title: A candidate gene study reveals association between a variant of the Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) gene and systemic sclerosis.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  Tag 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.
  
  
  RESULTS
  In 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).
  
  
  CONCLUSIONS
  A PPARG variant is associated with susceptibility to SSc, consistent with a role of PPAR-γ in the pathogenesis of SSc.
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA. roberta.marangoni@northwestern.edu.
authors.forename: Roberta Goncalves
authors.initials: RG
authors.lastname: Marangoni
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA. benjamin-korman@northwestern.edu.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Korman
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. yannick.allanore@cch.aphp.fr.|Paris Descartes University, Rheumatology A department, Cochin Hospital, APHP, Paris, France. yannick.allanore@cch.aphp.fr.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.affiliation: Université Paris 7, INSERM U699, Rhumatologie, Hôpital Bichat, Paris, France. philippe.dieude@bch.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieude
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. loren-armstrong@northwestern.edu.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Armstrong
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. m-rzhetskaya@northwestern.edu.
authors.forename: Margarita
authors.initials: M
authors.lastname: Rzhetskaya
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA. m-hinchcliff@northwestern.edu.
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA. m-carns@northwestern.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Carns
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA. s-podlusky@northwestern.edu.
authors.forename: Sofia
authors.initials: S
authors.lastname: Podlusky
authors.affiliation: Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. sanjiv.shah@northwestern.edu.
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. barbara.ruiz@inserm.fr.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.affiliation: Université Lille II, Médecine Interne, Lille, France. ehachulla@chru-lille.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.affiliation: Université Pierre et Marie Curie, Service de Médecine Interne, Hôpital Saint Antoine, Paris, France. kiet.tiev@sat.aphp.fr.
authors.forename: Kiet
authors.initials: K
authors.lastname: Tiev
authors.affiliation: INSERM CIC3, CHU Grenoble, Grenoble, France. Jean-Luc.Cracowski@ujf-grenoble.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA. j-varga@northwestern.edu.|Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. j-varga@northwestern.edu.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. ghayes@northwestern.edu.|Center of Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. ghayes@northwestern.edu.|Department of Anthropology, Northwestern University, Evanston, IL, USA. ghayes@northwestern.edu.
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
mesh_terms: D000328:Adult; D000483:Alleles; D005060:Europe / Q000453:epidemiology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics*; D047492:Peroxisome Proliferator-Activated Receptors / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics*; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D012313:RNA