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Is multiple sclerosis progression associated with the HLA-DR15 haplotype?

ABSTRACT: Background:The prevalence of multiple sclerosis is associated with the major histocompatibility complex class II DR15 haplotype HLA-DRB1*15:01?HLA-DRB5*01:01. Objective:To assess whether multiple sclerosis progression is associated with the main susceptibility haplotype HLA-DRB1*15:01?HLA-DRB5*01:01. Methods:Patients (n?=?1230) and healthy controls (n?=?2110) were genotyped for HLA-DRB1 and HLA-DRB5. The baseline Expanded Disability Status Scale (EDSS) score was determined and patients were followed for at least 3 years. Results:After follow-up of the consecutive cohort 349 patients were classified as having clinical isolated syndrome and 881 patients as having multiple sclerosis. The susceptibility allele HLA-DRB1*15:01 was more frequent in clinical isolated syndrome (odds ratio 1.56) and multiple sclerosis (odds ratio 3.17) compared to controls. HLA- DRB1*15:01 was the only enriched HLA-DRB1 allele in multiple sclerosis patients. Comparison of clinical characteristics between HLA-DRB1*15:01?HLA-DRB5*01:01 negative and positive patients with multiple sclerosis showed that baseline EDSS score, disease duration and frequency of the category secondary progressive multiple sclerosis with relapse were increased in the HLA-DRB1*15:01?HLA-DRB5*01:01 positive group. Conclusion:The study confirmed HLA-DRB1*15:01 and HLA-DRB5*01:01 as the main susceptibility alleles and showed weak indirect evidence for a role in progression of the disease.

SUBMITTER: Sturner KH

PROVIDER: S-EPMC6902395 | biostudies-literature | 2019 Oct-Dec

REPOSITORIES: biostudies-literature

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Is multiple sclerosis progression associated with the HLA-DR15 haplotype?

Stürner Klarissa Hanja KH Siembab Inessa I Schön Gerhard G Stellmann Jan-Patrick JP Heidari Nika N Fehse Boris B Heesen Christoph C Eiermann Thomas H TH Martin Roland R Binder Thomas Mc TM

Multiple sclerosis journal - experimental, translational and clinical 20191001 4

<h4>Background</h4>The prevalence of multiple sclerosis is associated with the major histocompatibility complex class II DR15 haplotype HLA-DRB1*15:01∼HLA-DRB5*01:01.<h4>Objective</h4>To assess whether multiple sclerosis progression is associated with the main susceptibility haplotype HLA-DRB1*15:01∼HLA-DRB5*01:01.<h4>Methods</h4>Patients (<i>n</i> = 1230) and healthy controls (<i>n</i> = 2110) were genotyped for HLA-DRB1 and HLA-DRB5. The baseline Expanded Disability Status Scale (EDSS) score w ...[more]

PMID: 31839982

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Project description:Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from 'hitchhiking' alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.

Project description:C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis that serves as a direct regulator of the human leukocyte antigen class II pathway in antigen-presenting cells. These findings are a first step in coupling multiple sclerosis-associated genes to the regulation of the strongest genetic factor in multiple sclerosis, human leukocyte antigen class II.

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Is multiple sclerosis progression associated with the HLA-DR15 haplotype?

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Is multiple sclerosis progression associated with the HLA-DR15 haplotype?

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