Genetic determinants of Multiple Sclerosis susceptibility in diverse ancestral backgrounds
Bette JacobsLuisa SchalkEmily Tregaskis-DanielsAntonio ScalfariAshwini NandoskarAngie DunneBruno GranCharles A. MeinCharlotte SellersCord SpilkerDavid RogElisa VisentinElizabeth Lindsey BezzinaEmeka UzochukwuEmma TallantyreEva WozniakEve SacreGhaniah Hassan‐SmithHelen FordJade HarrisJoan BradleyJoshua BreedonJudith BrookeKarim L. KreftKatila GeorgeMaria PapachatzakiMartin O’MalleyMichelle PeterMiriam MattoscioNeisha RhuleNikos EvangelouNimisha VinodOuti QuinnRamya ShamjiRashmi KaimalRebecca L. BoultonRiffat TanveerRod MiddletonRoxanne MurrayRuth BellfieldSadid HoqueShakeelah PatelSonia RajStephanie GumusStephanie MitchellStephen SawcerTarunya ArunTatiana PogrebanTerri-Louise BrownThamanna BegumVeronica AntoineWaqar RashidGrace FawehinmiClaire ReidyShanaz BegumS. HealeyH.T. CumminsKelly WestwoodDorothy M. SpencerShegufta FarooqKatharine HardingSarah WilliamsG. RadfordSimon WhiteNathan Alldred-DouglasLinford FernandesAdil HarroudJacob L. McCauleyAshley BeechamNicolas VinceNayane S. B. SilvaHuw R. MorrisEli SilberGavin GiovannoniAlastair J. NoyceRuth Dobson
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The genetic architecture of Multiple Sclerosis (MS) susceptibility has been extensively assessed in populations of European ancestry. Greater ancestral diversity in genetic analyses of MS susceptibility is needed to improve the utility of Multiple Sclerosis genetic risk scores, fine map causal variants underlying established associations, and thereby enhance the identification of drug targets. Here we report findings from a genetic study of Multiple Sclerosis susceptibility in an ancestrally-diverse United Kingdom-based cohort. Participants with Multiple Sclerosis were recruited via clinical sites, an online platform, and through the United Kingdom Multiple Sclerosis Register. Phenotype data were gathered using a standardised questionnaire. DNA was extracted from saliva samples obtained remotely or in person, and participants were genotyped using a commercial genotyping array. Following imputation, cases were combined with controls from the United Kingdom Biobank and subjected to stringent quality control and genetic ancestry inference. We defined two broad ancestral groups of South Asian and African ancestry. We performed within-ancestry case-control genome-wide association studies of Multiple Sclerosis susceptibility using logistic models accounting for population structure and sex. We examined both single nucleotide variants and imputed classical Human Leukocyte Antigen alleles. We curated two ancestrally-matched case-control genetic datasets (South Asian ancestry: NCase=175, NControl=6744; African ancestry: NCase=113, NControl=5177). In both ancestries, we found genetic variants within the Major Histocompatibility Complex associated with Multiple Sclerosis susceptibility (South Asian ancestry: lead variant chr6:32600515:G:A on hg38 co-ordinates, Odds Ratio=1.84, nearest gene HLA-DRB1, P=4.6x10-6; African ancestry: lead variant chr6:29919337:A:G, Odds Ratio=2.24, nearest gene HLA-A P=4.3x10-5). European-ancestry susceptibility alleles were over-represented in cases from both ancestries, with the degree of concordance stronger for the South Asian (ρ=0.31, P=8.1x10-6) than African (ρ=0.1, P=0.3) ancestry cohort. European-derived genetic risk scores performed better than chance but less well than in European ancestry cohorts, explaining 1.6% (South Asian, P=1.0x10-4) and 0.5% (African, P=0.08) of the liability to MS. The genetic architecture of MS susceptibility shows strong concordance across ancestral groups suggesting shared disease mechanisms. Larger studies in diverse populations are likely to enhance our understanding of how genetic variation contributes to MS susceptibility in people of all ancestral backgrounds.Cite
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Multiple sclerosis is a multifactorial and heterogeneous neurological disease; hence, several experimental animal models had to be developed to mimic the different features of human pathology. Three main classes of animal models have been developed: experimental autoimmune encephalomyelitis (EAE), cuprizone intoxication, and Theiler's murine encephalomyelitis virus (TMEV) infection. The EAE model is the most versatile as it allows the reproduction of different patterns of multiple sclerosis; it is mostly relevant for relapsing-remitting multiple sclerosis and has allowed the development of several first-line, disease-modifying drugs for the treatment of multiple sclerosis. The other two models are less flexible than the EAE model and, to date, have not led to the discovery of any clinically relevant therapies. The cuprizone model mostly mimics the acute and chronic courses of multiple sclerosis, and it may represent a useful tool to develop novel therapies to protect oligodendrocytes and stimulate remyelination. Finally, the TMEV infection is the reference model to specifically study viral-mediated mechanisms of acute and primary progressive multiple sclerosis.
Remyelination
Encephalomyelitis
Demyelinating disease
Animal model
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Background: There is a growing need for biomarkers that can help in early diagnosis of multiple sclerosis (MS) and in recognizing patients with MS activity.Moreover, many studies are recently focusing on biomarkers that may help in diagnosis of the transition from relapsing remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS).Circulating microRNAs (miRNAs) are now considered promising biomarkers.Objectives: Studying the role of plasma miRNA-145 and miRNA-484 in the diagnosis of MS, disease activity and in diagnosing the transition from RRMS to SPMS.Patients and Methods: Forty-six subjects of both sexes were included, 31 patients with MS )21 with RRMS, 8 with SPMS and Two patients with primary progressive multiple sclerosis (PPMS)) and 15 healthy controls.Expression analysis of plasma miRNAs; miR-145 and miR-484 were assessed by real-time quantitative polymerase chain reaction (PCR) after miRNA extraction.Results: MicroRNAs 145 and 484 could significantly discriminate between MS cases and controls, with best cut-off values > 0.6 and > 1.7 respectively.They could also significantly discriminate between active and inactive MS cases, with best cut-off values > 0.8 and > 2 respectively.Plasma miRNA-145 could discriminate between RRMS and SPMS cases, with best cut-off value ≤1.4.Conclusion: Plasma miRNAs 145 and 484 might be used as promising biomarkers for early diagnosis of MS and in diagnosis of disease activity.Plasma miRNA-145 could be also helpful in diagnosis of the transition from RRMS to SPMS.
Relapsing remitting
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Cladribine
Relapsing remitting
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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多発性硬化症（multiple sclerosis：MS）は，本邦の指定難病の一つに定められる中枢神経系の炎症性脱髄疾患である．時間的および空間的に多発する組織硬化を特徴とし，病変部に応じた症状を示す．典型的には再発と寛解を繰り返しながら神経症状が進行し，根治療法は未だ存在しない．MS患者検体やMS動物モデルである実験的自己免疫性脳脊髄炎（experimental autoimmune encephalomyelitis：EAE）を用いた多くの研究により，その本態は中枢神経系の髄鞘タンパク質を標的とした自己免疫疾患であることが明らかとなっている．病態形成には獲得免疫である自己反応性T細胞が中心的な役割を果たしており，近年の研究成果によりB細胞の役割も注目を集めている．MSは再発寛解型MSと進行型MSに分類され，再発寛解型MSに対してはこれらの獲得免疫を標的とする多くの疾患修飾薬が開発されている．進行型MSに対する治療薬はここ数年で承認が始まったばかりであり，神経障害が蓄積する進行期に有効な治療法の確立が待ち望まれている．進行型MSの病態では，獲得免疫だけでなく自然免疫やグリア細胞が免疫病態の重要な構成要素として認知されつつあるが，免疫細胞と神経細胞，グリア細胞間のクロストークの分子機序には未だ不明な点を多く残している．本稿では，MSの病態，および免疫細胞を標的する疾患修飾薬について概説するとともに，EAEを用いた我々の研究成果を交えてアストロサイトによるMS病態の制御機構について紹介する．
Pathogenesis
Encephalomyelitis
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Determining patients' perceptions of multiple sclerosis, a disease with varying symptoms and prognosis for each individual, can significantly contribute to directing care and treatment. Metaphors may be an opportunity to determine perceptions of this unique illness experience. The aim of this study was to reveal the perceptions of patients with multiple sclerosis about "multiple sclerosis" through metaphors.
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Demyelinating disease
Relapsing remitting
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Reports on fatty acids levels in multiple sclerosis remain inconclusive.To determine the erythrocyte membrane fatty acid levels in multiple sclerosis patients and correlate with Kurtzke Expanded Disability Status Scale.Fatty acid composition of 31 multiple sclerosis and 30 control individuals were measured by gas chromatography.The membrane phosphatidylcholine C20:4n - 6 concentration was lower in the multiple sclerosis patients when compared to that of the control group, P = 0.04 and it correlated inversely with the EDSS and FSS.Decrease in C20:4n - 6 in the erythrocyte membrane could be an indication of depleted plasma stores, and a reflection of disease severity.
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