Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis

Objective.Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.Methods.Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.Results.Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)].Conclusion.We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

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Association ofTNFAIP3Polymorphism with Susceptibility to Systemic Lupus Erythematosus in a Japanese Population

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/207578 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 25

Author(s):

Aya Kawasaki ◽

Ikue Ito ◽

Satoshi Ito ◽

Taichi Hayashi ◽

Daisuke Goto ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Japanese Population ◽

Association Studies ◽

Susceptibility Gene ◽

Allelic Association ◽

Genome Wide Association Studies ◽

Mrna Levels ◽

Nucleotide Polymorphisms ◽

Systemic Lupus

Recent genome-wide association studies demonstrated association of single nucleotide polymorphisms (SNPs) in theTNFAIP3region at 6q23 with systemic lupus erythematosus (SLE) in European-American populations. In this study, we investigated whether SNPs in theTNFAIP3region are associated with SLE also in a Japanese population. A case-control association study was performed on the SNPs rs13192841, rs2230926, and rs6922466 in 318 Japanese SLE patients and 444 healthy controls. Association of rs2230926 G allele with SLE was replicated in Japanese (allelic associationP=.033, odds ratio [OR] 1.47, recessive modelP=.023, OR 8.52). The association was preferentially observed in the SLE patients with nephritis. When theTNFAIP3mRNA levels of the HapMap samples were examined using GENEVAR database, the presence ofTNFAIP3rs2230926 G allele was associated with lower mRNA expression ofTNFAIP3(P=.013). These results indicated thatTNFAIP3is a susceptibility gene to SLE both in the Caucasian and Asian populations.

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Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.116434 ◽

2009 ◽

Vol 69 (3) ◽

pp. 550-555 ◽

Cited By ~ 85

Author(s):

Pravitt Gourh ◽

Frank C Arnett ◽

Filemon K Tan ◽

Shervin Assassi ◽

Dipal Divecha ◽

...

Keyword(s):

Systemic Sclerosis ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Costimulatory Molecule ◽

Susceptibility Gene ◽

Potential Interaction ◽

Gene Region ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Ox40 Ligand

ObjectiveIt is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.MethodsA total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.ResultsCase-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.ConclusionsPolymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.

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Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

Journal of Immunology Research ◽

10.1155/2015/153132 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 8

Author(s):

Yue-miao Zhang ◽

Fa-juan Cheng ◽

Xu-jie Zhou ◽

Yuan-yuan Qi ◽

Ping Hou ◽

...

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Clinical Information ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Single Nucleotide ◽

Genetic Studies ◽

Genome Wide ◽

Custom Made ◽

Regulatory Effects

Objectives. Numerous loci were identified to perturb gene expression intrans. As elevatedATG5expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated withATG5expression in a Chinese population with lupus nephritis (LN).Methods. The online expression quantitative trait loci database was searched fortrans-expression single nucleotide polymorphisms (trans-eSNPs) ofATG5. Taggingtrans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed.Results. Fourtrans-eSNPs were observed to be associated with susceptibility to LN (P< 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven othertrans-eSNPs showed marginal significant associations (0.05 <P< 0.1). Correlations between thetrans-eSNPs andATG5expression and different expression levels ofATG5in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes oftrans-eSNPs and severity or outcome of the patients.Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies.

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Response to Intravenous Cyclophosphamide Treatment for Lupus Nephritis Associated with Polymorphisms in the FCGR2B-FCRLA Locus

The Journal of Rheumatology ◽

10.3899/jrheum.150665 ◽

2016 ◽

Vol 43 (6) ◽

pp. 1045-1049 ◽

Cited By ~ 8

Author(s):

Kwangwoo Kim ◽

So-Young Bang ◽

Young Bin Joo ◽

Taehyeung Kim ◽

Hye-Soon Lee ◽

...

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Receptor Gene ◽

Genotype Imputation ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Single Nucleotide ◽

Genome Wide ◽

Cyclophosphamide Treatment

Objective.Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy.Methods.Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III–V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran–Armitage trend tests, and genotype imputation was used for defining the association locus.Results.Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r2 = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 × 10−8). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%).Conclusion.This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy.

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Genetic Variants behind Cardiovascular Diseases and Dementia

Genes ◽

10.3390/genes11121514 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1514

Author(s):

Wei-Min Ho ◽

Yah-Yuan Wu ◽

Yi-Chun Chen

Keyword(s):

White Matter ◽

Cardiovascular Diseases ◽

Genetic Variants ◽

White Matter Hyperintensities ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Pubmed Database ◽

Risk Snps

Cardiovascular diseases (CVDs) and dementia are the leading causes of disability and mortality. Genetic connections between cardiovascular risk factors and dementia have not been elucidated. We conducted a scoping review and pathway analysis to reveal the genetic associations underlying both CVDs and dementia. In the PubMed database, literature was searched using keywords associated with diabetes mellitus, hypertension, dyslipidemia, white matter hyperintensities, cerebral microbleeds, and covert infarctions. Gene lists were extracted from these publications to identify shared genes and pathways for each group. This included high penetrance genes and single nucleotide polymorphisms (SNPs) identified through genome wide association studies. Most risk SNPs to both diabetes and dementia participate in the phospholipase C enzyme system and the downstream nositol 1,4,5-trisphosphate and diacylglycerol activities. Interestingly, AP-2 (TFAP2) transcription factor family and metabolism of vitamins and cofactors were associated with genetic variants that were shared by white matter hyperintensities and dementia, and by microbleeds and dementia. Variants shared by covert infarctions and dementia were related to VEGF ligand–receptor interactions and anti-inflammatory cytokine pathways. Our review sheds light on future investigations into the causative relationships behind CVDs and dementia, and can be a paradigm of the identification of dementia treatments.

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Genetics of systemic sclerosis

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198320913695 ◽

2020 ◽

Vol 5 (3) ◽

pp. 192-201 ◽

Cited By ~ 1

Author(s):

Yuki Ishikawa ◽

Chikashi Terao

Keyword(s):

Systemic Sclerosis ◽

Disease Risk ◽

Association Studies ◽

Human Leukocyte ◽

Premature Death ◽

Microvascular Dysfunction ◽

Candidate Gene Approach ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Genetic Components

Systemic sclerosis is an autoimmune disease characterized by generalized fibrosis in connective tissues and internal organs as consequences of microvascular dysfunction and immune dysfunctions, which leads to premature death in affected individuals. The etiology of systemic sclerosis is complex and poorly understood, but as with most autoimmune diseases, it is widely accepted that both environmental and genetic factors contribute to disease risk. During the last decade, the number of genetic markers convincingly associated with systemic sclerosis has exponentially increased. In this article, we briefly mention the genetic components of systemic sclerosis. Then, we review the classical and novel genetic associations with systemic sclerosis, analyzing the firmest and replicated signals within non–human leukocyte antigen genes, identified by both candidate gene approach and genome-wide association studies. We also provide an insight into the future perspectives that will shed more light into the complex genetic background of the disease. Despite the remarkable advance of systemic sclerosis genetics during the last decade, the use of the new genetic technologies such as next-generation sequencing, as well as the deep phenotyping of the study cohorts, to fully characterize the genetic component of this disease is imperative to identify causal variants, which leads to more targeted and effective treatment of systemic sclerosis.

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Genomic Polymorphism at the Interferon-Induced Helicase (IFIH1) Locus Contributes to Graves’ Disease Susceptibility

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0173 ◽

2007 ◽

Vol 92 (8) ◽

pp. 3338-3341 ◽

Cited By ~ 78

Author(s):

Alison Sutherland ◽

Jocelyn Davies ◽

Catherine J. Owen ◽

Suresh Vaikkakara ◽

Christine Walker ◽

...

Keyword(s):

Lupus Erythematosus ◽

Large Scale ◽

Disease Patient ◽

Addison’S Disease ◽

Addison's Disease ◽

Graves Disease ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Genomic Polymorphism ◽

Intronic Polymorphism

Abstract Context: A recent large-scale analysis of nonsynonymous coding polymorphisms showed strong evidence that an alanine to threonine amino acid change at codon 946 of the interferon-induced helicase (IFIH1) gene (SNP ID rs1990760) was associated with type 1 diabetes. Previous investigations have also demonstrated that an intronic polymorphism (termed PD1.3; SNP ID rs11568821) in the programmed cell death (PDCD1) gene was associated with systemic lupus erythematosus and rheumatoid arthritis. Objective: We sought to replicate these genetic associations in Graves’ disease and autoimmune Addison’s disease patient cohorts. Patients and Methods: A total of 602 Graves’ disease subjects, 214 Addison’s disease subjects, and 446 healthy controls were genotyped for the IFIH1 and PDCD1 single-nucleotide polymorphisms using mass spectrometer analysis of primer extension products (Sequenom). Results: The alanine-carrying allele at the IFIH1 codon 946 polymorphism was present in 796 of 1204 (66%) Graves’ disease patient alleles compared with 508 of 892 (57%) control subject alleles [odds ratio 1.47 (5–95% confidence interval, 1.23–1.76); P = 1.9 × 10−5]. In contrast, there was no association of alleles at this marker in autoimmune Addison’s disease. Neither was there evidence for association in either patient cohort at the PD1.3 polymorphism. Conclusions: We confirm a significant contribution of the Ala946Thr IFIH1 polymorphism to organ-specific autoimmune diseases, extending the range of conditions associated with this variant to include Graves’ disease. This polymorphism may also contribute to several other autoimmune disorders.

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RACER: A data visualization strategy for exploring multiple genetic associations

10.1101/495366 ◽

2018 ◽

Cited By ~ 1

Author(s):

Olivia L. Sabik ◽

Charles R. Farber

Keyword(s):

Association Studies ◽

Causal Variant ◽

Visual Exploration ◽

Supplementary Information ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Genome Wide ◽

Causal Genes ◽

Visualization Strategy ◽

The Relationship

SummaryGenome-wide association studies (GWASs) have identified thousands of loci associated with risk of various diseases; however, the genes responsible for the majority of loci have not been identified. One means of uncovering potential causal genes is the identification of expression quantitative trait loci (eQTL) that colocalize with disease loci. Statistical methods have been developed to assess the likelihood that two associations (e.g. disease locus and eQTL) share a common causal variant, however, visualization of the two loci is often a crucial step in determining if a locus is pleiotropic. While the current convention is to plot two associations side-by-side, it is difficult to compare across two x-axes, even if they are identical. Thus, we have developed the Regional Association ComparER (RACER) package, which creates “mirror plots”, in which the two associations are plotted on a shared x-axis. Mirror plots provide an effective tool for the visual exploration and presentation of the relationship between two genetic associations.Availability and ImplementationRACER is provided under the GNU General Public License version 3 (GPL-3.0). Source code is available at https://github.com/oliviasabik/[email protected] informationSupplementary data are available online with the paper, see the Supplemental Data Manifest.

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Type I Interferon and the Spectrum of Susceptibility to Viral Infection and Autoimmune Disease: A Shared Genomic Signature

Frontiers in Immunology ◽

10.3389/fimmu.2021.757249 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jamie A. Sugrue ◽

Nollaig M. Bourke ◽

Cliona O’Farrelly

Keyword(s):

Autoimmune Disease ◽

Viral Infection ◽

Lupus Erythematosus ◽

Molecular Mechanisms ◽

Type I Interferons ◽

Type I ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Signalling Molecules ◽

Resistance To Viral Infection

Type I interferons (IFN-I) and their cognate receptor, the IFNAR1/2 heterodimer, are critical components of the innate immune system in humans. They have been widely explored in the context of viral infection and autoimmune disease where they play key roles in protection against infection or shaping disease pathogenesis. A false dichotomy has emerged in the study of IFN-I where interferons are thought of as either beneficial or pathogenic. This ‘good or bad’ viewpoint excludes more nuanced interpretations of IFN-I biology - for example, it is known that IFN-I is associated with the development of systemic lupus erythematosus, yet is also protective in the context of infectious diseases and contributes to resistance to viral infection. Studies have suggested that a shared transcriptomic signature underpins both potential resistance to viral infection and susceptibility to autoimmune disease. This seems to be particularly evident in females, who exhibit increased viral resistance and increased susceptibility to autoimmune disease. The molecular mechanisms behind such a signature and the role of sex in its determination have yet to be precisely defined. From a genomic perspective, several single nucleotide polymorphisms (SNPs) in the IFN-I pathway have been associated with both infectious and autoimmune disease. While overlap between infection and autoimmunity has been described in the incidence of these SNPs, it has been overlooked in work and discussion to date. Here, we discuss the possible contributions of IFN-Is to the pathogenesis of infectious and autoimmune diseases. We comment on genetic associations between common SNPs in IFN-I or their signalling molecules that point towards roles in protection against viral infection and susceptibility to autoimmunity and propose that a shared transcriptomic and genomic immunological signature may underlie resistance to viral infection and susceptibility to autoimmunity in humans. We believe that defining shared transcriptomic and genomic immunological signatures underlying resistance to viral infection and autoimmunity in humans will reveal new therapeutic targets and improved vaccine strategies, particularly in females.

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The role of polymorphic ERAP1 in autoinflammatory disease

Bioscience Reports ◽

10.1042/bsr20171503 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 15

Author(s):

Emma Reeves ◽

Edward James

Keyword(s):

Single Nucleotide Polymorphisms ◽

Autoinflammatory Disease ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Single Nucleotide ◽

Cell Functions ◽

The Impact

Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.

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