title: Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility.
abstract: BACKGROUND
  Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.
  
  
  METHODS
  We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants.
  
  
  RESULTS
  The CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10(-4)). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015).
  
  
  CONCLUSIONS
  Our results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. tfinkel@nemours.org.|Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA. tfinkel@nemours.org.|Present Address: Department of Pediatrics, Nemours Research Institute, Nemours Children's Hospital, 32827, Orlando, FL, USA. tfinkel@nemours.org.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Finkel
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, 07102, New Jersey, NJ, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, 07102, New Jersey, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.|Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.|Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Reuschel
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory, 21702, Frederick, MD, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Limou
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 75219, Dallas, TX, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Wise
authors.affiliation: Division of Rheumatology, Texas Scottish Rite Hospital, 75219, Dallas, TX, USA.
authors.forename: Marilynn
authors.initials: M
authors.lastname: Punaro
authors.affiliation: Division of Rheumatology, Children's Mercy- Kansas City, 64108, Kansas City, MO, USA.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Becker
authors.affiliation: Murdoch Childrens Research Institute, 3052, Parkville, VIC, Australia.|Paediatric Rheumatology Unit, Royal Children's Hospital, 3052, Parkville, VIC, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Munro
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Flatø
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Førre
authors.affiliation: Cincinnati Children's Hospital Medical Center, 45229, Cincinnati, OH, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, 27157, Winston-Salem, NC, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Cincinnati Children's Hospital Medical Center, 45229, Cincinnati, OH, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Glass
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Frackelton
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Debra K
authors.initials: DK
authors.lastname: Shivers
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Thomas
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Rosetta M
authors.initials: RM
authors.lastname: Chiavacci
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Kexiang
authors.initials: K
authors.lastname: Xu
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Snyder
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Qiu
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Mentch
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.|Department of Psychiatry and Behavioral Sciences, UUniversity of Southern California, 90089, Los Angeles, CA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory, 21702, Frederick, MD, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Institute of Immunology, Oslo University Hospital, 0027, Rikshospitalet, Oslo, Norway.
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.affiliation: Murdoch Childrens Research Institute, 3052, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, 3010, Melbourne, Australia.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Ellis
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA. hakonarson@email.chop.edu.|The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. hakonarson@email.chop.edu.|Division of Human Genetics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. hakonarson@email.chop.edu.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001171:Arthritis, Juvenile / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D019718:Receptors, CXCR4 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4
keywords: CXCR4; Genome-wide association study; Juvenile idiopathic arthritis; Targeted resequencing