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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

ABSTRACT: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

SUBMITTER: International Multiple Sclerosis Genetics Consortium

PROVIDER: S-EPMC3182531 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Sawcer Stephen S Hellenthal Garrett G Pirinen Matti M Spencer Chris C A CC Patsopoulos Nikolaos A NA Moutsianas Loukas L Dilthey Alexander A Su Zhan Z Freeman Colin C Hunt Sarah E SE Edkins Sarah S Gray Emma E Booth David R DR Potter Simon C SC Goris An A Band Gavin G Oturai Annette Bang AB Strange Amy A Saarela Janna J Bellenguez Céline C Fontaine Bertrand B Gillman Matthew M Hemmer Bernhard B Gwilliam Rhian R Zipp Frauke F Jayakumar Alagurevathi A Martin Roland R Leslie Stephen S Hawkins Stanley S Giannoulatou Eleni E D'alfonso Sandra S Blackburn Hannah H Martinelli Boneschi Filippo F Liddle Jennifer J Harbo Hanne F HF Perez Marc L ML Spurkland Anne A Waller Matthew J MJ Mycko Marcin P MP Ricketts Michelle M Comabella Manuel M Hammond Naomi N Kockum Ingrid I McCann Owen T OT Ban Maria M Whittaker Pamela P Kemppinen Anu A Weston Paul P Hawkins Clive C Widaa Sara S Zajicek John J Dronov Serge S Robertson Neil N Bumpstead Suzannah J SJ Barcellos Lisa F LF Ravindrarajah Rathi R Abraham Roby R Alfredsson Lars L Ardlie Kristin K Aubin Cristin C Baker Amie A Baker Katharine K Baranzini Sergio E SE Bergamaschi Laura L Bergamaschi Roberto R Bernstein Allan A Berthele Achim A Boggild Mike M Bradfield Jonathan P JP Brassat David D Broadley Simon A SA Buck Dorothea D Butzkueven Helmut H Capra Ruggero R Carroll William M WM Cavalla Paola P Celius Elisabeth G EG Cepok Sabine S Chiavacci Rosetta R Clerget-Darpoux Françoise F Clysters Katleen K Comi Giancarlo G Cossburn Mark M Cournu-Rebeix Isabelle I Cox Mathew B MB Cozen Wendy W Cree Bruce A C BA Cross Anne H AH Cusi Daniele D Daly Mark J MJ Davis Emma E de Bakker Paul I W PI Debouverie Marc M D'hooghe Marie Beatrice MB Dixon Katherine K Dobosi Rita R Dubois Bénédicte B Ellinghaus David D Elovaara Irina I Esposito Federica F Fontenille Claire C Foote Simon S Franke Andre A Galimberti Daniela D Ghezzi Angelo A Glessner Joseph J Gomez Refujia R Gout Olivier O Graham Colin C Grant Struan F A SF Guerini Franca Rosa FR Hakonarson Hakon H Hall Per P Hamsten Anders A Hartung Hans-Peter HP Heard Rob N RN Heath Simon S Hobart Jeremy J Hoshi Muna M Infante-Duarte Carmen C Ingram Gillian G Ingram Wendy W Islam Talat T Jagodic Maja M Kabesch Michael M Kermode Allan G AG Kilpatrick Trevor J TJ Kim Cecilia C Klopp Norman N Koivisto Keijo K Larsson Malin M Lathrop Mark M Lechner-Scott Jeannette S JS Leone Maurizio A MA Leppä Virpi V Liljedahl Ulrika U Bomfim Izaura Lima IL Lincoln Robin R RR Link Jenny J Liu Jianjun J Lorentzen Aslaug R AR Lupoli Sara S Macciardi Fabio F Mack Thomas T Marriott Mark M Martinelli Vittorio V Mason Deborah D McCauley Jacob L JL Mentch Frank F Mero Inger-Lise IL Mihalova Tania T Montalban Xavier X Mottershead John J Myhr Kjell-Morten KM Naldi Paola P Ollier William W Page Alison A Palotie Aarno A Pelletier Jean J Piccio Laura L Pickersgill Trevor T Piehl Fredrik F Pobywajlo Susan S Quach Hong L HL Ramsay Patricia P PP Reunanen Mauri M Reynolds Richard R Rioux John D JD Rodegher Mariaemma M Roesner Sabine S Rubio Justin P JP Rückert Ina-Maria IM Salvetti Marco M Salvi Erika E Santaniello Adam A Schaefer Catherine A CA Schreiber Stefan S Schulze Christian C Scott Rodney J RJ Sellebjerg Finn F Selmaj Krzysztof W KW Sexton David D Shen Ling L Simms-Acuna Brigid B Skidmore Sheila S Sleiman Patrick M A PM Smestad Cathrine C Sørensen Per Soelberg PS Søndergaard Helle Bach HB Stankovich Jim J Strange Richard C RC Sulonen Anna-Maija AM Sundqvist Emilie E Syvänen Ann-Christine AC Taddeo Francesca F Taylor Bruce B Blackwell Jenefer M JM Tienari Pentti P Bramon Elvira E Tourbah Ayman A Brown Matthew A MA Tronczynska Ewa E Casas Juan P JP Tubridy Niall N Corvin Aiden A Vickery Jane J Jankowski Janusz J Villoslada Pablo P Markus Hugh S HS Wang Kai K Mathew Christopher G CG Wason James J Palmer Colin N A CN Wichmann H-Erich HE Plomin Robert R Willoughby Ernest E Rautanen Anna A Winkelmann Juliane J Wittig Michael M Trembath Richard C RC Yaouanq Jacqueline J Viswanathan Ananth C AC Zhang Haitao H Wood Nicholas W NW Zuvich Rebecca R Deloukas Panos P Langford Cordelia C Duncanson Audrey A Oksenberg Jorge R JR Pericak-Vance Margaret A MA Haines Jonathan L JL Olsson Tomas T Hillert Jan J Ivinson Adrian J AJ De Jager Philip L PL Peltonen Leena L Stewart Graeme J GJ Hafler David A DA Hauser Stephen L SL McVean Gil G Donnelly Peter P Compston Alastair A

Nature 20110810 7359

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex f ...[more]

PMID: 21833088

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Project description:BackgroundMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a well-established genetic contribution to susceptibility. Over 200 genetic regions have been linked to the inherited risk of developing MS, but the disease-causing variants and their functional effects at the molecular level are still largely unresolved. We hypothesised that MS-associated single-nucleotide polymorphisms (SNPs) affect the recognition and enzymatic cleavage of primary microRNAs (pri-miRNAs).MethodsOur study focused on 11 pri-miRNAs (9 primate-specific) that are encoded in genetic risk loci for MS. The levels of mature miRNAs and potential isoforms (isomiRs) produced from those pri-miRNAs were measured in B cells obtained from the peripheral blood of 63 MS patients and 28 healthy controls. We tested for associations between SNP genotypes and miRNA expression in cis using quantitative trait locus (cis-miR-eQTL) analyses. Genetic effects on miRNA stem-loop processing efficiency were verified using luciferase reporter assays. Potential direct miRNA target genes were identified by transcriptome profiling and computational binding site assessment.FindingsMature miRNAs and isomiRs from hsa-mir-26a-2, hsa-mir-199a-1, hsa-mir-4304, hsa-mir-4423, hsa-mir-4464 and hsa-mir-4492 could be detected in all B-cell samples. When MS patient subgroups were compared with healthy controls, a significant differential expression was observed for miRNAs from the 5' and 3' strands of hsa-mir-26a-2 and hsa-mir-199a-1. The cis-miR-eQTL analyses and reporter assays pointed to a slightly more efficient Drosha-mediated processing of hsa-mir-199a-1 when the MS risk allele T of SNP rs1005039 is present. On the other hand, the MS risk allele A of SNP rs817478, which substitutes the first C in a CNNC sequence motif, was found to cause a markedly lower efficiency in the processing of hsa-mir-4423. Overexpression of hsa-mir-199a-1 inhibited the expression of 60 protein-coding genes, including IRAK2, MIF, TNFRSF12A and TRAF1. The only target gene identified for hsa-mir-4423 was TMEM47.InterpretationWe found that MS-associated SNPs in sequence determinants of pri-miRNA processing can affect the expression of mature miRNAs. Our findings complement the existing literature on the dysregulation of miRNAs in MS. Further studies on the maturation and function of miRNAs in different cell types and tissues may help to gain a more detailed functional understanding of the genetic basis of MS.FundingThis study was funded by the Rostock University Medical Center (FORUN program, grant: 889002), Sanofi Genzyme (grant: GZ-2016-11560) and Merck Serono GmbH (Darmstadt, Germany, an affiliate of Merck KGaA, CrossRef Funder ID: 10.13039/100009945, grant: 4501860307). NB was supported by the Stiftung der Deutschen Wirtschaft (sdw) and the FAZIT foundation. EP was supported by the Landesgraduiertenförderung Mecklenburg-Vorpommern.

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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Publications

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

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