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Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility.
Finkel, Terri H; Li, Jin; Wei, Zhi; Wang, Wei; Zhang, Haitao; Behrens, Edward M; Reuschel, Emma L; Limou, Sophie; Wise, Carol; Punaro, Marilynn; Becker, Mara L; Munro, Jane E; Flatø, Berit; Førre, Øystein; Thompson, Susan D; Langefeld, Carl D; Glass, David N; Glessner, Joseph T; Kim, Cecilia E; Frackelton, Edward; Shivers, Debra K; Thomas, Kelly A; Chiavacci, Rosetta M; Hou, Cuiping; Xu, Kexiang; Snyder, James; Qiu, Haijun; Mentch, Frank; Wang, Kai; Winkler, Cheryl A; Lie, Benedicte A; Ellis, Justine A; Hakonarson, Hakon.
Afiliación
  • Finkel TH; Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. tfinkel@nemours.org.
  • Li J; Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA. tfinkel@nemours.org.
  • Wei Z; Present Address: Department of Pediatrics, Nemours Research Institute, Nemours Children's Hospital, 32827, Orlando, FL, USA. tfinkel@nemours.org.
  • Wang W; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Zhang H; Department of Computer Science, New Jersey Institute of Technology, 07102, New Jersey, NJ, USA.
  • Behrens EM; Department of Computer Science, New Jersey Institute of Technology, 07102, New Jersey, NJ, USA.
  • Reuschel EL; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Limou S; Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Wise C; Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA.
  • Punaro M; Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Becker ML; Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA.
  • Munro JE; Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory, 21702, Frederick, MD, USA.
  • Flatø B; Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 75219, Dallas, TX, USA.
  • Førre Ø; Division of Rheumatology, Texas Scottish Rite Hospital, 75219, Dallas, TX, USA.
  • Thompson SD; Division of Rheumatology, Children's Mercy- Kansas City, 64108, Kansas City, MO, USA.
  • Langefeld CD; Murdoch Childrens Research Institute, 3052, Parkville, VIC, Australia.
  • Glass DN; Paediatric Rheumatology Unit, Royal Children's Hospital, 3052, Parkville, VIC, Australia.
  • Glessner JT; Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Norway.
  • Kim CE; Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Norway.
  • Frackelton E; Cincinnati Children's Hospital Medical Center, 45229, Cincinnati, OH, USA.
  • Shivers DK; Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, 27157, Winston-Salem, NC, USA.
  • Thomas KA; Cincinnati Children's Hospital Medical Center, 45229, Cincinnati, OH, USA.
  • Chiavacci RM; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Hou C; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Xu K; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Snyder J; Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Qiu H; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Mentch F; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Wang K; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Winkler CA; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Lie BA; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Ellis JA; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
  • Hakonarson H; The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
BMC Med Genet ; 17: 24, 2016 Mar 22.
Article en En | MEDLINE | ID: mdl-27005825
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).

CONCLUSION:

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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Artritis Juvenil / Receptores CXCR4 / Predisposición Genética a la Enfermedad Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: BMC Med Genet Asunto de la revista: GENETICA MEDICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Artritis Juvenil / Receptores CXCR4 / Predisposición Genética a la Enfermedad Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: BMC Med Genet Asunto de la revista: GENETICA MEDICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos