Submit to Genes Review for Genes Propose a Special Issue

Journal Browser

Genetics and Epigenetics of Autoimmune Diseases

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (25 December 2022) | Viewed by 13247

Share This Special Issue

Special Issue Editors

Dr. F. Yesim Demirci

E-Mail Website
Guest Editor

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
Interests: complex human diseases; immune-mediated conditions; autoimmune diseases; genetics; genomics; multi-omics; non-coding RNAs

Dr. Timothy B. Niewold

E-Mail Website
Guest Editor

Division of Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA
Interests: autoimmune diseases; genetics; immunology; complex disease; inteferons and cytokines

Special Issue Information

Dear Colleagues,

Autoimmune diseases (AIDs) encompass a wide spectrum of disorders that vary in prevalence, etiopathogenesis, and clinical findings. While monogenic forms also exist, most AIDs have a complex genetic basis (multifactorial, polygenic) and are mediated by the interplay of demographic, environmental, and genetic risk factors. Recent technological advances and genome-wide association studies have revealed a large number of susceptibility loci for AIDs, mainly implicating non-coding regulatory variants/regions. While the causal variants/genes and biological mechanisms remain elusive at most of these loci, the missing heritability suggests the presence of additional genetic loci/factors awaiting discovery.

Recent advances have also significantly improved our understanding of epigenetic mechanisms that influence immune/autoimmune processes, such as DNA methylation-, histone modification-, and small or long non-coding RNA-mediated gene expression regulation. However, epigenetic investigations are relatively new in most AIDs and much remains to be learned about the relationship between epigenetic regulation and genetic/environmental risk factors, and the cell type/context-specific epigenetic modulations.

For this Special Issue, we welcome research articles and narrative reviews on genetic and epigenetic factors influencing AID risk or clinical outcomes (e.g., molecular classification, prognosis, therapy response). We are particularly interested in articles involving association studies (e.g., those using genome-wide, fine-mapping, or polygenic risk score approaches) and/or epigenetic investigations at the DNA or RNA level (e.g., those using human samples, cell/tissue or animal models), which aim to further enhance our knowledge and understanding of AIDs.

Dr. F. Yesim Demirci
Dr. Timothy B. Niewold
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

autoimmune
genetic loci
polymorphisms
variants
regulatory elements
dna methylation
histone modification
non-coding rnas
miRNAs
lncRNAs

Published Papers (6 papers)

Download All Papers

Research

Jump to: Review

9 pages, 749 KiB

Open AccessArticle

Association of Fc Gamma Receptor 3B Gene Copy Number Variation with Rheumatoid Arthritis Susceptibility

by M. Muaaz Aslam, Peter John, Kang-Hsien Fan, Javaid Mehmood Malik, Eleanor Feingold, F. Yesim Demirci and M. Ilyas Kamboh

Genes 2022, 13(12), 2238; https://doi.org/10.3390/genes13122238 - 29 Nov 2022

Viewed by 1239

Abstract

Structural variations such as copy number variants (CNVs) have been associated with multiple autoimmune diseases. In this study, we explored the association of the Fc gamma receptor 3B gene (FCGR3B) copy number variation (CNV) with rheumatoid arthritis (RA) susceptibility and related serological traits in the Pakistani population. We also performed a meta-analysis of four published FCGR3B CNV studies along with the current study. A total of 927 subjects (597 RA cases, 330 healthy controls) were recruited from three rheumatology centers in Pakistan. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured in RA patients. FCGR3B copy number was assayed using the TaqMan^® CN assay (Hs04211858_cn, Applied Biosystems, Foster City, CA, USA) and the copy number was estimated by using CopyCaller^® software (version 2.1; Applied Biosystems, USA). Logistic regression was applied to calculate the odds ratio (OR) of RA risk associated with FCGR3B CNV using sex and age as covariates in R. Meta-analysis on four previously published studies and the current study was performed using the random-effect model. We observed a significant association between FCGR3B copy number < 2 and RA susceptibility (OR = 1.53; 95% CI: 1.05 to 2.22; p = 0.0259) and anti-CCP seropositivity (OR 2.56; 95% CI: 1.34 to 4.89; p = 0.0045). A non-significant association of FCGR3B copy number < 2 was also observed between increased rheumatoid factor (RF) seropositivity (OR = 1.74; 95% CI:0.93 to 3.26; p = 0.0816). Meta-analysis on 13,915 subjects (7005 RA cases and 6907 controls) also showed significant association of copy number < 2 with the increased risk of RA (OR = 1.30; 95% CI: 1.07 to 1.56; p = 0.00671). FCGR3B copy number < 2 is associated with increased RA risk and anti-CCP seropositivity. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Autoimmune Diseases)

► Show Figures

Figure 1

15 pages, 2902 KiB

Open AccessArticle

Discovery and Functional Characterization of Two Regulatory Variants Underlying Lupus Susceptibility at 2p13.1

by Mehdi Fazel-Najafabadi, Harikrishna-Reddy Rallabandi, Manish K. Singh, Guru P. Maiti, Jacqueline Morris, Loren L. Looger and Swapan K. Nath

Genes 2022, 13(6), 1016; https://doi.org/10.3390/genes13061016 - 5 Jun 2022

Cited by 3 | Viewed by 2426

Abstract

Genome-wide association studies have identified 2p13.1 as a prominent susceptibility locus for systemic lupus erythematosus (SLE)—a complex, multisystem autoimmune disease. However, the identity of underlying causal variant (s) and molecular mechanisms for increasing disease susceptibility are poorly understood. Using meta-analysis (cases = 10,252, controls = 21,604) followed by conditional analysis, bioinformatic annotation, and eQTL and 3D-chromatin interaction analyses, we computationally prioritized potential functional variants and subsequently experimentally validated their effects. Ethnicity-specific meta-analysis revealed striking allele frequency differences between Asian and European ancestries, but with similar odds ratios. We identified 20 genome-wide significant (p < 5 × 10⁻⁸) variants, and conditional analysis pinpointed two potential functional variants, rs6705628 and rs2272165, likely to explain the association. The two SNPs are near DGUOK, mitochondrial deoxyguanosine kinase, and its associated antisense RNA DGUOK-AS1. Using luciferase reporter gene assays, we found significant cell type- and allele-specific promoter activity at rs6705628 and enhancer activity at rs2272165. This is supported by ChIP-qPCR showing allele-specific binding with three histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), transcriptional coactivator p300, CCCTC-binding factor (CTCF), and transcription factor ARID3A. Transcriptome data across 28 immune cell types from Asians showed both SNPs are cell-type-specific but only in B-cells. Splicing QTLs showed strong regulation of DGUOK-AS1. Genotype-specific DGOUK protein levels are supported by Western blots. Promoter capture Hi-C data revealed long-range chromatin interactions between rs2272165 and several nearby promoters, including DGUOK. Taken together, we provide mechanistic insights into how two noncoding variants underlie SLE risk at the 2p13.1 locus. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Autoimmune Diseases)

► Show Figures

Figure 1

13 pages, 781 KiB

Open AccessArticle

Genetic Variants Associated with Neuropeptide Y Autoantibody Levels in Newly Diagnosed Individuals with Type 1 Diabetes

by Sara Juul Mansachs, Sofie Olund Villumsen, Jesper Johannesen, Alexander Lind, Simranjeet Kaur and Flemming Pociot

Genes 2022, 13(5), 869; https://doi.org/10.3390/genes13050869 - 12 May 2022

Viewed by 2029

Abstract

(1) Autoantibodies to the leucine variant of neuropeptide Y (NPY-LA) have been found in individuals with type 1 diabetes (T1D). We investigated the association between the levels of NPY-LA and single nucleotide polymorphisms (SNP) to better understand the genetic regulatory mechanisms of autoimmunity in T1D and the functional impacts of increased NPY-LA levels. (2) NPY-LA measurements from serum and SNP genotyping were done on 560 newly diagnosed individuals with T1D. SNP imputation with the 1000 Genomes reference panel was followed by an association analysis between the SNPs and measured NPY-LA levels. Additionally, functional enrichment and pathway analyses were done. (3) Three loci (DGKH, DCAF5, and LINC02261) were associated with NPY-LA levels (p-value < 1.5 × 10⁻⁶), which indicates an association with neurologic and vascular disorders. SNPs associated with variations in expression levels were found in six genes (including DCAF5). The pathway analysis showed that NPY-LA was associated with changes in gene transcription, protein modification, immunological functions, and the MAPK pathway. (4) Conclusively, we found NPY-LA to be significantly associated with three loci (DGKH, DCAF5, and LINC02261), and based on our findings we hypothesize that the presence of NPY-LA is associated with the regulation of the immune system and possibly neurologic and vascular disorders. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Autoimmune Diseases)

► Show Figures

Figure 1

20 pages, 1847 KiB

Open AccessArticle

Nucleic Acid-Sensing and Interferon-Inducible Pathways Show Differential Methylation in MZ Twins Discordant for Lupus and Overexpression in Independent Lupus Samples: Implications for Pathogenic Mechanism and Drug Targeting

by Miranda C. Marion, Paula S. Ramos, Prathyusha Bachali, Adam C. Labonte, Kip D. Zimmerman, Hannah C. Ainsworth, Sarah E. Heuer, Robert D. Robl, Michelle D. Catalina, Jennifer A. Kelly, Timothy D. Howard, Peter E. Lipsky, Amrie C. Grammer and Carl D. Langefeld

Genes 2021, 12(12), 1898; https://doi.org/10.3390/genes12121898 - 26 Nov 2021

Cited by 7 | Viewed by 2403

Abstract

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant for SLE. Genes implicated by the epigenetic analyses were then evaluated in 10 independent SLE gene expression datasets from the Gene Expression Omnibus (GEO). There were 59 differentially methylated loci between unaffected and affected MZ twins in whole blood, including 11 novel loci. All but two of these loci were hypomethylated in the SLE twins relative to the unaffected twins. The genes harboring these hypomethylated loci exhibited increased expression in multiple independent datasets of SLE patients. This pattern was largely consistent regardless of disease activity, cell type, or renal tissue type. The genes proximal to CpGs exhibiting differential methylation (DM) in the SLE-discordant MZ twins and exhibiting differential expression (DE) in independent SLE GEO cohorts (DM-DE genes) clustered into two pathways: the nucleic acid-sensing pathway and the type I interferon pathway. The DM-DE genes were also informatically queried for potential gene–drug interactions, yielding a list of 41 drugs including a known SLE therapy. The DM-DE genes delineate two important biologic pathways that are not only reflective of the heterogeneity of SLE but may also correlate with distinct IFN responses that depend on the source, type, and location of nucleic acid molecules and the activated receptors in individual patients. Cell- and tissue-specific analyses will be critical to the understanding of genetic factors dysregulating the nucleic acid-sensing and IFN pathways and whether these factors could be appropriate targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Autoimmune Diseases)

► Show Figures

Figure 1

7 pages, 226 KiB

Open AccessArticle

Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype

by Jürgen Enczmann, Vera Balz, Maximilian Hoffmann, Sebastian Kummer, Christina Reinauer, Carsten Döing, Katharina Förtsch, Alena Welters, Ertan Mayatepek, Thomas Meissner, Marc Jacobsen and Julia Seyfarth

Genes 2021, 12(12), 1879; https://doi.org/10.3390/genes12121879 - 25 Nov 2021

Cited by 5 | Viewed by 1988

Abstract

The highest genetic type 1 diabetes risk is conferred by HLA class II haplotypes defined by alleles at the HLA-DR and -DQ loci. The combination of HLA-DQA1*03:01 and DQB1*03:02 alleles (summarized as ‘HLA-DQ8′) is reported to be among the two most prevalent HLA class II haplotypes in Caucasian type 1 diabetes patients. This classification is based on conventional genotyping of exon 2 of the DQ gene locus and excludes exon 3. In this study, HLA genotyping on the type 1 diabetes susceptibility loci HLA-DRB1, DQA1 and DQB1 was performed using a high-resolution next generation sequencing method. In addition to the routinely examined exon 2, exon 3 was also sequenced. Samples from 229 children with type 1 diabetes were included and compared to a cohort of 9,786 controls. In addition to previously described HLA-DQ haplotypes in type 1 diabetes patients, we found that as well as HLA-DQA1*03:01,HLA-DQA1*03:03 also contributed to HLA-DQ8. HLA-DQA1*03:03 differs from HLA-DQA1*03:01 by one nucleotide substitution in exon 3 at position 160, leading to a single amino acid replacement. DRB1*04:05 was exclusively associated with DQA1*03:03 whereas the DRB1*04:01 haplotype comprised either DQA1*03:01 or DQA1*03:03. Significantly increased type 1 diabetes risk was confirmed for all these haplotypes with only minor differences between DQA1*03:01 and DQA1*03:03 alleles. This study identified the HLA-DQA1*03:03 allele as an addition to the already known type 1 diabetes risk haplotypes, and can contribute to more precise HLA genotyping approaches. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Autoimmune Diseases)

Review

Jump to: Research

28 pages, 1709 KiB

Open AccessReview

Scoping Review on Epigenetic Mechanisms in Primary Immune Thrombocytopenia

by Jian Hong Tan, Ahmad Hazim Syakir Ahmad Azahari, Adli Ali and Noor Akmal Shareela Ismail

Genes 2023, 14(3), 555; https://doi.org/10.3390/genes14030555 - 23 Feb 2023

Viewed by 1883

Abstract

Immune Thrombocytopenia (ITP) is an autoimmune blood disorder that involves multiple pathways responsible for the homeostasis of the immune system. Numerous pieces of literature have proposed the potential of immune-related genes as diagnostic and prognostic biomarkers, which mostly implicate the role of B cells and T cells in the pathogenesis of ITP. However, a more in-depth understanding is required of how these immune-related genes are regulated. Thus, this scoping review aims to collate evidence and further elucidate each possible epigenetics mechanism in the regulation of immunological pathways pertinent to the pathogenesis of ITP. This encompasses DNA methylation, histone modification, and non-coding RNA. A total of 41 studies were scrutinized to further clarify how each of the epigenetics mechanisms is related to the pathogenesis of ITP. Identifying epigenetics mechanisms will provide a new paradigm that may assist in the diagnosis and treatment of immune thrombocytopenia. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Autoimmune Diseases)

► Show Figures