymorphisms (RFLPs) were obtained with five restriction enzymes for DRB1 and with two restriction enzymes for DRB3. The digestion of DRB1 exon 2 with NciI, SacI, SacII, Hin1I each produced three genotypes and two alleles (viz., a and b) with frequencies of 0.69 and 0.31; 0.65 and 0.35; 0.91 and 0.09; 0.57 and 0.43, respectively. The digestion of DRB1 exon 2 with DdeI produced four genotypes and three alleles (viz., a, b and c) with frequencies of 0.62, 0.28 and 0.10, respectively. On the other hand, the digestion of DRB3 exon 2 with NdeII and BsaI each produced three genotypes and two alleles (viz., a and b) with frequencies of 0.72 and 0.28; 0.96 and 0.04, respectively. This study presents the genetic profiles of the exon 2 region of the MHC DRB1 and DRB3 genes in native Turkish sheep breeds. [ABSTRACT FROM AUTHOR]

Background Allergic rhinitis (AR) is a multifactorial immunologic disease that is influenced by both genetic and environment factors. House dust mites (HDMs) are important inhalant aeroallergens and are an epidemiologic risk factor for AR. Similarly, the human leukocyte antigen (HLA) class II genes DQB1 and DRB1 have been shown to be associated with AR and play an important role in the regulation of the immune response. The objective of this work was to elucidate the HLA-II gene alleles associated with AR in HDM-sensitive Han Chinese subjects. Methods A total of 142 patients with AR and 184 healthy subjects were recruited to this case-control study. Diagnosis of AR was based on medical history, laryngological examination, skin-prick tests, and HMD-specific immunoglobulin E (IgE) assays. Genotyping of HLA-DRB1 and HAL-DQB1 was performed by the polymerase chain reaction sequence-based genotyping method. Results A total of 35 alleles of the HLA-DRB1 locus and 19 alleles of the HLA-DQB1 locus were genotyped in the entire study cohort; the frequencies of alleles DQB1*06:01:01 (corrected p value [ pc] = 0.009; odds ratio [OR] = 2.684; 95% confidence interval [CI] = 1.482 to 4.994) and DRB1*08:03:02 ( pc = 0.009; OR = 3.754; 95% CI = 1.724 to 8.851) were significantly increased in HDM-sensitive AR patients compared to healthy controls and are considered to be a risk factor for AR in Chinese Han subjects. The frequency of haplotype DRB1*08:03-DQB1*06:01 in the HDM-sensitive AR group was also significantly higher than in the control group (9.5% vs 2.4%; pc = 0.005; OR = 4.182; 95% CI = 1.870 to 10.285). Serological antigen types assessment further demonstrated the frequency of HLA-DRB1*08 ( pc = 0.022; OR = 2.982; 95% CI = 1.46 to 6.400) to be significantly increased in HDM-sensitive AR patients, and the frequencies of DRB1*14 ( pc = 0.030; OR = 0.340; 95% CI = 0.154 to 0.694) and DQB1*05 ( pc = 0.030; OR = 0.459; 95% CI = 0.269 to 0.764) to be significantly decreased, compared to healthy controls, suggesting that HLA-DRB1*08 might be a risk factor, and DRB1*14 and DQB1*05 protective factors for HDM-sensitive AR. Conclusion HLA-DRB1*08:03:02 and HLA-DQB1*06:01:01 are associated with HMD-sensitive AR and may confer a risk for development of AR in Han Chinese subjects sensitized to HDM. [ABSTRACT FROM AUTHOR]

Abstract The DRB1 intron 2 (GT)n (GA)m microsatellite was genotyped in experimental flocks of seven Merinoland rams and 249 ewes as well as their offspring (381 lambs) from consecutive lambings. A total of 16 DRB1 alleles were detected, ranging between 353 and 857 bp. In comparison with carriers of other alleles, the ewes carrying the predominant 411 bp allele had higher values of all the recorded fertility traits. For ewes carrying the 394 and 857 bp alleles, the birth weight of lambs was about 400 g higher as compared to the residual group of ewes. The observed associations could be due to differences in disease resistance, cell recognition or tissue differentiation between carriers of various MHC haplotypes which can in turn affect individual fertility and growth performance.

In this study, we used the single strand conformation polymorphism (SSCP) method to analyze the associations between polymorphisms of exon 2 of the DRB1 and DQB1 genes and Cystic Echinococcosis (CE) in Chinese Merino sheep. We examined 96 CE positive sheep and 115 negative sheep in this study. The results showed thatthere were 53 genotypes controlled by 22 alleles in the DRB1 gene and 47 genotypes controlled by 17 alleles in the DQB1 gene. The comparison of allele frequencies in the CE positive and negative animals revealed that DRB1 alleles k (P<0.05), q, t (P<0.01) and alleles a, I (P<0.01). These results indicate a strong association between these alleles k,q,t and CE resistance, the alleles a, l are associated with CE susceptibility. We analyzed the DRB1 genotype frequencies and found that the genotypes KK and TT (P<0.05) are associated with CE resistance, while AA, LL (P<0.01), and AL (P<0.05) were related to CE susceptibility. In DQB1 exon 2 the d and e alleles (P<0.01) were related to CE resistance, while c and k (P<0.01) were significantly related to CE susceptibility. We analyzed the DQB1 genotype frequencies and found that DD and EG (P<0.01) were associated with CE resistance, while genotypes CC, KK, and CK (P<0.01) were associated with CE susceptibility. Using haplotype analysis and artificially infection tests with Echinococcus granulosus (EG), we found that the DRB1-TT/DQB1-EE was a CE resistant haplotype in Chinese Merino sheep. [ABSTRACT FROM AUTHOR]

As the only native insular Newfoundland canid between the extinction of the wolf in the 1930s and the recent arrival of coyotes, the red fox ( Vulpes vulpes deletrix Bangs 1898) poses interesting questions about genetic distinctiveness and the post-glacial colonization history of the island's depauperate mammalian fauna. Here, we characterized genetic variability at the major histocompatibility complex (MHC) class II DR β1 domain (DRB1) locus in 28 red foxes from six sampling localities island-wide and compared it with mitochondrial control region (CR) diversity and DRB1 diversity in other canids. Our goals were to describe novel DRB1 alleles in a new canid population and to make inferences about the role of selection in maintaining their diversity. As in numerous studies of vertebrates, we found an order-of-magnitude higher nucleotide diversity at the DRB1 locus compared with the CR and significantly positive nonsynonymous-to-synonymous substitution ratios, indicative of selection in the distant past. Although the evidence is weaker, the Ewens-Watterson test of neutrality and the geographical distribution of variation compared with the CR suggest a role for selection over the evolutionary timescale of populations. We report the first genetic data from the DRB1 locus in the red fox and establish baseline information regarding immunogenetic variation in this island canid population which should inform continued investigations of population demography, adaptive genetic diversity, and wildlife disease in red foxes and related species. [ABSTRACT FROM AUTHOR]

In Arabidopsis thaliana, efficient microRNA (miRNA) production requires DICERLIKE1 (DCL1) with the assistance of a partnering protein, DOUBLE-STRANDED RNA BINDING1 (DRB1) or DRB2. The presence of either of these DRB proteins is crucial to determine the mode of action of a miRNA; i.e., cleavage or translation inhibition. Here we studied the structural determinants for the role of DRB1 and DRB2 in the miRNA pathway. We developed a series of chimeric vectors encoding different functional domains of DRB1 and DRB2, and expressed these in the drb1 mutant background in Arabidopsis under the control of the native DRB1 promoter. Complementation of the drb1 developmental phenotype was used to assess the biological role that each functional domain of DRB1 and DRB2 mediates in the miRNA-guided transcript cleavage pathway. The DRB1 amino acid sequence differs considerably to that of DRB2, and analysis of drb1 transgenic lines revealed that the first dsRNA-binding domains of DRB1 and DRB2 are functionally similar; in contrast, the dsRBD2 of DRB1 and DRB2 appear functionally distinct. Our bioinformatic analysis further suggests that the C-terminal domain of DRB2 mediates a functional role in the miRNA pathway, whereas its counterpart in DRB1 is known to be dispensable. Our results provide evidence for the differences between DRB1 and DRB2 proteins in vivo, which may be essential for the selection of the miRNA regulatory mechanisms, and suggest that these features are conserved among land plants. [ABSTRACT FROM AUTHOR]

We found a haplotype with the deletion of the HLA‐DRB1 gene in two unrelated individuals originated from La Reunion Island, probably resulting from a deletion in the African haplotype A*30:02~C*18:02~B*57:03~DRB1*13:01. [ABSTRACT FROM AUTHOR]

Aim: To study the major histocompatibility complex (MHC) Class II DRB1 gene polymorphism in Rohilkhandi goat using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and nucleotide sequencing techniques. Materials and Methods: DNA was isolated from 127 Rohilkhandi goats maintained at sheep and goat farm, Indian Veterinary Research Institute, Izatnagar, Bareilly. A 284 bp fragment of exon 2 of DRB1 gene was amplified and digested using BsaI and TaqI restriction enzymes. Population genetic parameters were calculated using Popgene v 1.32 and SAS 9.0. The genotypes were then sequenced using Sanger dideoxy chain termination method and were compared with related breeds/species using MEGA 6.0 and Megalign (DNASTAR) software. Results: TaqI locus showed three and BsaI locus showed two genotypes. Both the loci were found to be in Hardy-Weinberg equilibrium (HWE), however, population genetic parameters suggest that heterozygosity is still maintained in the population at both loci. Percent diversity and divergence matrix, as well as phylogenetic analysis revealed that the MHC Class II DRB1 gene of Rohilkhandi goats was found to be in close cluster with Garole and Scottish blackface sheep breeds as compared to other goat breeds included in the sequence comparison. Conclusion: The PCR-RFLP patterns showed population to be in HWE and absence of one genotype at one locus (BsaI), both the loci showed excess of one or the other homozygote genotype, however, effective number of alleles showed that allelic diversity is present in the population. Sequence comparison of DRB1 gene of Rohilkhandi goat with other sheep and goat breed assigned Rohilkhandi goat in divergence with Jamanupari and Angora goats. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that HLA-DRB1 alleles reduce or increase the risk of developing ulcerative colitis-associated colorectal carcinoma (CRC) tumors. However, the role of HLA-DRB1 locus on the susceptibility to develop CRC tumor, in the absence of a history of inflammatory bowel diseases (IBDs), is unclear. The aim of our study was to determine whether HLA-DRB1 alleles are associated with IBD-independent CRC tumor. HLA-DRB1 allele polymorphisms were identified by sequence-based typing method in 53 CRC patients and 57 sex- and age-matched healthy Caucasian controls. Pearson's chi-squared analysis with Yate's correction or Fisher's exact test with Bonferroni's correction, as appropriate, were used to compare the allele frequency (AF) differences of HLA-DRB1 in patients and controls. A total of 29 HLA-DRB1 alleles were recognized. A detailed study of these alleles allowed to identify DRB1*13:01 and DRB1*11:01 alleles that were significantly associated with an increased and reduced risk to develop CRC tumor, respectively. AF of DRB1*13:01, in CRC patients, was significantly higher than that of healthy controls, even following Bonferroni's correction ( p = 0.029). In contrast, the presence of the DRB1*11:01 allele was negatively associated with CRC tumor as evidenced by the significantly lower AF in CRC patients than that of healthy controls ( p = 0.005). However, following Bonferroni's correction, the AF of DRB*11:01 lost its statistical significance. These results suggest that HLA-DRB1*13:01 allele could be a potential marker for predicting genetic susceptibility to CRC tumor. In contrast, the protective role of DRB1*11:01 remains unclear. [ABSTRACT FROM AUTHOR]

Takayasu arteritis (TA) is a chronic large-vessel vasculitis of unknown etiology. Human leukocyte antigen ( HLA ) alleles play an important role in the development of TA. Sequence specific primer-polymerase chain reaction was used to detect 10 alleles of the HLA-DQA1 gene and 13 alleles of the HLA-DQB1 , -DRB1 gene. A significant increase in the frequencies of DRB1 ∗ 07 ( Pc < 0.01, OR = 3.44, CI: 2.15–5.52) was observed among TA patients compared with the control group. The significantly increased frequencies of the haplotype DQA1 ∗ 03:01-DQB1 ∗ 03:01-DRB1 ∗ 07 (Corrected P -values < 0.01) were observed in TA patients. But in the analysis of clinical manifestations, there are no significant associations with the HLA-DRB1 ∗ 07 allele. [ABSTRACT FROM AUTHOR]

From a historical and genetic point of view, the Otomi of the Mezquital Valley are a frontier people that have played an important role in the population dynamics of the Mexican Central Plateau. Due to the antiquity of their presence in the area, the Otomi may be bearers of ancient genetic variability, shared mainly today with other groups belonging to the Otomanguean linguistic family and with the Nahua. In this study we analyzed the HLA class II allele frequencies reported in Mexican indigenous populations, in order to provide an intraregional-level historical perspective of the genetic relationships between the Otomi of the Mezquital Valley and indigenous populations from other regions of Mexico. We examined genetic variation in HLA-DRB1 and -DQB1 loci in 66 nonrelated individuals belonging to seven indigenous communities from the Ixmiquilpan municipality in the Mezquital Valley, in the State of Hidalgo, Mexico. The variability of the HLA-DRB1 gene among the Otomi of the Mezquital Valley was mainly concentrated in five alleles: -DRB1*08:02 (31.06%), -DRB1*04:07 (25.77%), -DRB1*14:06 (7.55%), -DRB1*14:02 (6.06%), and -DRB1*16:02 (4.55%); these alleles have been previously described in other indigenous populations. The most frequent alleles at the HLA-DQB1 locus were -DQB1*03:02 (34.09%), -DQB1*04:02 (31.03%), and -DQB1*03:01 (19.7%). Furthermore, the HLA-DQB1*02:02 allele was found in the Otomi group with a frequency of 2.27%; this allele has not been reported in Mexican indigenous populations. In conclusion, the genetic constitution of the Otomi population is intermediate to the northern groups and the genetic variability shared by the peoples of the central regions of Mexico. Furthermore, HLA-DRB1 and -DQB1 allelic variability among the Otomi provides insight into the historical processes implied in the biological admixture with European, Asian, and African populations as well as in the admixture with the population of Mexico City associated with long-standing migratory processes. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex is one of the best studied systems in vertebrates providing evidence for the long-term action of selection. Here, we examined the intra- and inter-population genetic diversity of the MHC class II DRB locus in European brown hare ( Lepus europaeus) and correlated the results with genetic variability already estimated from the MHC DQA locus and from maternally (mitochondrial DNA (mtDNA)) and biparentally (allozymes, microsatellites) inherited loci. L. europaeus showed remarkable genetic polymorphism in both DQA and DRB1 loci. The Anatolian populations exhibited the highest genetic polymorphism for both loci. Balancing selection has established increased variability in the European populations despite the founder effects after the last glaciation. Different evolutionary rates were traced for DRB1 and DQA loci, as evidenced by the higher number of common DRB1 than DQA alleles and the greater differences between DRB1 alleles with common origin in comparison with DQA alleles. The high number of rare alleles with low frequencies detected implies that frequency-dependent selection drives MHC evolution in the brown hare through the advantage of rare alleles. Both loci were under the influence of positive selection within the peptide-binding region. The functional polymorphism, recorded as amino acid substitutions within the binding pockets, fell also within distinct geographic patterns, yet it was much narrower than the genetic polymorphism. We hypothesize that certain structural and functional characteristics of the binding pockets set limitations to the actual shape of genetic polymorphism in MHC. [ABSTRACT FROM AUTHOR]

The article presents a study on the antibody response to human leukocyte antigen (HLA)-DRBI, and common viruses in pediatric multiple sclerosis (MS), which aims to determine if antibodies in MS patients with viruses such as Epstein Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) are higher. Methods used include multivariate analysis, pediatric control, and polymerase chain reaction. Result shows that high antibody response is not associated with DRB1 positive patients.

The Major Histocompatibility Complex (MHC) is a multigene family of outstanding polymorphism. MHC molecules bind antigenic peptides in the peptide-binding region (PBR) that consists of five binding pockets (P). In this study, we compared the genetic diversity of domestic pigs to that of the modern representatives of their wild ancestors, the wild boar, in two MHC loci, the oligomorphic DQA and the polymorphic DRB1. MHC nucleotide polymorphism was compared with the actual functional polymorphism in the PBR and the binding pockets P1, P4, P6, P7, and P9. The analysis of approximately 200 wild boars collected throughout Europe and 120 domestic pigs from four breeds (three pureblood, Pietrain, Leicoma, and Landrace, and one mixed Danbred) revealed that wild boars and domestic pigs share the same levels of nucleotide and amino acid polymorphism, allelic richness, and heterozygosity. Domestication did not appear to act as a bottleneck that would narrow MHC diversity. Although the pattern of polymorphism was uniform between the two loci, the magnitude of polymorphism was different. For both loci, most of the polymorphism was located in the PBR region and the presence of positive selection was supported by a statistically significant excess of nonsynonymous substitutions over synonymous substitutions in the PBR. P4 and P6 were the most polymorphic binding pockets. Functional polymorphism, i.e., the number and the distribution of pocket variants within and among populations, was significantly narrower than genetic polymorphism, indicative of a hierarchical action of selection pressures on MHC loci. [ABSTRACT FROM AUTHOR]

Background: Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for malignant lesions and cervical cancer. A widely studied element in the search for genetic factors influencing risk HPV infection diseases is allelic variation of the human leukocyte antigen (HLA) locus. The study was designed to search for HLA susceptibility alleles contributing to the persistence of HPV infection in Mexican women. Methods: A total of 172 subjects were divided into three groups: 1) HPV-persistent patients; 2) HPV-cleared; and 3) HPV-reinfected patients. They were screened for HPV types using a polymerase chain reaction (PCR). PCR-sequence specific oligonucleotide probes (PCR-SSOP) was used for HLA DRB1 and DQB1 typing. Results: We observed that HLA-DQB1*0501 allele might be associated with susceptibility of reinfection with HPV (p = 0.01, OR = 4.9, CI 95% = 1.3 -18.7). Allele frequency of HLA-DRB1*14 was particularly reduced in patients with cancer when compared with the HPV-persistent group (p = 0.04), suggesting that this allele is a possible protective factor for the development of cervical cancer (OR = 2.98). HLA-DRB1*07 might be associated with viral clearance (p = 0.04). Conclusions: Genetic markers for HPV infection susceptibility are different in each population, in Mexicans several HLA-DQB1 alleles might be associated with an enhanced risk for viral persistence. In contrast, DRB1*14, seems to confer protection against cervical cancer. [ABSTRACT FROM AUTHOR]

Evidence suggests an association between autism and immune dysfunction. The associations between human lymphocyte antigen (HLA)-A2, B44, DRβ1∗04 (DR4), C4B, and haplotype B44-SC30-DR4 and autism have been reported in western countries but there is a lack of such information in Asian population. This study aimed to assess the association between HLA-DRB1 allele frequencies and the clinical phenomenology of autism. The sample included 141 participants (male, 87.2%), who were diagnosed with autistic disorder based on clinical assessments and structured interviews using the Chinese version of the Autism Diagnostic Interview-Revised, and 156 healthy controls (male, 38.6%). The HLA-DRB1 alleles were determined by sequencing-based typing method. A subsample of patients (n=39) were assessed for intelligence and neuropsychological functions. The results showed that the pattern of DRB1 allele frequencies was significantly different between patients with autism and the controls (P=0.047). After adjusting for sex by haplotype regression, the frequencies of DR4, DR11, and DR14 were significantly different between patients with autism and healthy controls. In addition, patients with autism and DR4, DR11, or DR14 had different performance on intelligence and neuropsychology tests. Despite a relatively small sample size and a case-control association design, the findings suggest HLA-DRB1 gene might be associated with autism in Han Chinese. The true functional variants associated with autism in our samples remain to be further clarified. It warrants a replication study of a larger family sample and to validate the HLA genetic association with autism and its influence on neuropsychological function. (ClinicalTrials.gov ID: NCT00494754). [ABSTRACT FROM AUTHOR]

Abstract: The pathogenesis of coronary artery disease (CAD) is closely associated with inflammation, in which human leukocyte antigens (HLA), especially HLA-DR molecules, play important roles. However, whether various HLA-DRB1 alleles can contribute differing susceptibility to CAD has not been elucidated. In this study, we demonstrated a significantly lower frequency of HLA-DRB1*12:02:01 in the CAD group (9.82%) than in controls (18.22%) after age adjustment (odds ratio [OR] = 0.489, p = 0.0036). Logistic regression analysis indicated that carriers of HLA-DRB1*12:02:01 exhibited a lower risk of CAD events after adjustment for age, gender, and other confounders (p = 0.014, OR = 0.526 [95% confidence interval 0.314–0.878]). The female carriers of HLA-DRB1*12:02:01 exhibited a much lower risk of CAD events both before (OR = 0.424, p = 0.0387) and after age adjustment (OR = 0.302, p = 0.0058). In another female cohort, the frequency of HLA-DRB1*12:02:01 also differed between the female CAD group (8.23%) and the female controls (18.75%; OR = 0.389, p = 0.0116). Further analysis indicated that HLA-DRB1*12:02:01 was not frequent in participants with premature CAD or more diseased blood vessels. In summary, our data demonstrate that HLA-DRB1*12:02:01 plays a protective role against CAD in southern Han Chinese, especially in females. The mechanism behind the protective effect requires further exploration. [Copyright &y& Elsevier]

Abstract: Sarcoidosis is a multiorgan immune-mediated disease of unknown etiology with varying clinical pictures. We studied 3 genes in the major histocompatibility complex region (HLA-DRB1 and complement C4A and C4B) in patients with resolved disease after a 2-year follow-up (n = 90) and in patients whose disease was still active at that time point (n = 98) and compared them with controls (n = 150). Our primary aim was to detect genetic differences between the patient groups. We observed that the susceptibility allele for sarcoidosis was HLA-DRB1*15:01 (p = 0.011; odds ratio [OR] = 1.67) and the protective allele was HLA-DRB1*01:01 (p = 0.001; OR = 0.43). HLA-DRB1*03:01 was associated with resolving disease when compared with the persistent group (p = 0.011; OR = 2.22). The probability of having resolving disease was even greater if the patient had HLA-DRB1*03:01 and did not have extrapulmonary lesions (p = 0.001; OR = 3.39). By evaluating amino acid variants of the HLA-DRB1 gene, we determined that specific amino acids in pockets 4, 7, and 9 were associated with the prognosis of sarcoidosis. Our results support the importance of HLA-DRB1 as a predisposing gene for sarcoidosis. Particularly, HLA-DRB1*03:01 and polymorphisms of DRB1 pocket residues were associated with a favorable prognosis. Thus, accurate categorization of disease phenotype and HLA-DRB1 sequencing offer a basis for disease course estimation of sarcoidosis. [Copyright &y& Elsevier]

An unanticipated discovery was made while examining genetics of the immune response in patients treated with botulinum neurotoxin (BoNT), which included cervical dystonia (CD) patients. Initial examination of HLA DQA1:DQB1 frequencies revealed an unexpectedly high number of DQA1**0102:DQB1**0604 homozygotes (hz) in the CD patients. We typed the BoNT-treated CD Caucasian subset for HLA-DRB1, DQA1, and DQB1 and succeeded in typing HLA-DRB1, -DQA1, and -DQB1 for 75 of the patients. Two statistical methods found the DQB1 locus associated with CD and one method found a probable association of DQB1**0604. Examination of the allele and haplotype pairing indicated that DQB1**0604 hz comprised most to all of the positive association. Other than this genotype, one other allele, DQB1**0504 contributes to the association of the DQB1 locus. These findings indicate a probable infectious and/or autoimmune component in some CD patients. However, longer distance associations within an extended and conserved DQB1**0604 bearing haplotype leave a possibility that a locus proximal to DQB1 might be involved. [ABSTRACT FROM AUTHOR]

Abstract: Few studies have examined the relationship between human leukocyte antigen (HLA) polymorphisms and adult glioma, particularly at class II loci. We evaluated the association between selected HLA class II polymorphisms and adult glioma in a large, hospital-based case-control study, using unconditional logistic regression. DQB1*06 (OR=1.67, 95% CI=1.17–2.39) and DRB1*13 (OR=1.69, 95% CI=1.08–2.64) alleles were associated with an increased risk of glioma, while the DQB1*05 allele showed an inverse association (OR=0.63, 95% CI=0.43–0.93). These results, which were of borderline significance once controlled for the false discovery rate, suggest a potential role for the DQB1*06, DQB1*05, and DRB1*13 alleles in glioma susceptibility. [Copyright &y& Elsevier]

The immunopolymorphism database (IPD) provides a single nomenclature for alleles at the major histocompatibility complex (MHC) loci for a range of different species. The minimum requirements for inclusion of a sheep class II DRB1 sequence is a submission that includes all polymorphic sites within the second exon from at least two independent polymerase chain reactions (PCR). In order to meet these requirements, we have developed a DNA-based genotyping method for the rapid analysis of allelic diversity at the DRB1 locus in domestic sheep, Ovis aries. Using a series of primers located within introns flanking exon 2 and genomic DNA from a cohort of 214 sheep representing 15 different breeds and crossbreeds, the complete exon 2 sequences of 38 Ovar-DRB1 alleles were obtained. This sequence resource allowed the development of a generic set of locus-specific primers which amplify a fragment that includes all polymorphic sites within the second exon. Bidirectional sequence analysis of the PCR product provides a composite sequence where each polymorphic site is represented by the corresponding International Union of Biochemistry nucleotide code. A Basic Local Alignment Search Tool search of alleles held within the IPD or National Center for Biotechnology Information databases allows individual allele sequences to be identified. Low levels of homozygosity (7.48%) within the cohort and verification of previously genotyped samples confirmed the broad allelic specificity of this method. It improves on currently available methods and is broadly applicable to the analysis of MHC diversity in studies investigating linkages with resistance or susceptibility to disease. [ABSTRACT FROM AUTHOR]

The origin of allelic polymorphism in genes of the major histocompatibility complex represents a central topic in evolutionary genetics as it is probably the most polymorphic region in the nuclear genome of vertebrates. Accordingly, the analyses of genetic variability at these loci provide evidence complementary to the population genetics studies based on neutral loci. In this study, four wild boar populations, two from Italy (Florence region and Castelporziano Presidential Reserve, outside Rome) and one each from Hungary and Poland, were characterized at a highly polymorphic fragment including part of intron 1 and exon 2 of swine leukocyte antigen (SLA) class II DRB1 gene by direct sequencing and by cloning. Excluding the false alleles, a total of 18 different sequences were observed in 57 individuals. The high ratio of nonsynonymous (dN) vs synonymous (dS) substitution rates in the peptide-binding region supports the hypothesis that balancing selection is operating at this locus. A duplication event at the DRB1 gene was documented only in one Italian population with both copies being putatively active. This is the first evidence of a polymorphism for the number of copies of an SLA gene. [ABSTRACT FROM AUTHOR]

Previous studies initiated defining the role of host genetics in influencing the outcome of exposure to ovine progressive pneumonia virus. However, specific genes influencing host control of virus replication and disease progression have not been identified. This study, using 383 ewes of the Columbia, Polypay, and Rambouillet breeds, tested the hypothesis that host control of OPPV as measured by provirus levels in the peripheral blood associates with certain breeds and MHC class II Ovis aries ( Ovar) -DRB1 expressed alleles. Rambouillet ewes were less likely to have measurable provirus levels as compared to Columbia ewes at ages 5 and 6 ( P value < 0.02), and they exhibited lower provirus levels when compared to both Columbia and Polypay ewes of the same ages ( P value < 0.05). The presence of DRB1*0403- or DRB1*07012-expressed alleles were significantly associated ( P value = 0.019 and 0.0002, respectively) with lower OPP provirus levels but only were only found in 11% of the ewe flock. Analysis of each segregating amino acid in the β1 domain of DR β-chain revealed that amino acids Y31, T32, N37, T51, Q60, or N74 significantly associated ( P value range = 0.0003–0.018) with lower OPP provirus levels, whereas amino acids H32, A38, or I67 associated ( P value range = 0.013–0.043) with higher OPP provirus levels. These results suggest that Ovar-DRB1 contributes as one host genetic factor that controls OPP provirus levels, but does not fully account for the breed-specific OPP proviral differences. [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in Western countries, but its incidence is low in Asian populations. In the present study we determined the frequency of DRB1 and DQB1 alleles in 87 Iranian CLL patients and 100 healthy controls using a polymerase chain reaction (PCR) technique. An increased frequency of DRB1*07 (p = 0.04), DQB1*06 (p = 0.01) alleles, and DRB1*13/DQB1*03 haplotype (p = 0.01) and decreased frequency of the DQB1*03 (p = 0.01) allele were observed in our patients compared with healthy controls. Comparison between patients with indolent (n = 42) and progressive (n = 38) disease revealed a significant increase in DRB1*04 and DRB5 alleles in progressive patients. Similarly, a higher frequency of DRB5 (p = 0.01) allele was observed in CD38+ compared with CD38- patients. Classification of the patients into immunoglobulin variable region heavy-chain genes mutated and unmutated subtypes did not reveal significant differences for the expression of any of the HLA alleles or haplotypes between these two subtypes. Our findings observed in an Iranian population indicate that CLL could be associated with distinct HLA class II alleles and haplotypes of which the DQB1*06 allele and DRB1*13/DQB1*03 haplotype have not already been reported in CLL patients from other ethnic backgrounds. Some HLA class II alleles may contribute to disease progression in CLL. [Copyright &y& Elsevier]

The human leukocyte antigen (HLA) system could play an essential role in multiple myeloma (MM) disease control. This report describes the results comparing HLA-DRB1 phenotypic frequencies in 181 MM patients (53 smoldering/indolent MM and 128 symptomatic MM patients) and healthy individuals. Higher DRB1*01 phenotypic frequencies were found in the smoldering patients compared with symptomatic MM patients (38% vs 14%, P = 0.001) and with the healthy individuals (38% vs 22%, P = 0.01). Additionally, higher DRB1*07 phenotypic frequencies were found in symptomatic MM compared with control population (38% vs 28%, P = 0.01). The present data suggest that HLA-DRB1*01 individuals may have a better ability to efficiently present myeloma-related antigens to immunocompetent cells, which could favor a better immune response against the tumor. This would translate into a more appropriate disease control associated with more indolent disease and prolonged survival. [ABSTRACT FROM AUTHOR]

The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR) = 2.20, Pc = 0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR = 2.31, Pc = 0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese. [ABSTRACT FROM AUTHOR]

Determining the genomic organization of the Ovis aries ( Ovar) major histocompatibility complex class IIa region is essential for future functional studies related to antigen presentation. In this study, a bacterial artificial chromosome (BAC) library of genomic DNA from peripheral blood leukocytes (PBL) of a Rambouillet ram was constructed, and BAC clone consisting of the major histocompatibility complex (MHC) class II DQB2, DQA2, DQB1, DQA1, and DRB1 loci was identified and completely sequenced. The BAC clone consists of 160,889 bp of finished sequence with the loci arranged in the following order: DQB2, DQA2, DQB1, DQA1, and DRB1 with 14.3, 25, 6.6, and 40.9 Kb spanning between the loci, respectively. All five of these loci were transcribed in the animal used to generate the MHC class II BAC clone. Repeat or retrotransposable elements along with MHC class II cis promoter elements consisting of S, X, and Y boxes were identified in the sequence. In addition, 16 non-coding conserved sequences amongst primates, carnivores, and ruminants were identified ( p < 0.001). These conserved sequences include binding sites for transcription factors with known roles in immune cells, and they provide a basis for further functional investigation of the genes in this region. This is the first ruminant finished sequence of the DQB2-DRB1 region, and this sequence information will aid in whole genome and transcriptome analyses of MHC class II. [ABSTRACT FROM AUTHOR]

Background: Recognition of HLA alleles is useful in transplantation and in anthropological and disease studies. Acute lymphoblastic leukemia (ALL) is the most common blood cancer. It is now generally agreed that both genetic and environmental factors play an interactive role in the development of ALL disease. It is unknown whether there exists a restriction to certain MHC genotypes in leukemia like ALL. Methods: Genetic construct of HLA DRB1 was studied in Iranian normal populations and in patients with acute lymphoblastic leukemia using PCR-SSP method. Results: It was shown that the most common allele in DRB1 locus in normal population was DRB1∗11 (20%), whereas DRB1∗09 was the least frequent allele (0.9%). Additionally, this study presented the results of HLA-DRB1 typing in 106 ALL patients and compared them with normal individuals. Comparison of the results between the normal population and the patient group revealed that there was allelic association between the DRB1∗13 and the disease. Results showed that the difference between the frequencies of DRB1∗13 in patients and normal individuals was significant (p = 0.04), but there was a moderate difference among the frequencies of DRB1∗04, ∗07, and ∗09 in childhood (0–15 years) ALL. The frequencies of DRB1∗13, ∗04, and ∗07 in patients were 2.5, 16, 4.5% and, in normal individuals, were 11.4, 10, and 8.3%, respectively. Conclusions: It should be concluded that DRB1∗13, which showed a decrease in patients, should be protective against acute lymphoblastic leukemia (ALL), whereas DRB1∗04, which was moderately increased in patients, could be considered a susceptible allele for childhood ALL. [Copyright &y& Elsevier]

The HLA region harbors some of the most polymorphic loci in the human genome. Among them is the class II locus HLA-DRB1, with more than 400 known alleles. The age of the polymorphism and the rate at which new alleles are generated at HLA loci has caused much controversy over the years. Previous studies have mostly been restricted to the 270 base pairs that constitute the second exon and represent the most variable part of the gene. Here, we investigate the evolutionary history of the HLA-DRB1 locus on the basis of an analysis of 15 genomic full-length alleles (10–15 kb). In addition, the variation in 49 complete coding sequences and 322 exon 2 sequences were analyzed. When excluding exon 2 from the analysis, the diversity at the synonymous sites was found to be similar to the intron diversity. The overall diversity in noncoding region was also similar to the genome average. The DRB1* 03 lineage has been found in human, chimpanzee, bonobo, gorilla, and orangutan. An ancestral “proto HLA-DRB1*03 lineage” appeared to have diverged in the last 5 million years into the human-specific lineages *08, *11, *13, and *14. With exception to exon 2, both the coding- and the noncoding diversity suggests a recent origin (<1 million years ago) for most of the alleles at the HLA-DRB1 locus. Sites encoding for amino acids involved in antigen binding [antigen recognizing sites (ARS)] appear to have a more ancient origin. Taken together, the recent origin of most alleles, the high diversity between allelic lineages, and the ancient origin of sequence motifs in exon 2, is consistent with a relatively rapid generation of novel alleles by gene conversion like events. [ABSTRACT FROM AUTHOR]

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