Class II HLA interactions modulate genetic risk for multiple sclerosis.
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ABSTRACT:
SUBMITTER: Moutsianas L
PROVIDER: S-EPMC4874245 | biostudies-literature | 2015 Oct
REPOSITORIES: biostudies-literature
Publications
Class II HLA interactions modulate genetic risk for multiple sclerosis.
Moutsianas Loukas L Jostins Luke L Beecham Ashley H AH Dilthey Alexander T AT Xifara Dionysia K DK Ban Maria M Shah Tejas S TS Patsopoulos Nikolaos A NA Alfredsson Lars L Anderson Carl A CA Attfield Katherine E KE Baranzini Sergio E SE Barrett Jeffrey J Binder Thomas M C TMC Booth David D Buck Dorothea D Celius Elisabeth G EG Cotsapas Chris C D'Alfonso Sandra S Dendrou Calliope A CA Donnelly Peter P Dubois Bénédicte B Fontaine Bertrand B Fugger Lars L Goris An A Gourraud Pierre-Antoine PA Graetz Christiane C Hemmer Bernhard B Hillert Jan J Kockum Ingrid I Leslie Stephen S Lill Christina M CM Martinelli-Boneschi Filippo F Oksenberg Jorge R JR Olsson Tomas T Oturai Annette A Saarela Janna J Søndergaard Helle Bach HB Spurkland Anne A Taylor Bruce B Winkelmann Juliane J Zipp Frauke F Haines Jonathan L JL Pericak-Vance Margaret A MA Spencer Chris C A CCA Stewart Graeme G Hafler David A DA Ivinson Adrian J AJ Harbo Hanne F HF Hauser Stephen L SL De Jager Philip L PL Compston Alastair A McCauley Jacob L JL Sawcer Stephen S McVean Gil G
Nature genetics 20150907 10
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence ...[more]
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Project description:Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4 × 10(-06)), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6 × 10(-05)), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.
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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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Project description:BackgroundThe etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular, are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS.MethodsHLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N?=?117) and age- and sex-matched healthy controls (HC; N?=?89).ResultsSignificantly higher DNA viral loads (p?=?0.048) and EBNA-1 antibody titer (p?=?0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p?=?0.02) and HLA-DRB1*15+ (p?=?0.02) MS patients, whereas it was lower in HLA-A*02+ (p?=?0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p?<?0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p?=?0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution.ConclusionsHost HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.
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Project description:Multiple Sclerosis (MS) displays a heterogeneous clinical onset and progression, which are mostly unpredictable, but demyelination of the central nervous system (CNS) leads to substantial deficits of sensory, motor, autonomic, and neurocognitive functions. Considering all genetic studies on MS, including the advanced genome-wide association studies, the risk linked to HLA alleles remains the highest among other susceptibility genetic variants. However, given the genetic variability of HLA alleles in different ethnic groups, we conducted a systematic review of reviews and meta-analyses aiming at summarizing all the results on the association between MS and HLA class II genes. We systematically searched meta-analyses and systematic reviews dealing with MS and HLA in all ethnicities. From 154 records, we included 5 articles collecting HLA data from 15,232 MS patients and 24,194 ethnically matched controls. DRB1∗15 (OR ranging from 1.39 in Chinese Han to 2.59 in Caucasians) and DQB1∗06:02 (OR ranging from 1.91 in Caucasians to 2.49 in Colombian) alleles confer an increased risk for MS transethnically (Caucasians, Chinese, South Americans, Carribeans, Middle Easterners, Japanese, and North Africans). DRB1∗01, DRB1∗09, DRB1∗11, DRB1∗12, and DRB1∗16 alleles were protective, in agreement with the type of amino-acidic (aa) residues (ranging from position 9 to 90) included in pockets 1, 4, 6, 7, and 9, which are most involved in peptide presentation. Changes in aa residues affect the capability of HLA molecules in binding myelin peptides. DQB1∗06:02 risk allele seems to be the most interesting target as humanized mice expressing only DQB1∗06:02 develop MS-like disease mediated by autoimmune reactions against myelin oligodendrocytic basic protein that stabilizes the myelin. Our summary of results from a high number of patients and controls suggests that allelic variants from both DQB1 and DRB1 genes are equally involved in MS susceptibility/protection transethnically.
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Project description:ImportanceAlthough multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive.ObjectivesTo investigate whether MS risk-associated HLA alleles also affect disease phenotypes.Design, setting, and participantsA cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015.Main outcomes and measuresCumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set.ResultsOf the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0-1.4] and 0 [-0.3 to 0.5], respectively; P = 1.8 × 10-27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (standard β = -1.20 × 10-1; P = 1.7 × 10-2 and standard β = -1.67 × 10-1; P = 2.3 × 10-4, respectively), which were driven mainly by the HLA-DRB1*15:01 haplotype. In addition, we observed the distinct role of the HLA-A*24:02-B*07:02-DRB1*15:01 haplotype among the other common DRB1*15:01 haplotypes and a nominally protective effect of HLA-B*44:02 to the subcortical gray atrophy (standard β = -1.28 × 10-1; P = 5.1 × 10-3 and standard β = 9.52 × 10-2; P = 3.6 × 10-2, respectively).Conclusions and relevanceWe confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits.
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