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Article ; Online: Structure-based selection of human metabolite binding P4 pocket of DRB115:01 and DRB115:03, with implications for multiple sclerosis.

Misra, Maneesh K / Damotte, Vincent / Hollenbach, Jill A

2018 Volume 20, Issue 1, Page(s) 46–55

Abstract: Binding of small molecules in the human leukocyte antigen (HLA) peptide-binding groove may result in conformational changes of bound peptide and an altered immune response, but previous studies have not considered a potential role for endogenous ... ...

Abstract	Binding of small molecules in the human leukocyte antigen (HLA) peptide-binding groove may result in conformational changes of bound peptide and an altered immune response, but previous studies have not considered a potential role for endogenous metabolites. We performed virtual screening of the complete Human Metabolite Database (HMDB) for docking to the multiple sclerosis (MS) susceptible DRB115:01 allele and compared the results to the closely related yet non-susceptible DRB115:03 allele; and assessed the potential impact on binding of human myelin basic peptide (MBP). We observed higher energy scores for metabolite binding to DRB115:01 than DRB115:03. Structural comparison of docked metabolites with DRB115:01 and DRB115:03 complexed with MBP revealed that Phenylalanine
MeSH term(s)	Alleles ; Binding Sites ; HLA-DRB1 Chains/chemistry ; HLA-DRB1 Chains/genetics ; HLA-DRB1 Chains/metabolism ; Humans ; Molecular Docking Simulation ; Multiple Sclerosis/genetics ; Myelin Basic Protein/metabolism ; Protein Binding
Chemical Substances	HLA-DRB1 Chains ; MBP protein, human ; Myelin Basic Protein
Language	English
Publishing date	2018-01-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2060566-3
ISSN	1476-5470 ; 1466-4879
ISSN (online)	1476-5470
ISSN	1466-4879
DOI	10.1038/s41435-017-0009-5
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Zs.A 5592: Show issues

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Article ; Online: The immunogenetics of neurological disease.

Misra, Maneesh K / Damotte, Vincent / Hollenbach, Jill A

Immunology

2017 Volume 153, Issue 4, Page(s) 399–414

Abstract: Genes encoding antigen-presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, ... ...

Abstract	Genes encoding antigen-presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin-like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non-coding variation in immunogenetic loci using high-throughput high-resolution next-generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.
MeSH term(s)	Animals ; Genetic Variation/genetics ; Genetic Variation/immunology ; Humans ; Immunogenetics ; Nervous System Diseases/genetics ; Nervous System Diseases/immunology
Language	English
Publishing date	2017-12-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.12869
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Article ; Online: A splice acceptor variant in HLA-DRA affects the conformation and cellular localization of the class II DR alpha-chain.

Didonna, Alessandro / Damotte, Vincent / Shams, Hengameh / Matsunaga, Atsuko / Caillier, Stacy J / Dandekar, Ravi / Misra, Maneesh K / Mofrad, Mohammad R K / Oksenberg, Jorge R / Hollenbach, Jill A

Immunology

2020 Volume 162, Issue 2, Page(s) 194–207

Abstract: Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen-derived peptides to ... ...

Abstract	Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen-derived peptides to CD4
MeSH term(s)	Adult ; Aged ; Amino Acids/immunology ; Antigen-Presenting Cells/immunology ; Binding Sites/immunology ; Cell Line ; Cell Line, Tumor ; Cell Membrane/immunology ; Endoplasmic Reticulum/immunology ; Female ; HEK293 Cells ; HLA-DR alpha-Chains/immunology ; HeLa Cells ; Histocompatibility Antigens Class II/immunology ; Humans ; Leukocytes, Mononuclear/immunology ; Male ; Middle Aged ; Peptides/immunology ; Protein Isoforms/immunology ; T-Lymphocytopenia, Idiopathic CD4-Positive/immunology
Chemical Substances	Amino Acids ; HLA-DR alpha-Chains ; Histocompatibility Antigens Class II ; Peptides ; Protein Isoforms
Language	English
Publishing date	2020-10-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.13273
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Article: pRNFL as a marker of disability worsening in the medium/long term in patients with MS.

Cordano, Christian / Nourbakhsh, Bardia / Devereux, Michael / Damotte, Vincent / Bennett, Daniel / Hauser, Stephen L / Cree, Bruce A C / Gelfand, Jeffrey M / Green, Ari J

Neurology(R) neuroimmunology & neuroinflammation

2018 Volume 6, Issue 2, Page(s) e533

MeSH term(s)	Adult ; Biomarkers ; Disability Evaluation ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis/diagnostic imaging ; Retrospective Studies ; Sensitivity and Specificity ; Tomography, Optical Coherence
Chemical Substances	Biomarkers
Language	English
Publishing date	2018-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2767740-0
ISSN	2332-7812
ISSN	2332-7812
DOI	10.1212/NXI.0000000000000533
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Article: Rituximab before and during pregnancy: A systematic review, and a case series in MS and NMOSD.

Das, Gitanjali / Damotte, Vincent / Gelfand, Jeffrey M / Bevan, Carolyn / Cree, Bruce A C / Do, Lynn / Green, Ari J / Hauser, Stephen L / Bove, Riley

Neurology(R) neuroimmunology & neuroinflammation

2018 Volume 5, Issue 3, Page(s) e453

Abstract: Objective: To evaluate the safety of rituximab treatment before and during pregnancy in women with MS and neuromyelitis optica spectrum disorders (NMOSDs) who may be at risk of relapses by performing a systematic literature review combined with a ... ...

Abstract	Objective: To evaluate the safety of rituximab treatment before and during pregnancy in women with MS and neuromyelitis optica spectrum disorders (NMOSDs) who may be at risk of relapses by performing a systematic literature review combined with a retrospective single-center case series. Methods: Studies were systematically identified in the PubMed, Google Scholar, and EMBASE using the key terms "pregnancy" and "rituximab"; 22 articles were included for review (>17,000 screened). Then, patients with MS and NMOSD from 1 center (University of California, San Francisco) exposed to rituximab before conception were identified through medical record review. Results: Systematic review: We identified 102 pregnancies with rituximab use within 6 months of conception: 78 resulted in live births and 12 in spontaneous abortions. Of 54 live births with reported gestational age, 31 occurred at term (37 weeks+) and 2 before 32 weeks. When checked, B-cell counts were low in 39% of newborns and normalized within 6 months. Case series: we identified 11 pregnancies (1 ongoing) in 10 women (7 MS and 3 NMOSD) treated with rituximab within 6 months of conception. All completed pregnancies resulted in term live births of healthy newborns (1 lost to follow-up at term). No maternal relapses occurred before/during pregnancy; 1 occurred postpartum (NMOSD). Conclusion: No major safety signal was observed with rituximab use within 6 months of conception. Beyond the need for monitoring neonatal B cells, these observations support prospectively monitoring a larger patient cohort to determine whether rituximab may safely protect women with MS and NMOSD who are planning a pregnancy against relapses.
Language	English
Publishing date	2018-03-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2767740-0
ISSN	2332-7812
ISSN	2332-7812
DOI	10.1212/NXI.0000000000000453
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Article ; Online: Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping.

Belloy, Michael E / Eger, Sarah J / Le Guen, Yann / Damotte, Vincent / Ahmad, Shahzad / Ikram, M Arfan / Ramirez, Alfredo / Tsolaki, Anthoula C / Rossi, Giacomina / Jansen, Iris E / de Rojas, Itziar / Parveen, Kayenat / Sleegers, Kristel / Ingelsson, Martin / Hiltunen, Mikko / Amin, Najaf / Andreassen, Ole / Sánchez-Juan, Pascual / Kehoe, Patrick /

Amouyel, Philippe / Sims, Rebecca / Frikke-Schmidt, Ruth / van der Flier, Wiesje M / Lambert, Jean-Charles / He, Zihuai / Han, Summer S / Napolioni, Valerio / Greicius, Michael D

Alzheimer's research & therapy

2022 Volume 14, Issue 1, Page(s) 22

Abstract: Background: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE ... ...

Abstract	Background: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE2/3/4 genotype quality. Here, we present a novel APOE2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. Methods:* We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE4/4 carriers. Additional supporting analyses were performed in APOE3/4 and 3/3 strata. Outcomes were compared under two different APOE2/3/4 filtering approaches. Results:* Using more conventional APOE2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions:* We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.
MeSH term(s)	Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Genetic Predisposition to Disease/genetics ; Genotype ; Humans ; Middle Aged ; Quality Control
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E
Language	English
Publishing date	2022-02-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-022-00962-4
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Article ; Online: A specific amino acid motif of

Hollenbach, Jill A / Norman, Paul J / Creary, Lisa E / Damotte, Vincent / Montero-Martin, Gonzalo / Caillier, Stacy / Anderson, Kirsten M / Misra, Maneesh K / Nemat-Gorgani, Neda / Osoegawa, Kazutoyo / Santaniello, Adam / Renschen, Adam / Marin, Wesley M / Dandekar, Ravi / Parham, Peter / Tanner, Caroline M / Hauser, Stephen L / Fernandez-Viña, Marcelo / Oksenberg, Jorge R

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 15, Page(s) 7419–7424

Abstract: Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped ... ...

Abstract	Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to
MeSH term(s)	Amino Acid Motifs ; Female ; Genotype ; Genotyping Techniques ; HLA-DRB1 Chains/chemistry ; HLA-DRB1 Chains/genetics ; Humans ; Male ; Models, Molecular ; Parkinson Disease/genetics ; Risk Factors ; Smoking/genetics
Chemical Substances	HLA-DRB1 Chains
Language	English
Publishing date	2019-03-25
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1821778116
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Article ; Online: Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study.

Steele, Natasha Z R / Carr, Jessie S / Bonham, Luke W / Geier, Ethan G / Damotte, Vincent / Miller, Zachary A / Desikan, Rahul S / Boehme, Kevin L / Mukherjee, Shubhabrata / Crane, Paul K / Kauwe, John S K / Kramer, Joel H / Miller, Bruce L / Coppola, Giovanni / Hollenbach, Jill A / Huang, Yadong / Yokoyama, Jennifer S

PLoS medicine

2017 Volume 14, Issue 3, Page(s) e1002272

Abstract: Background: Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte ...

Abstract	Background: Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. Methods and findings: Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A03:01~B07:02~DRB115:01~DQA101:02~DQB106:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A03:01~B07:02 (p = 0.03, OR = 1.11 [1.01-1.23]) and class II haplotype DRB115:01- DQA101:02- DQB106:02 (DR15) (p = 0.03, OR = 1.08 [1.01-1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A03:01~B07:02 was associated with higher CSF amyloid levels (p = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± standard error = -0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes. Conclusions: We provide evidence that variation in the HLA locus-including risk haplotype DR15-contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan-neuronal disease vulnerability.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Case-Control Studies ; Chromosome Mapping ; Female ; HLA Antigens/cerebrospinal fluid ; HLA Antigens/genetics ; Haplotypes ; Humans ; Male ; Middle Aged ; Risk Factors ; San Francisco/epidemiology ; United States/epidemiology
Chemical Substances	HLA Antigens
Language	English
Publishing date	2017-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2185925-5
ISSN	1549-1676 ; 1549-1277
ISSN (online)	1549-1676
ISSN	1549-1277
DOI	10.1371/journal.pmed.1002272
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Article ; Online: Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels.

Sarnowski, Chloé / Ghanbari, Mohsen / Bis, Joshua C / Logue, Mark / Fornage, Myriam / Mishra, Aniket / Ahmad, Shahzad / Beiser, Alexa S / Boerwinkle, Eric / Bouteloup, Vincent / Chouraki, Vincent / Cupples, L Adrienne / Damotte, Vincent / DeCarli, Charles S / DeStefano, Anita L / Djoussé, Luc / Fohner, Alison E / Franz, Carol E / Kautz, Tiffany F /

Lambert, Jean-Charles / Lyons, Michael J / Mosley, Thomas H / Mukamal, Kenneth J / Pase, Matthew P / Portilla Fernandez, Eliana C / Rissman, Robert A / Satizabal, Claudia L / Vasan, Ramachandran S / Yaqub, Amber / Debette, Stephanie / Dufouil, Carole / Launer, Lenore J / Kremen, William S / Longstreth, William T / Ikram, M Arfan / Seshadri, Sudha

Communications biology

2022 Volume 5, Issue 1, Page(s) 336

Abstract: Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total- ... ...

Abstract	Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10
MeSH term(s)	Black or African American/genetics ; Alzheimer Disease/genetics ; Exome ; Genome-Wide Association Study ; Humans ; Tauopathies
Language	English
Publishing date	2022-04-08
Publishing country	England
Document type	Journal Article ; Meta-Analysis
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03287-y
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Article ; Online: Harnessing electronic medical records to advance research on multiple sclerosis.

Damotte, Vincent / Lizée, Antoine / Tremblay, Matthew / Agrawal, Alisha / Khankhanian, Pouya / Santaniello, Adam / Gomez, Refujia / Lincoln, Robin / Tang, Wendy / Chen, Tiffany / Lee, Nelson / Villoslada, Pablo / Hollenbach, Jill A / Bevan, Carolyn D / Graves, Jennifer / Bove, Riley / Goodin, Douglas S / Green, Ari J / Baranzini, Sergio E /

Cree, Bruce Ac / Henry, Roland G / Hauser, Stephen L / Gelfand, Jeffrey M / Gourraud, Pierre-Antoine

Multiple sclerosis (Houndmills, Basingstoke, England)

2018 Volume 25, Issue 3, Page(s) 408–418

Abstract: Background: Electronic medical records (EMR) data are increasingly used in research, but no studies have yet evaluated similarity between EMR and research-quality data and between characteristics of an EMR multiple sclerosis (MS) population and known ... ...

Abstract	Background: Electronic medical records (EMR) data are increasingly used in research, but no studies have yet evaluated similarity between EMR and research-quality data and between characteristics of an EMR multiple sclerosis (MS) population and known natural MS history. Objectives: To (1) identify MS patients in an EMR system and extract clinical data, (2) compare EMR-extracted data with gold-standard research data, and (3) compare EMR MS population characteristics to expected MS natural history. Methods: Algorithms were implemented to identify MS patients from the University of California San Francisco EMR, de-identify the data and extract clinical variables. EMR-extracted data were compared to research cohort data in a subset of patients. Results: We identified 4142 MS patients via search of the EMR and extracted their clinical data with good accuracy. EMR and research values showed good concordance for Expanded Disability Status Scale (EDSS), timed-25-foot walk, and subtype. We replicated several expected MS epidemiological features from MS natural history including higher EDSS for progressive versus relapsing-remitting patients and for male versus female patients and increased EDSS with age at examination and disease duration. Conclusion: Large real-world cohorts algorithmically extracted from the EMR can expand opportunities for MS clinical research.
MeSH term(s)	Academic Medical Centers ; Adult ; Biomedical Research ; Electronic Health Records ; Female ; Humans ; Information Storage and Retrieval ; Male ; Middle Aged ; Multiple Sclerosis/epidemiology ; Multiple Sclerosis/physiopathology ; Natural Language Processing ; Severity of Illness Index
Language	English
Publishing date	2018-01-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1290669-4
ISSN	1477-0970 ; 1352-4585
ISSN (online)	1477-0970
ISSN	1352-4585
DOI	10.1177/1352458517747407
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