A candidate gene study reveals association between a variant of the Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) gene and systemic sclerosis

IntroductionThe multifunctional nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) has potent anti-fibrotic effects, and its expression and activity are impaired in patients with systemic sclerosis (SSc). We investigated PPAR-γ gene (PPARG) single nucleotide polymorphisms (SNPs) associated with SSc.MethodsTag SNPs spanning PPARG were genotyped in a European ancestry US discovery cohort comprising 152 SSc patients and 450 controls, with replication of our top signal in a European cohort (1031 SSc patients and 1014 controls from France). Clinical parameters and disease severity were analyzed to evaluate clinical associations with PPARG variants.ResultsIn the discovery cohort, a single PPARG intronic SNP (rs10865710) was associated with SSc (p = 0.010; odds ratio = 1.52 per C allele, 95% confidence interval 1.10-2.08). This association was replicated in the French validation cohort (p = 0.052; odds ratio = 1.16 per C allele, 95% confidence interval 1.00-1.35). Meta-analysis of both cohorts indicated stronger evidence for association (p = 0.002; odds ratio = 1.22 per C allele, 95% confidence interval 1.07-1.40). The rs10865710 C allele was also associated with pulmonary arterial hypertension in the French SSc cohort (p = 0.002; odds ratio = 2.33 per C allele, 95% confidence interval 1.34-4.03).ConclusionsA PPARG variant is associated with susceptibility to SSc, consistent with a role of PPAR-γ in the pathogenesis of SSc.

• Publication year

  2015

• Venue

  Arthritis Research & Therapy

• Publication date

  2015-05-19

• Fields of study

  Medicine

• Identifiers
  DOI 10.1186/s13075-015-0641-2PMID 25986483PMCID 4437446
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Identification of IL12RB1 as a Novel Systemic Sclerosis Susceptibility Locus

  2014cited by this paper
• Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

  2014cited by this paper
• A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

  2014cited by this paper
• Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.

  2014influential reference
• Clinical implications of shared genetics and pathogenesis in autoimmune diseases

  2013cited by this paper
• PPARγ signaling and metabolism: the good, the bad and the future

  2013cited by this paper
• A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.

  2013cited by this paper
• Unraveling the genetic component of systemic sclerosis

  2012cited by this paper
• Regulation of Matrix Remodeling by Peroxisome Proliferator-Activated Receptor-γ: A Novel Link Between Metabolism and Fibrogenesis

  2012cited by this paper
• The genetics of scleroderma: looking into the postgenomic era

  2012cited by this paper
• Peroxisome Proliferator-Activated Receptor-&ggr; Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

  2012cited by this paper
• Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker?

  2012cited by this paper
• Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study

  2012cited by this paper
• Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities

  2012cited by this paper
• An Integrated Encyclopedia of DNA Elements in the Human Genome

  2012cited by this paper
• A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.

  2012cited by this paper
• Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up.

  2012cited by this paper
• The PPARγ Agonist Rosiglitazone Is Antifibrotic for Scleroderma Lung Fibroblasts: Mechanisms of Action and Differential Racial Effects

  2011cited by this paper
• C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis.

  2011cited by this paper
• HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants

  2011cited by this paper
• Genome-Wide Scan Identifies TNIP1, PSORS1C1, and RHOB as Novel Risk Loci for Systemic Sclerosis

  2011cited by this paper
• Genetics of Systemic Sclerosis: An Update

  2011cited by this paper
• The genetics of systemic sclerosis: an update.

  2011cited by this paper
• Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

  2011cited by this paper
• NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis

  2010cited by this paper
• Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts.

  2010cited by this paper
• Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases.

  2010cited by this paper
• Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

  2010cited by this paper
• Integrating common and rare genetic variation in diverse human populations

  2010cited by this paper
• PPARgamma and the pathobiology of pulmonary arterial hypertension.

  2010cited by this paper
• SCAN: SNP and copy number annotation

  2010cited by this paper
• PPARγ Downregulation by TGFß in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

  2010cited by this paper
• Scleroderma.

  2009cited by this paper
• Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma.

  2009cited by this paper
• A-Kinase Anchoring in Dendritic Cells Is Required for Antigen Presentation

  2009cited by this paper
• Loss of peroxisome proliferator-activated receptor gamma in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis.

  2009cited by this paper
• Assessing the understanding of biobank participants

  2009cited by this paper
• Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-gamma.

  2008cited by this paper
• An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension.

  2008cited by this paper
• Association of peroxisome proliferator-activated receptorgamma gene Pro12Ala and C161T polymorphisms with metabolic syndrome.

  2008cited by this paper
• Systemic sclerosis: a prototypic multisystem fibrotic disorder.

  2007cited by this paper
• PPARgamma gene C161T substitution is associated with reduced risk of coronary artery disease and decreased proinflammatory cytokine expression.

  2007cited by this paper
• Transferability of tag SNPs in genetic association studies in multiple populations

  2006cited by this paper
• The many faces of PPARgamma.

  2005cited by this paper
• Haploview: analysis and visualization of LD and haplotype maps

  2005cited by this paper
• Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma.

  2004cited by this paper
• Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population.

  2003cited by this paper
• Measuring inconsistency in meta-analyses

  2003cited by this paper
• PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth*

  2001cited by this paper
• PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth.

  2001cited by this paper
• Guilt by association

  2000cited by this paper
• The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.

  2000cited by this paper
• Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.

  1994cited by this paper
• Molecular characterization of two human autoantigens: unique cDNAs encoding 95- and 160-kD proteins of a putative family in the Golgi complex

  1993cited by this paper
• Scleroderma (systemic sclerosis): classification, subsets and pathogenesis.

  1988cited by this paper
• Preliminary criteria for the classification of systemic sclerosis (scleroderma).

  1980cited by this paper
• Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee.

  1980cited by this paper

• Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM

  2025cites this paper
• PPARγ: A Key to Personalized Treatment

  2025cites this paper
• Aging and homeostasis of the hypodermis in the age-related deterioration of skin function

  2024cites this paper
• Polymorphisms within DIO2 and GADD45A genes increase the risk of liver disease progression in chronic hepatitis b carriers

  2023cites this paper
• Enrichr in silico analysis of MS-based extracted candidate proteomic biomarkers highlights pathogenic pathways in systemic sclerosis

  2023cites this paper
• The Immunogenetics of Systemic Sclerosis.

  2022cites this paper
• Genetic Association between TNFA Polymorphisms (rs1799964 and rs361525) and Susceptibility to Cancer in Systemic Sclerosis

  2022cites this paper
• Genetic associations of non-MHC susceptibility loci with systemic sclerosis in a Han Chinese population.

  2021cites this paper
• In situ evidence of collagen V and signaling pathway of found inflammatory zone 1 (FIZZ1) is associated with silicotic granuloma in lung mice.

  2020cites this paper
• The roles of PPARγ and its agonists in autoimmune diseases: A comprehensive review

  2020cites this paper
• Systemic Sclerosis

  2019cites this paper
• Rationally-based therapeutic disease modification in systemic sclerosis: Novel strategies.

  2019cites this paper
• Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression

  2019cites this paper
• Emerging targets of disease-modifying therapy for systemic sclerosis

  2019cites this paper
• Regulation of Inflammation in Autoimmune Disease

  2019cites this paper
• Circulating peroxisome proliferator-activated receptor γ is elevated in systemic sclerosis

  2019cites this paper
• Research advance of γ molecular and gene polymorphism

  2019cites this paper
• Genetic implications in the pathogenesis of systemic sclerosis

  2018cites this paper
• Lung Involvements in Rheumatic Diseases: Update on the Epidemiology, Pathogenesis, Clinical Features, and Treatment

  2018cites this paper
• Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis

  2018cites this paper
• TNIP1 in Autoimmune Diseases: Regulation of Toll-like Receptor Signaling

  2018influential citation
• Biological Actions of PPAR-in Health and Disease

  2017cites this paper
• Unfolding the pathogenesis of scleroderma through genomics and epigenomics.

  2017cites this paper
• Serum chemerin in systemic sclerosis: a novel marker of early diffuse disease?

  2017cites this paper
• Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta

  2017cites this paper
• Genomic and genetic studies of systemic sclerosis: A systematic review.

  2017cites this paper
• Use of biologics and other novel therapies for the treatment of systemic sclerosis

  2017cites this paper
• Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPAR α/δ/γ SNPs Associated with Disease

  2017cites this paper
• Regulation of NKX2-5 in blood vessels

  2017cites this paper
• Emerging drugs and therapeutics for systemic sclerosis

  2016cites this paper
• Genetic factors and systemic sclerosis.

  2016cites this paper
• Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways.

  2015cites this paper