Publications by authors named "Dimitri S Monos"

33 Publications

Association of KIR Genes and MHC Class I Ligands with Atopic Dermatitis.

J Immunol 2021 09 18;207(6):1522-1529. Epub 2021 Aug 18.

Department of Medicine, Vanderbilt School of Medicine, Nashville, TN.

Atopic dermatitis (AD) is a chronic illness that is associated with immune dysregulation. NK cell function has previously been associated with AD. NK cells directly interact with polymorphic HLA class I ligand variants using killer cell Ig-like receptors (KIRs). The purpose of this study was to identify potential associations between NK cell function and AD by evaluating variation in the presence of KIR genes as well as KIR gene interactions with the appropriate HLA class I KIR-specific ligands. Human DNA from the genetics of AD case-control study was used to genotype HLA class I KIR-specific ligands and the presence of KIR genes. In the full cohort, an increased risk of AD was noted for (1.51 [1.13, 2.01]), (1.72 [1.26, 2.34]), and 2DS1 (1.41 [1.04, 1.91]). Individuals with or and the HLA-C*C2 epitope were at an increased risk of AD (1.74 [1.21, 2.51] and 1.48 [1.04, 2.12], respectively). The HLA-B*-21T (TT) leader sequence increased the risk of AD across ethnicity. African Americans with , , , and are more likely to have AD, and the risk increased for and in the presence of appropriate HLA-C C2 epitope. The risk of AD also increased for individuals with the HLA-B*-21T leader sequence. Future studies should focus on gene allelic variation as well as consider cell-based measurements of KIR and the associated HLA class I epitopes.
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http://dx.doi.org/10.4049/jimmunol.2100379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429237PMC
September 2021

HLA Class I Polymorphisms Influencing Both Peptide Binding and KIR Interactions Are Associated with Remission among Children with Atopic Dermatitis: A Longitudinal Study.

J Immunol 2021 05 16;206(9):2038-2044. Epub 2021 Apr 16.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA;

Atopic dermatitis (AD) is a disease of immune dysregulation and skin barrier dysfunction with a relapsing, remitting course and has been associated with several different genetic risk variants. HLA represent a highly variable set of genes that code for cell surface protein molecules involved in the Ag-specific immune response, including the regulation or functioning of T cells, NK cells, and APCs. The purpose of this study was to evaluate associations between HLA class I polymorphisms and the progression of AD over time. We evaluated the associations of AD symptoms and HLA class I polymorphisms based on high-resolution two-field typing in a longitudinal cohort of children with AD (up to 10 y of follow-up). Seven hundred and ninety-two children were evaluated every 6 mo, resulting in 12,752 AD evaluations. Using generalized estimating equations and corrected values, B*44:02 was found to be associated with AD remission (1.83 [1.35, 2.47]; = 0.0015). The HLA-B residues at position 116 (d-aspartate) and 80 (T-threonine) were associated with remission (1.42 [1.13, 1.76], = 0.003; corrected = 0.028) and (1.45 [1.17, 1.80], = 0.0008; corrected = 0.0024), respectively. B80T is a killer-cell Ig-like receptor (KIR) site. Our findings reveal that two axes of immune response (T cell and NK cell) may influence disease progression. Identifying binding pocket changes in addition to other factors (e.g., allergens) that increase the risk or severity of AD can improve our understanding of the immunologic mechanisms associated with AD and may lead to personalized therapies for improving patient care.
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http://dx.doi.org/10.4049/jimmunol.2001252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062288PMC
May 2021

Analysis of single nucleotide polymorphisms in chronic beryllium disease.

Respir Res 2021 Apr 16;22(1):107. Epub 2021 Apr 16.

Department of Pneumology, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany.

Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.
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http://dx.doi.org/10.1186/s12931-021-01691-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051053PMC
April 2021

Spatial constrains and information content of sub-genomic regions of the human genome.

iScience 2021 Feb 10;24(2):102048. Epub 2021 Jan 10.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Complexity metrics and machine learning (ML) models have been utilized to analyze the lengths of segmental genomic entities of DNA sequences (exonic, intronic, intergenic, repeat, unique) with the purpose to ask questions regarding the segmental organization of the human genome within the size distribution of these sequences. For this we developed an integrated methodology that is based upon the reconstructed phase space theorem, the non-extensive statistical theory of Tsallis, ML techniques, and a technical index, integrating the generated information, which we introduce and named complexity factor (COFA). Our analysis revealed that the size distribution of the genomic regions within chromosomes are not random but follow patterns with characteristic features that have been seen through its complexity character, and it is part of the dynamics of the whole genome. Finally, this picture of dynamics in DNA is recognized using ML tools for clustering, classification, and prediction with high accuracy.
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http://dx.doi.org/10.1016/j.isci.2021.102048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843455PMC
February 2021

Rheumatoid Arthritis Known HLA Associations are Unlikely To Be Associated With Atopic Dermatitis.

J Rheumatol 2021 02 15;48(2):308-309. Epub 2020 Oct 15.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia.

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http://dx.doi.org/10.3899/jrheum.200583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324011PMC
February 2021

Genomic characterization of MICA gene using multiple next generation sequencing platforms: A validation study.

HLA 2020 10 21;96(4):430-444. Epub 2020 Aug 21.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

We have developed a protocol regarding the genomic characterization of the MICA gene by next generation sequencing (NGS). The amplicon includes the full length of the gene and is about 13 kb. A total of 156 samples were included in the study. Ninety-seven of these samples were previously characterized at MICA by legacy methods (Sanger or sequence specific oligonucleotide) and were used to evaluate the accuracy, precision, specificity, and sensitivity of the assay. An additional 59 DNA samples of unknown ethnicity volunteers from the United States were only genotyped by NGS. Samples were chosen to contain a diverse set of alleles. Our NGS approach included a first round of sequencing on the Illumina MiSeq platform and a second round of sequencing on the MinION platform by Oxford Nanopore Technology (ONT), on selected samples for the purpose of either characterizing new alleles or setting phase among multiple polymorphisms to resolve ambiguities or generate complete sequence for alleles that were only partially reported in the IMGT/HLA database. Complete consensus sequences were generated for every allele sequenced with ONT, extending from the 5' untranslated region (UTR) to the 3' UTR of the MICA gene. Thirty-two MICA sequences were submitted to the IMGT/HLA database including either new alleles or filling up the gaps (exonic, intronic and/or UTRs) of already reported alleles. Some of the challenges associated with the characterization of these samples are discussed.
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http://dx.doi.org/10.1111/tan.13998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589345PMC
October 2020

Utilizing nanopore sequencing technology for the rapid and comprehensive characterization of eleven HLA loci; addressing the need for deceased donor expedited HLA typing.

Hum Immunol 2020 Aug 25;81(8):413-422. Epub 2020 Jun 25.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

The comprehensive characterization of human leukocyte antigen (HLA) genomic sequences remains a challenging problem. Despite the significant advantages of next-generation sequencing (NGS) in the field of Immunogenetics, there has yet to be a single solution for unambiguous, accurate, simple, cost-effective, and timely genotyping necessary for all clinical applications. This report demonstrates the benefits of nanopore sequencing introduced by Oxford Nanopore Technologies (ONT) for HLA genotyping. Samples (n = 120) previously characterized at high-resolution three-field (HR-3F) for 11 loci were assessed using ONT sequencing paired to a single-plex PCR protocol (Holotype) and to two multiplex protocols OmniType (Omixon) and NGSgo®-MX6-1 (GenDx). The results demonstrate the potential of nanopore sequencing for delivering accurate HR-3F typing with a simple, rapid, and cost-effective protocol. The protocol is applicable to time-sensitive applications, such as deceased donor typings, enabling better assessments of compatibility and epitope analysis. The technology also allows significantly shorter turnaround time for multiple samples at a lower cost. Overall, the nanopore technology appears to offer a significant advancement over current next-generation sequencing platforms as a single solution for all HLA genotyping needs.
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http://dx.doi.org/10.1016/j.humimm.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870017PMC
August 2020

Complex Linkage Disequilibrium Effects in HLA-DPB1 Expression and Molecular Mismatch Analyses of Transplantation Outcomes.

Transplantation 2021 03;105(3):637-647

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.

Background: HLA molecular mismatch (MM) is a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation. HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk.

Methods: One hundred three HLA-DP-mismatched solid organ transplantation pairs were retrospectively analyzed. MM was computed using amino acids (aa), eplets, and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or rs9277534-G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD), and population-based analyses were performed.

Results: A high-risk AA:GX (recipient:donor) expression combination (X = A or G) demonstrated strong association with HLA-DP dnDSA (P = 0.001). MM was also associated with HLA-DP dnDSA when evaluated by itself (eplet P = 0.007, aa P = 0.003, Grantham P = 0.005, Epstein P = 0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (relative risk = 18.6, P = 0.007 with eplet; relative risk = 15.8, P = 0.02 with aa), while MM was no longer significant (eplet P = 0.56, aa P = 0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging single-nucleotide polymorphism and polymorphisms along HLA-DPB1.

Conclusions: The MM and expression risk factors each appear to be strong predictors of HLA-DP dnDSA and to possess clinical utility; however, these two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in dnDSA risk assessment and possibly transplantation overall.
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http://dx.doi.org/10.1097/TP.0000000000003272DOI Listing
March 2021

Lifetime and Stability of Silicon Nitride Nanopores and Nanopore Arrays for Ionic Measurements.

ACS Nano 2020 06 27;14(6):6715-6728. Epub 2020 Apr 27.

Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

Nanopores are promising for many applications including DNA sequencing and molecular filtration. Solid-state nanopores are preferable over their biological counterparts for applications requiring durability and operation under a wider range of external parameters, yet few studies have focused on optimizing their robustness. We report the lifetime and durability of pores and porous arrays in 10 to 100 nm-thick, low-stress silicon nitride (SiN) membranes. Pores are fabricated using a transmission electron microscope (TEM) and/or electron beam lithography (EBL) and reactive ion etching (RIE), with diameters from 2 to 80 nm. We store them in various electrolyte solutions (KCl, LiCl, MgCl) and record open pore conductance over months to quantify pore stability. Pore diameters increase with time, and diameter etch rate increases with electrolyte concentration from Δ/Δ ∼ 0.2 to ∼ 3 nm/day for 0.01 to 3 M KCl, respectively. TEM confirms the range of diameter etch rates from ionic measurements. Using electron energy loss spectroscopy (EELS), we observe a N-deficient region around the edges of TEM-drilled pores. Pore expansion is caused by etching of the Si/SiO pore walls, which resembles the dissolution of silicon found in minerals such as silica (SiO) in salty ocean water. The etching process occurs where the membrane was exposed to the electron beam and can result in pore formation. However, coating pores with a conformal 1 nm-thick hafnium oxide layer prevents expansion in 1 M KCl, in stark contrast to bare SiN pores (∼ 1.7 nm/day). EELS data reveal the atomic composition of bare and HfO-coated pores.
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http://dx.doi.org/10.1021/acsnano.9b09964DOI Listing
June 2020

Partially CD3-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy.

Biol Blood Marrow Transplant 2020 03 22;26(3):493-501. Epub 2019 Nov 22.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3/CD19 depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.022DOI Listing
March 2020

Clonally expanded alpha-chain T-cell receptor (TCR) transcripts are present in aneurysmal lesions of patients with Abdominal Aortic Aneurysm (AAA).

PLoS One 2019 16;14(7):e0218990. Epub 2019 Jul 16.

Department of Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States of America.

Abdominal aortic aneurysm (AAA) is a life-threatening immunological disease responsible for 1 to 2% of all deaths in 65 year old or older individuals. Although mononuclear cell infiltrates have been demonstrated in AAA lesions and autoimmunity may be responsible for the initiation and account for the propagation of the disease, the information available about the pathogenesis of AAA is limited. To examine whether AAA lesions from patients with AAA contain clonally expanded α-chain TCR transcripts, we amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR these α-chain TCR transcripts. The amplified transcripts were cloned and sequenced. Substantial proportions of identical α-chain TCR transcripts were identified in AAA lesions of 4 of 5 patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results were statistically significant by the bimodal distribution. Three of 5 of these patients were typed by DNA-based HLA-typing and all three expressed DRB1 alleles containing the DRβGln70 amino acid residue that has been demonstrated to be associated with AAA. All three patients exhibited clonally expanded T cells in AAA lesions. Four of the 5 patients with AAA who exhibited clonal expansions of α-chain TCR transcripts, also exhibited clonal expansions of β-chain TCR transcripts in AAA lesions, as we have demonstrated previously (J Immunol 192:4897, 2014). αβ TCR-expressing T cells infiltrating AAA lesions contain T-cell clones which have undergone proliferation and clonal expansion in vivo in response to as yet unidentified specific antigens that may be self or nonself. These results provide additional evidence supporting the hypothesis that AAA is a specific antigen-driven T-cell autoimmune disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218990PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634378PMC
February 2020

Resolving MiSeq-Generated Ambiguities in HLA-DPB1 Typing by Using the Oxford Nanopore Technology.

J Mol Diagn 2019 09 4;21(5):852-861. Epub 2019 Jun 4.

Immunogenetics Laboratory, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

The technical limitations of current next-generation sequencing technologies, combined with an ever-increasing number of human leukocyte antigen (HLA) alleles, form the basis for the additional ambiguities encountered at an increasing rate in clinical practice. HLA-DPB1 characterization, particularly, generates a significant percentage of ambiguities (25.5%), posing a challenge for accurate and unambiguous HLA-DPB1 genotyping. Phasing of exonic heterozygous positions between exon 2 and all other downstream exons has been the major cause of ambiguities. In this study, the Oxford Nanopore MinION, a third-generation sequencing technology, was used to resolve the phasing. The accurate MiSeq sequencing data, combined with the long reads obtained from the MinION platform, allow for the resolution of the tested ambiguities.
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http://dx.doi.org/10.1016/j.jmoldx.2019.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734860PMC
September 2019

Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer.

Sci Transl Med 2018 04;10(436)

Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, = 5), in combination with bevacizumab (cohort 2, = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.
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http://dx.doi.org/10.1126/scitranslmed.aao5931DOI Listing
April 2018

Sensitive and frequent identification of high avidity neo-epitope specific CD8 T cells in immunotherapy-naive ovarian cancer.

Nat Commun 2018 03 15;9(1):1092. Epub 2018 Mar 15.

Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, CH-1066, Switzerland.

Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8 T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8 T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.
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http://dx.doi.org/10.1038/s41467-018-03301-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854609PMC
March 2018

An Expanded Role for HLA Genes: Encodes a microRNA that Regulates IgA and Other Immune Response Transcripts.

Front Immunol 2017 19;8:583. Epub 2017 May 19.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

We describe a novel functional role for the locus mediated by its intron-encoded microRNA (miRNA), miR-6891-5p. We show that inhibition of miR-6891-5p impacts the expression of nearly 200 transcripts within the B-lymphoblastoid cell line (B-LCL) COX, affecting a large number of metabolic pathways, including various immune response networks. The top affected transcripts following miR-6891-5p inhibition are those encoding the heavy chain of IgA. We identified a conserved miR-6891-5p target site on the 3'UTR of both immunoglobulin heavy chain alpha 1 and 2 ( and ) transcripts and demonstrated that this miRNA modulates the expression of and . B-LCLs from IgA-deficient patients expressed significantly elevated levels of miR-6891-5p when compared with unaffected family members. Upon inhibition of miR-6891-5p, IgA mRNA expression levels were increased, and IgA secretion was restored in the B-LCL of an IgA-deficient patient. These findings indicate that miR-6891-5p regulates and gene expression at the posttranscriptional level and suggest that increase in miR-6891-5p levels may contribute to the etiology of selective IgA deficiency.
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http://dx.doi.org/10.3389/fimmu.2017.00583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437213PMC
May 2017

Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Nat Commun 2015 Oct 9;6:8442. Epub 2015 Oct 9.

RCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo 71013, Italy.

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
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http://dx.doi.org/10.1038/ncomms9442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633631PMC
October 2015

Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.

Genome Med 2015 Oct 1;7:90. Epub 2015 Oct 1.

Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN, USA.

Background: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.

Methods: We describe here the design and implementation of a customized genome-wide genotyping array, the 'TxArray', comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios.

Results: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.

Conclusions: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.
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http://dx.doi.org/10.1186/s13073-015-0211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589899PMC
October 2015

Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis.

Hum Immunol 2015 Aug 22;76(8):571-7. Epub 2015 Aug 22.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Atopic dermatitis (AD) is a waxing and waning illness of childhood that is likely caused by interactions between an altered skin barrier and immune dysregulation. The goal of our study was to evaluate the association of DRB1 genetic variants and the persistence of AD using whole exome sequencing and high resolution typing. DRB1 was interrogated based on previous reports that utilized high throughput techniques. We evaluated an ongoing nation-wide long-term cohort of children with AD in which patients are asked every 6months about their medication use and their AD symptoms. In total, 87 African-American and 50 European-American children were evaluated. Genetic association analysis was performed using a software tool focusing on amino acid variable positions shared by HLA-DRB1 alleles covering the antigen presenting domain. Amino acid variations at position 9 (pocket 9), position 26, and position 78 (pocket 4) were marginally associated with the prevalence of AD. However, the odds ratio was 0.30 (0.14, 0.68; p=0.003) for residue 78, 0.27 (0.10, 0.69; p=0.006) for residue 26 and not significant for residue 9 with respect to the persistence of AD. In conclusion, amino acid variations at peptide-binding pockets of HLA-DRB1 were associated with the persistence of AD in African-American children.
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http://dx.doi.org/10.1016/j.humimm.2015.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593755PMC
August 2015

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

Nat Med 2015 Sep 24;21(9):1018-27. Epub 2015 Aug 24.

Division of Rheumatology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.
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http://dx.doi.org/10.1038/nm.3933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863040PMC
September 2015

Aneurysmal lesions of patients with abdominal aortic aneurysm contain clonally expanded T cells.

J Immunol 2014 May 21;192(10):4897-912. Epub 2014 Apr 21.

Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140;

Abdominal aortic aneurysm (AAA) is a common disease with often life-threatening consequences. This vascular disorder is responsible for 1-2% of all deaths in men aged 65 years or older. Autoimmunity may be responsible for the pathogenesis of AAA. Although it is well documented that infiltrating T cells are essentially always present in AAA lesions, little is known about their role in the initiation and/or progression of the disease. To determine whether T cells infiltrating AAA lesions contain clonally expanded populations of T cells, we amplified β-chain TCR transcripts by the nonpalindromic adaptor-PCR/Vβ-specific PCR and/or Vβ-specific PCR, followed by cloning and sequencing. We report in this article that aortic abdominal aneurysmal lesions from 8 of 10 patients with AAA contained oligoclonal populations of T cells. Multiple identical copies of β-chain TCR transcripts were identified in these patients. These clonal expansions are statistically significant. These results demonstrate that αβ TCR(+) T lymphocytes infiltrating aneurysmal lesions of patients with AAA have undergone proliferation and clonal expansion in vivo at the site of the aneurysmal lesion, in response to unidentified self- or nonself Ags. This evidence supports the hypothesis that AAA is a specific Ag-driven T cell disease.
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http://dx.doi.org/10.4049/jimmunol.1301009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009497PMC
May 2014

HLA-A and HLA-DRB1 amino acid polymorphisms are associated with susceptibility and protection to pulmonary tuberculosis in a Greek population.

Hum Immunol 2012 Jun 12;73(6):641-6. Epub 2012 Apr 12.

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Background: Pulmonary tuberculosis remains the single deadliest infectious disease causing high mortality in humans leading to 1.4 million deaths annually. Inherited genetic factors may explain why some people resist infection more successfully than others.

Methods: The polymorphisms of HLA-class I (-A, -B) and class II (-DRB1, -DQB1) genes have been evaluated using DNA-based typing in a population of 86 non-immunosuppressed, unrelated Greek patients with PTb and 46 healthy unrelated people without a history of PTb, who were all tested purified protein derivative positive (>14 mm).

Results: The HLA-A R(114) and HLA-DRβN(37) residues are associated with susceptibility. They operate independently from each other and their effect is detected when the population is evaluated for their concurrent presence (A R(114) positive or DRβN(37) positive or A R(114) and DRβN(37) positive). Furthermore the HLA-A S(77) appears to have a protective role, however in the presence of the DRβN(37), the A-S(77) does not exert its protective effect.

Conclusion: The HLA residues A-S(77), A-R(114) and DRβN(37) in combination with PTb antigenic elements possibly modulate T-cell responses against MTb that lead to either protection or susceptibility. The HLA-A and -DRB1-dependent T-cell networks may interact among themselves and influence each other resulting in different PTb phenotypes.
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http://dx.doi.org/10.1016/j.humimm.2012.03.008DOI Listing
June 2012

A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci.

PLoS Genet 2011 Sep 29;7(9):e1002293. Epub 2011 Sep 29.

The Center for Applied Genomics, The Children's Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America.

Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹ resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹ lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.
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http://dx.doi.org/10.1371/journal.pgen.1002293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183083PMC
September 2011

Common variants at five new loci associated with early-onset inflammatory bowel disease.

Nat Genet 2009 Dec 15;41(12):1335-40. Epub 2009 Nov 15.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.
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http://dx.doi.org/10.1038/ng.489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267927PMC
December 2009

Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes.

Diabetes 2009 Jan 7;58(1):290-5. Epub 2008 Oct 7.

Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Objective: Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject-parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals.

Research Design And Methods: From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects.

Results: Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 x 10(-8)) and BACH2 (1.13; combined P = 1.25 x 10(-6)).

Conclusions: Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.
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http://dx.doi.org/10.2337/db08-1022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606889PMC
January 2009

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.

Nat Genet 2008 Oct 31;40(10):1211-5. Epub 2008 Aug 31.

Department of Pediatrics, Children's Research Institute and Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.
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http://dx.doi.org/10.1038/ng.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770437PMC
October 2008

SKDM human leukocyte antigen (HLA) tool: A comprehensive HLA and disease associations analysis software.

Hum Immunol 2008 Aug 2;69(8):522-5. Epub 2008 Jul 2.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.

The immensely polymorphic and gene-rich landscape of the major histocompatibility complex on chromosome 6 necessitates a thorough and consistent investigation of its constituting elements. The human leukocyte antigens (HLAs) are an example of such polymorphic elements, implicated in many immune-based diseases. So far, analyses of HLA molecules in the context of diseases have been ad hoc, frequently incomplete, and extremely cumbersome. SKDM provides a comprehensive and automated workflow for detecting and dissecting HLA associations in diseases. We created a Java application to consistently perform our proposed method of analysis of HLAs in case-control datasets. The SKDM HLA tool can test for HLA allele differences between two populations and, by retrieving amino acid sequences, evaluates each polymorphic amino acid residue or a pocket of amino acids as an independent variant. Once primary associations are identified, the program examines zygosity and tests for strongest association, interaction, and linkage disequilibrium among amino acid epitopes of the same HLA molecule or between HLA isotypes. A summary of the analysis is output in plain language. The software and a user's manual are freely available at http://sourceforge.net/projects/skdm.
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http://dx.doi.org/10.1016/j.humimm.2008.05.011DOI Listing
August 2008

A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study.

Diabetes 2008 Apr 15;57(4):1143-6. Epub 2008 Jan 15.

Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, PA 19104-4318, USA.

Objective: In stage 1 of our genome-wide association (GWA) study for type 1 diabetes, one locus at 16p13 was detected (P = 1.03 x 10(-10)) and confirmed in two additional cohorts. Here we describe the results of testing, in these additional cohorts, 23 loci that were next in rank of statistical significance.

Research Design And Methods: Two independent cohorts were studied. The Type 1 Diabetes Genetics Consortium replication cohort consisted of 549 families with at least one child diagnosed with diabetes (946 total affected) and DNA from both parents. The Canadian replication cohort consisted of 364 nuclear family trios with one type 1 diabetes-affected offspring and two parents (1,092 individuals).

Results: One locus at 12q13, with the highest statistical significance among the 23, was confirmed. It involves type 1 diabetes association with the minor allele of rs1701704 (P = 9.13 x 10(-10), OR 1.25 [95% CI 1.12-1.40]).

Conclusions: We have discovered a type 1 diabetes locus at 12q13 that is replicated in an independent cohort of type 1 diabetic patients and confers a type 1 diabetes risk comparable with that of the 16p13 locus we recently reported. These two loci are identical to two loci identified by the whole-genome association study of the Wellcome Trust Case-Control Consortium, a parallel independent discovery that adds further support to the validity of the GWA approach.
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http://dx.doi.org/10.2337/db07-1305DOI Listing
April 2008

A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.

Nature 2007 Aug 15;448(7153):591-4. Epub 2007 Jul 15.

Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.
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http://dx.doi.org/10.1038/nature06010DOI Listing
August 2007
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