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

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

Nemours Children's Hospital, Florida

The Children's Hospital of Philadelphia
University of Pennsylvania
Department of Computer Science
Leidos Inc
Scottish Rite Hospital for Children
Children's Mercy Hospitals and Clinics
Murdoch Children's Research Institute
Royal Children's Hospital
University of Oslo
Cincinnati Children's Hospital Medical Center
Wake Forest University
University of Southern California
University of Melbourne

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English
Article number	24
Journal	BMC Medical Genetics
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s12881-016-0285-3
State	Published - 22 Mar 2016

Keywords

CXCR4
Genome-wide association study
Juvenile idiopathic arthritis
Targeted resequencing

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10.1186/s12881-016-0285-3

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Finkel, T. H., Li, J., Wei, Z., Wang, W., Zhang, H., Behrens, E. M., Reuschel, E. L., Limou, S., Wise, C., Punaro, M., Becker, M. L., Munro, J. E., Flatø, B., Førre, Ø., Thompson, S. D., Langefeld, C. D., Glass, D. N., Glessner, J. T., Kim, C. E., ... Hakonarson, H. (2016). Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility. BMC Medical Genetics, 17(1), Article 24. https://doi.org/10.1186/s12881-016-0285-3

@article{fcfc8b6a3202452c8309371560f0bdf7,

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). 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",

author = "Finkel, \{Terri H.\} and Jin Li and Zhi Wei and Wei Wang and Haitao Zhang and Behrens, \{Edward M.\} and Reuschel, \{Emma L.\} and Sophie Limou and Carol Wise and Marilynn Punaro and Becker, \{Mara L.\} and Munro, \{Jane E.\} and Berit Flat{\o} and {\O}ystein F{\o}rre and Thompson, \{Susan D.\} and Langefeld, \{Carl D.\} and Glass, \{David N.\} and Glessner, \{Joseph T.\} and Kim, \{Cecilia E.\} and Edward Frackelton and Shivers, \{Debra K.\} and Thomas, \{Kelly A.\} and Chiavacci, \{Rosetta M.\} and Cuiping Hou and Kexiang Xu and James Snyder and Haijun Qiu and Frank Mentch and Kai Wang and Winkler, \{Cheryl A.\} and Lie, \{Benedicte A.\} and Ellis, \{Justine A.\} and Hakon Hakonarson",

note = "Publisher Copyright: {\textcopyright} 2016 Finkel et al.",

year = "2016",

month = mar,

day = "22",

doi = "10.1186/s12881-016-0285-3",

language = "English",

volume = "17",

journal = "BMC Medical Genetics",

issn = "1471-2350",

publisher = "BioMed Central Ltd.",

number = "1",

}

Finkel, TH, Li, J, Wei, Z, Wang, W, Zhang, H, Behrens, EM, Reuschel, EL, Limou, S, Wise, C, Punaro, M, Becker, ML, Munro, JE, Flatø, B, Førre, Ø, Thompson, SD, Langefeld, CD, Glass, DN, Glessner, JT, Kim, CE, Frackelton, E, Shivers, DK, Thomas, KA, Chiavacci, RM, Hou, C, Xu, K, Snyder, J, Qiu, H, Mentch, F, Wang, K, Winkler, CA, Lie, BA, Ellis, JA & Hakonarson, H 2016, 'Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility', BMC Medical Genetics, vol. 17, no. 1, 24. https://doi.org/10.1186/s12881-016-0285-3

TY - JOUR

T1 - Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility

AU - Finkel, Terri H.

AU - Li, Jin

AU - Wei, Zhi

AU - Wang, Wei

AU - Zhang, Haitao

AU - Behrens, Edward M.

AU - Reuschel, Emma L.

AU - Limou, Sophie

AU - Wise, Carol

AU - Punaro, Marilynn

AU - Becker, Mara L.

AU - Munro, Jane E.

AU - Flatø, Berit

AU - Førre, Øystein

AU - Thompson, Susan D.

AU - Langefeld, Carl D.

AU - Glass, David N.

AU - Glessner, Joseph T.

AU - Kim, Cecilia E.

AU - Frackelton, Edward

AU - Shivers, Debra K.

AU - Thomas, Kelly A.

AU - Chiavacci, Rosetta M.

AU - Hou, Cuiping

AU - Xu, Kexiang

AU - Snyder, James

AU - Qiu, Haijun

AU - Mentch, Frank

AU - Wang, Kai

AU - Winkler, Cheryl A.

AU - Lie, Benedicte A.

AU - Ellis, Justine A.

AU - Hakonarson, Hakon

PY - 2016/3/22

Y1 - 2016/3/22

N2 - 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.

AB - 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.

KW - CXCR4

KW - Genome-wide association study

KW - Juvenile idiopathic arthritis

KW - Targeted resequencing

UR - https://www.scopus.com/pages/publications/84961612900

U2 - 10.1186/s12881-016-0285-3

DO - 10.1186/s12881-016-0285-3

M3 - Article

C2 - 27005825

AN - SCOPUS:84961612900

SN - 1471-2350

VL - 17

JO - BMC Medical Genetics

JF - BMC Medical Genetics

IS - 1

M1 - 24

ER -

Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility

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Keywords

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