Publications by authors named "Samantha L Smith"

15 Publications

  • Page 1 of 1

Characterisation of CD4+ T-cell subtypes using single cell RNA sequencing and the impact of cell number and sequencing depth.

Sci Rep 2020 11 13;10(1):19825. Epub 2020 Nov 13.

Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.

CD4+ T-cells represent a heterogeneous collection of specialised sub-types and are a key cell type in the pathogenesis of many diseases due to their role in the adaptive immune system. By investigating CD4+ T-cells at the single cell level, using RNA sequencing (scRNA-seq), there is the potential to identify specific cell states driving disease or treatment response. However, the impact of sequencing depth and cell numbers, two important factors in scRNA-seq, has not been determined for a complex cell population such as CD4+ T-cells. We therefore generated a high depth, high cell number dataset to determine the effect of reduced sequencing depth and cell number on the ability to accurately identify CD4+ T-cell subtypes. Furthermore, we investigated T-cell signatures under resting and stimulated conditions to assess cluster specific effects of stimulation. We found that firstly, cell number has a much more profound effect than sequencing depth on the ability to classify cells; secondly, this effect is greater when cells are unstimulated and finally, resting and stimulated samples can be combined to leverage additional power whilst still allowing differences between samples to be observed. While based on one individual, these results could inform future scRNA-seq studies to ensure the most efficient experimental design.
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http://dx.doi.org/10.1038/s41598-020-76972-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666207PMC
November 2020

Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms.

Ann Rheum Dis 2020 Oct 26. Epub 2020 Oct 26.

Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

Objectives: Juvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.

Methods: We performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes.

Results: Our analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology and as a potential drug target.

Conclusions: In a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.
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http://dx.doi.org/10.1136/annrheumdis-2020-218481DOI Listing
October 2020

Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing.

Blood Adv 2020 04;4(7):1388-1406

The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, and.

Human natural killer (NK) cells in peripheral blood perform many functions, and classification of specific subsets has been a longstanding goal. We report single-cell RNA sequencing of NK cells, comparing gene expression in unstimulated and interleukin (IL)-2-activated cells from healthy cytomegalovirus (CMV)-negative donors. Three NK cell subsets resembled well-described populations; CD56brightCD16-, CD56dimCD16+CD57-, and CD56dimCD16+CD57+. CD56dimCD16+CD57- cells subdivided to include a population with higher chemokine mRNA and increased frequency of killer-cell immunoglobulin-like receptor expression. Three novel human blood NK cell populations were identified: a population of type I interferon-responding NK cells that were CD56neg; a population exhibiting a cytokine-induced memory-like phenotype, including increased granzyme B mRNA in response to IL-2; and finally, a small population, with low ribosomal expression, downregulation of oxidative phosphorylation, and high levels of immediate early response genes indicative of cellular activation. Analysis of CMV+ donors established that CMV altered the proportion of NK cells in each subset, especially an increase in adaptive NK cells, as well as gene regulation within each subset. Together, these data establish an unexpected diversity in blood NK cells and provide a new framework for analyzing NK cell responses in health and disease.
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http://dx.doi.org/10.1182/bloodadvances.2019000699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160259PMC
April 2020

Sperm Head-Tail Linkage Requires Restriction of Pericentriolar Material to the Proximal Centriole End.

Dev Cell 2020 04 12;53(1):86-101.e7. Epub 2020 Mar 12.

Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

The centriole, or basal body, is the center of attachment between the sperm head and tail. While the distal end of the centriole templates the cilia, the proximal end associates with the nucleus. Using Drosophila, we identify a centriole-centric mechanism that ensures proper proximal end docking to the nucleus. This mechanism relies on the restriction of pericentrin-like protein (PLP) and the pericentriolar material (PCM) to the proximal end of the centriole. PLP is restricted proximally by limiting its mRNA and protein to the earliest stages of centriole elongation. Ectopic positioning of PLP to more distal portions of the centriole is sufficient to redistribute PCM and microtubules along the entire centriole length. This results in erroneous, lateral centriole docking to the nucleus, leading to spermatid decapitation as a result of a failure to form a stable head-tail linkage.
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http://dx.doi.org/10.1016/j.devcel.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170007PMC
April 2020

Micro-computed tomography as a platform for exploring development.

Development 2019 12 11;146(23). Epub 2019 Dec 11.

Cell Biology and Physiology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA

Understanding how events at the molecular and cellular scales contribute to tissue form and function is key to uncovering the mechanisms driving animal development, physiology and disease. Elucidating these mechanisms has been enhanced through the study of model organisms and the use of sophisticated genetic, biochemical and imaging tools. Here, we present an accessible method for non-invasive imaging of at high resolution using micro-computed tomography (µ-CT). We show how rapid processing of intact animals, at any developmental stage, provides precise quantitative assessment of tissue size and morphology, and permits analysis of inter-organ relationships. We then use µ-CT imaging to study growth defects in the brain through the characterization of () and (), orthologs of the two most commonly mutated genes in human microcephaly patients. Our work demonstrates the power of combining µ-CT with traditional genetic, cellular and developmental biology tools available in model organisms to address novel biological mechanisms that control animal development and disease.
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http://dx.doi.org/10.1242/dev.176685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918772PMC
December 2019

Dual-Task Interference Between Swimming and Verbal Memory.

Hum Factors 2020 Nov 12;62(7):1132-1140. Epub 2019 Sep 12.

George Mason University, Fairfax, VA, USA.

Objective: A dual-task study was performed to explore the performance effects for swimming, word recall, and the combination of the two tasks performed simultaneously.

Background: Dual-task interference studies have been performed for a variety of tasks; however, there has not been much dual-task interference research where one of the tasks is a naturalistic physically strenuous task. Swimming is a unique physical task that requires spatial orientation on three dimensional axes, similar to that of flying, but has no risk of falling. Previous studies have been conducted in other activity combinations with word-free recall, such as running and climbing, but swimming has yet to be explored.

Method: A verbal memory recall task and swimming task were performed in isolated (single-task) and simultaneous conditions. A comparison of effects across these different activities was also explored.

Results: Swimming and the word-recall task resulted in significant dual-task interference: almost as much as when word recall was paired with another verbal task, but more than running and less than climbing.

Conclusion: Consistent with other dual-task studies, this study observed dual-task interference between the physical swimming task and the cognitive verbal memory task.

Application: Future technologies and training for personnel who engage in water rescue or commercial diving, such as underwater welding and fiber optic cable, may be improved by these findings.
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http://dx.doi.org/10.1177/0018720819871743DOI Listing
November 2020

Direct Targeting of the mTOR (Mammalian Target of Rapamycin) Kinase Improves Endothelial Permeability in Drug-Eluting Stents-Brief Report.

Arterioscler Thromb Vasc Biol 2018 09;38(9):2217-2224

From the CVPath Institute, Gaithersburg, MD (E.H., L.G., S.L.S., K.H.P., R.F., A.S., H.M., M.D.K., S.T., A.C., H.J., F.D.K., R.V., A.V.F.).

Objective- Drug-eluting stents eluting canonical mTOR (mammalian target of rapamycin) inhibitors are widely used to treat coronary artery disease but accelerate the development of atherosclerosis within the stent (neoatherosclerosis)-a leading cause of late stent failure. We recently showed that canonical mTOR inhibitors bind FKBP12.6 (12.6-kDa FK506-binding protein 12), displace it from calcium release channels, resulting in activation of PKCα (protein kinase Cα) and dissociation of p-120-catenin (p120) from VE-CAD (vascular endothelial cadherin; promoting endothelial barrier dysfunction [EBD]). However, the relevance of these findings to drug-eluting stents remains unknown. Newer generation direct mTOR kinase inhibitors do not bind FKBP12.6 and offer the potential of improving endothelial barrier function while maintaining antirestenotic efficacy, but their actual effects are unknown. We examined the effects of 2 different pharmacological targeting strategies-canonical mTOR inhibitor everolimus and mTOR kinase inhibitors Torin-2-on EBD after stenting. Approach and Results- Using the rabbit model of stenting and a combination of Evans blue dye, confocal and scanning electron microscopy studies, everolimus-eluting stents resulted in long-term EBD compared with bare metal stents. EBD was mitigated by using stents that eluted mTOR kinase inhibitors (Torin-2-eluting stent). At 60 days after stent placement, everolimus-eluting stents demonstrated large areas of Evans blue dye staining and evidence of p120 VE-CAD dissociation consistent with EBD. These findings were absent in bare metal stents and significantly attenuated in Torin-2-eluting stent. As proof of concept of the role of EBD in neoatherosclerosis, 100 days after stenting, animals were fed an enriched cholesterol diet for an additional 30 days. Everolimus-eluting stents demonstrated significantly more macrophage infiltration (consistent with neoatherosclerosis) compared with both bare metal stents and Torin-2-eluting stent. Conclusions- Our results pinpoint interactions between FKBP12.6 and canonical mTOR inhibitors as a major cause of vascular permeability and neoatherosclerosis, which can be overcome by using mTOR kinase inhibitors. Our study suggests further refinement of molecular targeting of the mTOR complex may be a promising strategy (Graphic Abstract).
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http://dx.doi.org/10.1161/ATVBAHA.118.311321DOI Listing
September 2018

A Pilot Investigation of Individual and Dyad Instructional Arrangements.

Behav Anal Pract 2018 Jun 2;11(2):115-128. Epub 2018 Mar 2.

Melmark New England, 461 River Road, Andover, MA 01810 USA.

An essential goal for individuals with autism spectrum disorder (ASD) is to reach maximal independence on a variety of tasks that facilitate academic and vocational engagement and community integration. One-to-one instructional arrangements do not adequately prepare individuals with autism to function within various group contexts and limit opportunities for positive social interactions with one or more peers. Furthermore, group instructional formats have multiple benefits, including potentially increased instructional time and additional learning opportunities. The purpose of this pilot study was to evaluate the acquisition and maintenance of verbal behavior targets in individual and dyad instruction, as well as to compare levels of engagement across these instructional arrangements. Results suggest that three of the four participants acquired more targets during individual instruction, and three of the four participants maintained more targets within individual instruction. In addition, three of the four participants spent less time in instruction and more time on break during dyad instruction. These findings demonstrate the diversity of outcomes for dyad instruction for people with ASD. Directions for future research and suggestions for clinical implementation are provided.
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http://dx.doi.org/10.1007/s40617-018-0234-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959817PMC
June 2018

Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies.

J Am Heart Assoc 2018 03 23;7(6). Epub 2018 Mar 23.

Recombinetics, Inc, St Paul, MN

Background: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene.

Methods And Results: Ossabaw and Landrace gain-of-function founders were generated by transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques.

Conclusions: The Ossabaw gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.
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http://dx.doi.org/10.1161/JAHA.117.006207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907533PMC
March 2018

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis.

J Clin Invest 2018 03 19;128(3):1106-1124. Epub 2018 Feb 19.

CVPath Institute, Gaithersburg, Maryland, USA.

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.
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http://dx.doi.org/10.1172/JCI93025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824873PMC
March 2018

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

Arthritis Rheumatol 2018 06 21;70(6):957-962. Epub 2018 Apr 21.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.

Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA.

Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years.

Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
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http://dx.doi.org/10.1002/art.40443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984672PMC
June 2018

Heart-resident macrophages: are they involved in the rhythm of every beat?

J Thorac Dis 2017 Aug;9(8):2264-2267

CVPath Institute, Gaithersburg, Maryland, USA.

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http://dx.doi.org/10.21037/jtd.2017.07.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594139PMC
August 2017

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity.

Am J Pathol 2016 11;186(11):2887-2908

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia.

Inhaled diacetyl vapors are associated with flavorings-related lung disease, a potentially fatal airway disease. The reactive α-dicarbonyl group in diacetyl causes protein damage in vitro. Dicarbonyl/l-xylulose reductase (DCXR) metabolizes diacetyl into acetoin, which lacks this α-dicarbonyl group. To investigate the hypothesis that flavorings-related lung disease is caused by in vivo protein damage, we correlated diacetyl-induced airway damage in mice with immunofluorescence for markers of protein turnover and autophagy. Western immunoblots identified shifts in ubiquitin pools. Diacetyl inhalation caused dose-dependent increases in bronchial epithelial cells with puncta of both total ubiquitin and K63-ubiquitin, central mediators of protein turnover. This response was greater in Dcxr-knockout mice than in wild-type controls inhaling 200 ppm diacetyl, further implicating the α-dicarbonyl group in protein damage. Western immunoblots demonstrated decreased free ubiquitin in airway-enriched fractions. Transmission electron microscopy and colocalization of ubiquitin-positive puncta with lysosomal-associated membrane proteins 1 and 2 and with the multifunctional scaffolding protein sequestosome-1 (SQSTM1/p62) confirmed autophagy. Surprisingly, immunoreactive SQSTM1 also accumulated in the olfactory bulb of the brain. Olfactory bulb SQSTM1 often congregated in activated microglial cells that also contained olfactory marker protein, indicating neuronophagia within the olfactory bulb. This suggests the possibility that SQSTM1 or damaged proteins may be transported from the nose to the brain. Together, these findings strongly implicate widespread protein damage in the etiology of flavorings-related lung disease.
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http://dx.doi.org/10.1016/j.ajpath.2016.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222965PMC
November 2016

Proteomic analysis reveals APC-dependent post-translational modifications and identifies a novel regulator of β-catenin.

Development 2016 07 10;143(14):2629-40. Epub 2016 Jun 10.

Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA

Wnt signaling generates patterns in all embryos, from flies to humans, and controls cell fate, proliferation and metabolic homeostasis. Inappropriate Wnt pathway activation results in diseases, including colorectal cancer. The adenomatous polyposis coli (APC) tumor suppressor gene encodes a multifunctional protein that is an essential regulator of Wnt signaling and cytoskeletal organization. Although progress has been made in defining the role of APC in a normal cellular context, there are still significant gaps in our understanding of APC-dependent cellular function and dysfunction. We expanded the APC-associated protein network using a combination of genetics and a proteomic technique called two-dimensional difference gel electrophoresis (2D-DIGE). We show that loss of Drosophila Apc2 causes protein isoform changes reflecting misregulation of post-translational modifications (PTMs), which are not dependent on β-catenin transcriptional activity. Mass spectrometry revealed that proteins involved in metabolic and biosynthetic pathways, protein synthesis and degradation, and cell signaling are affected by Apc2 loss. We demonstrate that changes in phosphorylation partially account for the altered PTMs in APC mutants, suggesting that APC mutants affect other types of PTM. Finally, through this approach Aminopeptidase P was identified as a new regulator of β-catenin abundance in Drosophila embryos. This study provides new perspectives on the cellular effects of APC that might lead to a deeper understanding of its role in development.
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http://dx.doi.org/10.1242/dev.130567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958330PMC
July 2016

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.

Arthritis Rheumatol 2016 06 21;68(6):1353-60. Epub 2016 Apr 21.

NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, and Central Manchester NHS Trust, and Arthritis Research UK Centre for Genetics and Genomics, University of Manchester, Manchester, UK.

Objective: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA.

Methods: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients.

Results: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10(-8) and cg26401028, P = 1.69 × 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10(-7) and P = 1.05 × 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204).

Conclusion: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.
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http://dx.doi.org/10.1002/art.39590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914881PMC
June 2016