Publications by authors named "Adam Santaniello"

22 Publications

  • Page 1 of 1

An electronic, unsupervised patient-reported Expanded Disability Status Scale for multiple sclerosis.

Mult Scler 2020 Nov 25:1352458520968814. Epub 2020 Nov 25.

UCSF MS and Neuroinflammation Center, Weill Institute for Neurosciences, Department of Neurology, Division of Neuroinflammation and Glial Biology, University of California San Francisco, San Francisco, CA, USA.

Background: In persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments.

Objective: The aim of this study was to develop and validate a scalable, electronic, unsupervised patient-reported EDSS (ePR-EDSS) that would capture MS-related disability across the spectrum of severity.

Methods: We enrolled 136 adult MS patients, split into a preliminary testing Cohort 1 ( = 50), and a validation Cohort 2 ( = 86), which was evenly distributed across EDSS groups. Each patient completed an ePR-EDSS either immediately before or after a MS clinician's Neurostatus EDSS evaluation.

Results: In Cohort 2, mean age was 50.6 years (range = 26-80) and median EDSS was 3.5 (interquartile range (IQR) = [1.5, 5.5]). The ePR-EDSS and EDSS agreed within 1-point for 86% of examinations; kappa for agreement within 1-point was 0.85 ( < 0.001). The correlation coefficient between the two measures was 0.91 (<0.001).

Discussion: The ePR-EDSS was highly correlated with EDSS, with good agreement even at lower EDSS levels. For clinical care, the ePR-EDSS could enable the longitudinal monitoring of a patient's disability. For research, it provides a valid and rapid measure across the entire spectrum of disability and permits broader participation with fewer in-person assessments.
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http://dx.doi.org/10.1177/1352458520968814DOI Listing
November 2020

TopoDB: a novel multifunctional management system for laboratory animal colonies.

Database (Oxford) 2020 01;2020

Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.

Animal models are widely employed in basic research to test mechanistic hypotheses in a complex biological environment as well as to evaluate the therapeutic potential of candidate compounds in preclinical settings. Rodents, and in particular mice, represent the most common in vivo models for their small size, short lifespan and possibility to manipulate their genome. Over time, a typical laboratory will develop a substantial number of inbred strains and transgenic mouse lines, requiring a substantial effort, in both logistic and economic terms, to maintain an animal colony for research purposes and to safeguard the integrity of results. To meet this need, here we present TopoDB, a robust and extensible web-based platform for the rational management of laboratory animals. TopoDB allows an easy tracking of individual animals within the colony and breeding protocols as well as the convenient storage of both genetic and phenotypic data generated in the different experiments. Altogether, these features facilitate and enhance the design of in vivo research, thus reducing the number of necessary animals and the housing costs. In summary, TopoDB represents a novel valuable tool in modern biomedical research. Database URL: https://github.com/UCSF-MS-DCC/TopoDB.
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http://dx.doi.org/10.1093/database/baaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673335PMC
January 2020

A Precision Medicine Tool for Patients With Multiple Sclerosis (the Open MS BioScreen): Human-Centered Design and Development.

J Med Internet Res 2020 07 6;22(7):e15605. Epub 2020 Jul 6.

Department of Neurology, UCSF Weill Institute for Neurosciences, San Francisco, CA, United States.

Background: Patients with multiple sclerosis (MS) face several challenges in accessing clinical tools to help them monitor, understand, and make meaningful decisions about their disease course. The University of California San Francisco MS BioScreen is a web-based precision medicine tool initially designed to be clinician facing. We aimed to design a second, openly available tool, Open MS BioScreen, that would be accessible, understandable, and actionable by people with MS.

Objective: This study aimed to describe the human-centered design and development approach (inspiration, ideation, and implementation) for creating the Open MS BioScreen platform.

Methods: We planned an iterative and cyclical development process that included stakeholder engagement and iterative feedback from users. Stakeholders included patients with MS along with their caregivers and family members, MS experts, generalist clinicians, industry representatives, and advocacy experts. Users consisted of anyone who wants to track MS measurements over time and access openly available tools for people with MS. Phase I (inspiration) consisted of empathizing with users and defining the problem. We sought to understand the main challenges faced by patients and clinicians and what they would want to see in a web-based app. In phase II (ideation), our multidisciplinary team discussed approaches to capture, display, and make sense of user data. Then, we prototyped a series of mock-ups to solicit feedback from clinicians and people with MS. In phase III (implementation), we incorporated all concepts to test and iterate a minimally viable product. We then gathered feedback through an agile development process. The design and development were cyclical-many times throughout the process, we went back to the drawing board.

Results: This human-centered approach generated an openly available, web-based app through which patients with MS, their clinicians, and their caregivers can access the site and create an account. Users can enter information about their MS (basic level as well as more advanced concepts), visualize their data longitudinally, access a series of algorithms designed to empower them to make decisions about their treatments, and enter data from wearable devices to encourage realistic goal setting about their ambulatory activity. Agile development will allow us to continue to incorporate precision medicine tools, as these are validated in the clinical research arena.

Conclusions: After engaging intended users into the iterative human-centered design of the Open MS BioScreen, we will now monitor the adaptation and dissemination of the tool as we expand its functionality and reach. The insights generated from this approach can be applied to the development of a number of self-tracking, self-management, and user engagement tools for patients with chronic conditions.
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http://dx.doi.org/10.2196/15605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381029PMC
July 2020

Telomere Length Is Associated with Disability Progression in Multiple Sclerosis.

Ann Neurol 2019 11 2;86(5):671-682. Epub 2019 Oct 2.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA.

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).

Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.

Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).

Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.
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http://dx.doi.org/10.1002/ana.25592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135931PMC
November 2019

Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years.

JAMA Neurol 2019 Nov;76(11):1359-1366

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Importance: Blood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed.

Objective: To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set.

Design, Setting, And Participants: Single-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses.

Main Outcomes And Measures: The main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy.

Results: Mean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (β, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (β, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (β, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (β, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years' follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: β, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: β, 0.972; 95% CI, 0.948-0.998; P = .04).

Conclusions And Relevance: This study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay's utility for decision-making in individual patients.
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http://dx.doi.org/10.1001/jamaneurol.2019.2137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692664PMC
November 2019

Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population.

Hum Immunol 2019 Oct 22;80(10):807-822. Epub 2019 Jul 22.

Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA; Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA.

The human leukocyte antigen (HLA) genes are extremely polymorphic and are useful molecular markers to make inferences about human population history. However, the accuracy of the estimation of genetic diversity at HLA loci very much depends on the technology used to characterize HLA alleles; high-resolution genotyping of long-range HLA gene products improves the assessment of HLA population diversity as well as other population parameters compared to lower resolution typing methods. In this study we examined allelic and haplotype HLA diversity in a large healthy European American population sourced from the UCSF-DNA bank. A high-resolution next-generation sequencing method was applied to define non-ambiguous 3- and 4-field alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 loci in samples provided by 2248 unrelated individuals. A number of population parameters were examined including balancing selection and various measurements of linkage disequilibrium were calculated. There were no detectable deviations from Hardy-Weinberg proportions at HLA-A, HLA-DRB1, HLA-DQA1 and HLA-DQB1. For the remaining loci moderate and significant deviations were detected at HLA-C, HLA-B, HLA-DRB3/4/5, HLA-DPA1 and HLA-DPB1 loci mostly from population substructures. Unique 4-field associations were observed among alleles at 2 loci and haplotypes extending large intervals that were not apparent in results obtained using testing methodologies with limited sequence coverage and phasing. The high diversity at HLA-DPA1 results from detection of intron variants of otherwise well conserved protein sequences. It may be speculated that divergence in exon sequences may be negatively selected. Our data provides a valuable reference source for future population studies that may allow for precise fine mapping of coding and non-coding sequences determining disease susceptibility and allo-immunogenicity.
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http://dx.doi.org/10.1016/j.humimm.2019.07.275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778037PMC
October 2019

A specific amino acid motif of mediates risk and interacts with smoking history in Parkinson's disease.

Proc Natl Acad Sci U S A 2019 04 25;116(15):7419-7424. Epub 2019 Mar 25.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158.

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to , but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V ( = 10; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V ( = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.
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http://dx.doi.org/10.1073/pnas.1821778116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462083PMC
April 2019

Silent progression in disease activity-free relapsing multiple sclerosis.

Ann Neurol 2019 05 30;85(5):653-666. Epub 2019 Mar 30.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA.

Objective: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.

Methods: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.

Results: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).

Interpretation: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.
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http://dx.doi.org/10.1002/ana.25463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518998PMC
May 2019

Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.

Ann Neurol 2018 07 3;84(1):51-63. Epub 2018 Jul 3.

UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA.

Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.

Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.

Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.

Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.
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http://dx.doi.org/10.1002/ana.25263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119489PMC
July 2018

Harnessing electronic medical records to advance research on multiple sclerosis.

Mult Scler 2019 03 9;25(3):408-418. Epub 2018 Jan 9.

MS Genetics, Department of Neurology, School of Medicine, University of California San Francisco (UCSF), San Francisco, CA, USA/Université de Nantes, INSERM, UMR 1064, ATIP-Avenir, Equipe 5 Centre de Recherche en Transplantation et Immunologie, Nantes, France.

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.
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http://dx.doi.org/10.1177/1352458517747407DOI Listing
March 2019

Long-term evolution of multiple sclerosis disability in the treatment era.

Ann Neurol 2016 10 13;80(4):499-510. Epub 2016 Aug 13.

Department of Neurology, University of California, San Francisco, San Francisco, CA.

Objective: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value.

Methods: This is a prospective study of 517 actively managed MS patients enrolled at a single center.

Results: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS).

Interpretation: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510.
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http://dx.doi.org/10.1002/ana.24747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105678PMC
October 2016

Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis.

JAMA Neurol 2016 07;73(7):795-802

Department of Neurology, School of Medicine, University of California, San Francisco5Bioengineering Graduate Group, University of California, San Francisco and Berkeley6Department of Radiology and Biomedical Imaging, University of California, San Francisc.

Importance: Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive.

Objectives: To investigate whether MS risk-associated HLA alleles also affect disease phenotypes.

Design, Setting, And Participants: A 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 Measures: Cumulative 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.

Results: Of 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 Relevance: We 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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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081075PMC
http://dx.doi.org/10.1001/jamaneurol.2016.0980DOI Listing
July 2016

iCTNet2: integrating heterogeneous biological interactions to understand complex traits.

F1000Res 2015 5;4:485. Epub 2015 Aug 5.

Department of Neurology, University of California San Francisco, San Francisco, CA, 94158, USA; Graduate Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, CA, 94143-0523, USA.

iCTNet (integrated Complex Traits Networks) version 2 is a Cytoscape app and database that allows researchers to build heterogeneous networks by integrating a variety of biological interactions, thus offering a systems-level view of human complex traits. iCTNet2 is built from a variety of large-scale biological datasets, collected from public repositories to facilitate the building, visualization and analysis of heterogeneous biological networks in a comprehensive fashion via the Cytoscape platform. iCTNet2 is freely available at the Cytoscape app store.
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http://dx.doi.org/10.12688/f1000research.6836.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706053PMC
February 2016

Mitochondrial DNA sequence variation in multiple sclerosis.

Neurology 2015 Jul 1;85(4):325-30. Epub 2015 Jul 1.

From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.

Objective: To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium.

Methods: We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco.

Results: An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07-1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06-1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01-1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10-2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99-2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14-1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk.

Conclusions: Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.
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http://dx.doi.org/10.1212/WNL.0000000000001744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520811PMC
July 2015

An ImmunoChip study of multiple sclerosis risk in African Americans.

Brain 2015 Jun 28;138(Pt 6):1518-30. Epub 2015 Mar 28.

1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.
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http://dx.doi.org/10.1093/brain/awv078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553906PMC
June 2015

Precision medicine in chronic disease management: The multiple sclerosis BioScreen.

Ann Neurol 2014 Nov 14;76(5):633-42. Epub 2014 Oct 14.

Department of Neurology, School of Medicine, University of California, San Francisco, San Francisco, CA.

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine-that is, the application of information technology to medicine-has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real-time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence-based medicine, support shared decision making, and ultimately lead to improved outcomes.
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http://dx.doi.org/10.1002/ana.24282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214886PMC
November 2014

Genetic risk variants in African Americans with multiple sclerosis.

Neurology 2013 Jul 14;81(3):219-27. Epub 2013 Jun 14.

Department of Neurology, School of Medicine, University of California, San Francisco, CA, USA.

Objectives: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls).

Methods: Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations.

Results: The following major histocompatibility complex risk alleles were replicated: HLA-DRB1*15:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54-2.63], p = 2.50e-07), HLA-DRB1*03:01 (OR = 1.58 [1.29-1.94], p = 1.11e-05), as well as HLA-DRB1*04:05 (OR = 2.35 [1.26-4.37], p = 0.007) and the African-specific risk allele of HLA-DRB1*15:03 (OR = 1.26 [1.05-1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55-0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p < 0.01, outside the major histocompatibility complex region, 8 MS SNPs were also found to be associated with MS in African Americans.

Conclusion: MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.
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http://dx.doi.org/10.1212/WNL.0b013e31829bfe2fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770164PMC
July 2013

Blood RNA profiling in a large cohort of multiple sclerosis patients and healthy controls.

Hum Mol Genet 2013 Oct 6;22(20):4194-205. Epub 2013 Jun 6.

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS). It is characterized by the infiltration of autoreactive immune cells into the CNS, which target the myelin sheath, leading to the loss of neuronal function. Although it is accepted that MS is a multifactorial disorder with both genetic and environmental factors influencing its development and course, the molecular pathogenesis of MS has not yet been fully elucidated. Here, we studied the longitudinal gene expression profiles of whole-blood RNA from a cohort of 195 MS patients and 66 healthy controls. We analyzed these transcriptomes at both the individual transcript and the biological pathway level. We found 62 transcripts to be significantly up-regulated in MS patients; the expression of 11 of these genes was counter-regulated by interferon treatment, suggesting partial restoration of a 'healthy' gene expression profile. Global pathway analyses linked the proteasome and Wnt signaling to MS disease processes. Since genotypes from a subset of individuals were available, we were able to identify expression quantitative trait loci (eQTL), a number of which involved two genes of the MS gene signature. However, all these eQTL were also present in healthy controls. This study highlights the challenge posed by analyzing transcripts from whole blood and how these can be mitigated by using large, well-characterized cohorts of patients with longitudinal follow-up and multi-modality measurements.
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http://dx.doi.org/10.1093/hmg/ddt267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781642PMC
October 2013

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

Nature 2011 Aug 10;476(7359):214-9. Epub 2011 Aug 10.

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.
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http://dx.doi.org/10.1038/nature10251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182531PMC
August 2011

Aggregation of multiple sclerosis genetic risk variants in multiple and single case families.

Ann Neurol 2011 Jan;69(1):65-74

Department of Neurology, School of Medicine, University of California at San Francisco, San Francisco, CA, USA.

Objective: Multiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome-wide association studies have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple- and single-case families.

Methods: A weighted log-additive integrative approach termed MS genetic burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1,213 independent MS families (810 sporadic and 403 multicase families).

Results: MSGB analysis demonstrated a higher aggregation of susceptibility variants in multicase compared to sporadic MS families. In addition, the aggregation of non-major histocompatibility complex single nucleotide polymorphisms depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, although a greater MSGB in siblings of MS patients was associated with an increased risk of MS (odds ratio, 2.1; p = 0.001), receiver operating characteristic curves of MSGB differences between probands and sibs (area under the receiver operator curves, 0.57 [95% confidence interval, 0.53-0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data.

Interpretation: The primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis on assembling large case-control datasets, multigenerational, multiaffected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits.
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http://dx.doi.org/10.1002/ana.22323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511846PMC
January 2011

Genetic variation in the odorant receptors family 13 and the mhc loci influence mate selection in a multiple sclerosis dataset.

BMC Genomics 2010 Nov 10;11:626. Epub 2010 Nov 10.

Department of Neurology, University of California, San Francisco, CA 94143-0435, USA.

Background: When selecting mates, many vertebrate species seek partners with major histocompatibility complex (MHC) genes different from their own, presumably in response to selective pressure against inbreeding and towards MHC diversity. Attempts at replication of these genetic results in human studies, however, have reached conflicting conclusions.

Results: Using a multi-analytical strategy, we report validated genome-wide relationships between genetic identity and human mate choice in 930 couples of European ancestry. We found significant similarity between spouses in the MHC at class I region in chromosome 6p21, and at the odorant receptor family 13 locus in chromosome 9. Conversely, there was significant dissimilarity in the MHC class II region, near the HLA-DQA1 and -DQB1 genes. We also found that genomic regions with significant similarity between spouses show excessive homozygosity in the general population (assessed in the HapMap CEU dataset). Conversely, loci that were significantly dissimilar among spouses were more likely to show excessive heterozygosity in the general population.

Conclusions: This study highlights complex patterns of genomic identity among partners in unrelated couples, consistent with a multi-faceted role for genetic factors in mate choice behavior in human populations.
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http://dx.doi.org/10.1186/1471-2164-11-626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091764PMC
November 2010

A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.

PLoS One 2010 Jun 25;5(6):e11296. Epub 2010 Jun 25.

Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.

Background: In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.

Methodology/principal Findings: A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.

Conclusions: A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011296PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892470PMC
June 2010