Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Andlauer, Till F. M.; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew T.; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, M.; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A.; Loleit, Verena; Luessi, Felix; Meuth, Sven G.; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan‐Patrick; Stürner, Klarissa Hanja; Tackenberg, Björn; Bergh, Florian Then; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K.; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O.; Dankowski, Theresa; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B.; Berger, Klaus; Bertram, Lars; Franke, André; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl‐Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M.; Meitinger, Thomas; Moebus, Susanne; Müller‐Nurasyid, Martina; Nöthen, Markus M.; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Mélanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Żołędziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller‐Myhsok, Bertram

doi:10.1126/sciadv.1501678

Cited by 127 publications

(128 citation statements)

References 78 publications

(142 reference statements)

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“…When inherited in trans to HLA-DRB1*08:01, this allele can result in a higher MS risk. In contrast, if inherited in trans to HLA-DRB1*14:01, it can result in a lower MS risk [5,11]. Intriguingly, inheritance of HLA-A*02:01 was reported to protect against MS, possibly through negative selection of pathogenic T-cells in the thymus [11].…”

Section: Dendritic Cells (Dc)mentioning

confidence: 99%

“…Actually, several MHC molecules have been associated with MS susceptibility. Important examples include: HLA-DRB1*15:01 (OR=5.8), HLA-A*02:01 (OR=0.63), HLA-B*38:01 (OR=0.36), HLA-DRB1*13:03 (OR=1.96), HLA-DRB1*02/HLA-DQB1*06:02 (OR=4.6), HLA-C*05, HLA-DRB1*03:01 (OR=2.01), HLA-DPB1*03:01 (OR=1.33), and HLA-DRB1*08:01 (OR=1.63) [5][6][7][8][9][10].…”

Section: Dendritic Cells (Dc)mentioning

confidence: 99%

“…Another interesting molecule that co-localized with MHC class II on DC and was found to be associated with MS is CLEC16A (p<6.30 × 10 −14 , OR>1.15) [5,15]. This molecule has been recently found to regulate the pathway of MHC class II endosome formation and trafficking in DC [16].…”

Section: Dendritic Cells (Dc)mentioning

confidence: 99%

“…It seems that patients express higher levels of CD58 during the remission phase of the disease. Looking at the molecular level, three variants of the CD58 gene (rs12044852, rs1335532 and rs2300747) have been associated with an increased risk of MS (p<9.71 × 10 -4 , OR>1.18) [5][6]11,15,41]. The rs2300747 AA was reported to correlate with lower CD58 expression in the relapsing phases of the disease [42].…”

Section: Regulatory T Cells (Treg)mentioning

confidence: 99%

“…If anything, this could explain the lower number of Tregs in MS, a result of an miR-223-NF-ĸB mis-regulated pathway. Recently, DLEU1, another regulator of the NF-ĸB pathway, has been associated with MS susceptibility (p=9.95 × 10 -9 , OR=0.86) [5].…”

Section: Regulatory T Cells (Treg)mentioning

confidence: 99%

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Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

Eiman¹

2016

Immunome Res

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Multiple sclerosis (MS) is a complex, multifactorial autoimmune disorder of the central nervous system (CNS) that causes inflammation, demyelination and neurodegeneration. The increased prevalence of this disease in Arabian Gulf Countries (AGCs) has captivated the author. The following is a deliberative review of the disease with respect to its molecular basis. Briefly, it considers disease pathophysiology though the molecular composition of the cell; the genome, epigenome and mitochondrial genome; and relates these factors to environmental, etiological factors, including: vitamin D, UVR, EBV infection, smoking and obesity. All in all, this review aims to explain the reasons underlying the increasing prevalence of MS in AGCs.

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Section: Dendritic Cells (Dc)mentioning

confidence: 99%

Section: Dendritic Cells (Dc)mentioning

confidence: 99%

Section: Dendritic Cells (Dc)mentioning

confidence: 99%

Section: Regulatory T Cells (Treg)mentioning

confidence: 99%

Section: Regulatory T Cells (Treg)mentioning

confidence: 99%

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Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

Eiman¹

2016

Immunome Res

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HLA Genetic Risk Burden in Multiple Sclerosis

2016

Self Cite

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Brain proteome‐wide association study linking‐genes in multiple sclerosis pathogenesis

Jia

Qin

et al. 2022

Ann Clin Transl Neurol

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Objectives To identify genes that confer MS risk via the alteration of cis‐regulated protein abundance and verify their aberrant expression in human brain. Methods Utilizing a two‐stage proteome‐wide association study (PWAS) design, MS GWAS data ( N = 41,505) was respectively integrated with two distinct human brain proteomes from the dorsolateral prefrontal cortex, including ROSMAP ( N = 376) in the discovery stage and Banner ( N = 152) in the confirmation stage. In the following, Bayesian colocalization analysis was conducted for GWAS and protein quantitative trait loci signals to prioritize candidate genes. Differential expression analysis was then used to verify the dysregulation of risk genes in white matter and gray matter for evidence at the transcription level. Results A total of 51 genes whose protein abundance had association with the MS risk were identified, of which 18 genes overlapped in the discovery and confirmation PWAS. Bayesian colocalization indicated six causal genes with genetic risk variants for the MS risk. The differential expression analysis of SHMT1 ( P FDR = 4.82 × 10 −2 ) , FAM120B ( P FDR = 8.13 × 10 −4 ) in white matter and ICA1L ( P FDR = 3.44 × 10 −2 ) in gray matter confirmed the dysregulation at the transcription level. Further investigation of expression found SHMT1 significantly up‐regulated in white matter lesion, and FAM120B up‐regulated in both white matter lesion and normal appearing white matter . ICA1L was down‐regulated in both gray matter lesion and normal appearing gray matter. Interpretation Dysregulation of SHMT1, FAM120B and ICA1L may confer MS risk. Our findings shed new light on the pathogenesis of MS and prioritized promising targets for future therapy research.

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Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Abstract: Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.

Cited by 127 publications

References 78 publications

Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

HLA Genetic Risk Burden in Multiple Sclerosis

Brain proteome‐wide association study linking‐genes in multiple sclerosis pathogenesis

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