Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility

Terri H Finkel; Jin Li; Zhi Wei; Wei Wang; Haitao Zhang; Edward M Behrens; Emma L Reuschel; Sophie Limou; Carol Wise; Marilynn Punaro; Mara L Becker; Jane E Munro; Berit Flatø; Øystein Førre; Susan D Thompson; Carl D Langefeld; David N Glass; Joseph T Glessner; Cecilia E Kim; Edward Frackelton; Debra K Shivers; Kelly A Thomas; Rosetta M Chiavacci; Cuiping Hou; Kexiang Xu; James Snyder; Haijun Qiu; Frank Mentch; Kai Wang; Cheryl A Winkler; Benedicte A Lie; Justine A Ellis; Hakon Hakonarson

doi:10.1186/s12881-016-0285-3

Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility

BMC Med Genet. 2016 Mar 22:17:24. doi: 10.1186/s12881-016-0285-3.

Authors

Terri H Finkel^{1

2

3}, Jin Li⁴, Zhi Wei⁵, Wei Wang⁵, Haitao Zhang⁴, Edward M Behrens^{6

7}, Emma L Reuschel^{6

7}, Sophie Limou⁸, Carol Wise⁹, Marilynn Punaro¹⁰, Mara L Becker¹¹, Jane E Munro^{12

13}, Berit Flatø¹⁴, Øystein Førre¹⁴, Susan D Thompson¹⁵, Carl D Langefeld¹⁶, David N Glass¹⁵, Joseph T Glessner⁴, Cecilia E Kim⁴, Edward Frackelton⁴, Debra K Shivers⁶, Kelly A Thomas⁴, Rosetta M Chiavacci⁴, Cuiping Hou⁴, Kexiang Xu⁴, James Snyder⁴, Haijun Qiu⁴, Frank Mentch⁴, Kai Wang^{4

17}, Cheryl A Winkler⁸, Benedicte A Lie¹⁸, Justine A Ellis^{12

19}, Hakon Hakonarson^{20

21

22}

Affiliations

¹ Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. [email protected].
² Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA. [email protected].
³ Present Address: Department of Pediatrics, Nemours Research Institute, Nemours Children's Hospital, 32827, Orlando, FL, USA. [email protected].
⁴ The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
⁵ Department of Computer Science, New Jersey Institute of Technology, 07102, New Jersey, NJ, USA.
⁶ Division of Rheumatology, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA.
⁷ Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA.
⁸ Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research Inc., Frederick National Laboratory, 21702, Frederick, MD, USA.
⁹ Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 75219, Dallas, TX, USA.
¹⁰ Division of Rheumatology, Texas Scottish Rite Hospital, 75219, Dallas, TX, USA.
¹¹ Division of Rheumatology, Children's Mercy- Kansas City, 64108, Kansas City, MO, USA.
¹² Murdoch Childrens Research Institute, 3052, Parkville, VIC, Australia.
¹³ Paediatric Rheumatology Unit, Royal Children's Hospital, 3052, Parkville, VIC, Australia.
¹⁴ Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Norway.
¹⁵ Cincinnati Children's Hospital Medical Center, 45229, Cincinnati, OH, USA.
¹⁶ Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, 27157, Winston-Salem, NC, USA.
¹⁷ Department of Psychiatry and Behavioral Sciences, UUniversity of Southern California, 90089, Los Angeles, CA, USA.
¹⁸ Institute of Immunology, Oslo University Hospital, 0027, Rikshospitalet, Oslo, Norway.
¹⁹ Department of Paediatrics, University of Melbourne, 3010, Melbourne, Australia.
²⁰ Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA. [email protected].
²¹ The Center for Applied Genomics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. [email protected].
²² Division of Human Genetics, The Children's Hospital of Philadelphia, 19104, Philadelphia, PA, USA. [email protected].

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.

Keywords: CXCR4; Genome-wide association study; Juvenile idiopathic arthritis; Targeted resequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Adolescent
Amino Acid Sequence
Arthritis, Juvenile / genetics*
Case-Control Studies
Child
Child, Preschool
Female
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
Genotyping Techniques
Humans
Male
Molecular Sequence Data
Polymorphism, Single Nucleotide
Principal Component Analysis
Receptors, CXCR4 / genetics*
Sequence Analysis, DNA
White People / genetics

Substances

CXCR4 protein, human
Receptors, CXCR4

Abstract

Publication types

MeSH terms

Substances

Grants and funding