title: Lupus risk variants in the PXK locus alter B-cell receptor internalization.
abstract: Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3' UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10(-10), OR 0.81 (0.75-0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
authors.affiliation: Immunology Graduate Program and Medical Scientist Training Program, University of Cincinnati College of Medicine Cincinnati, OH, USA ; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Vaughn
authors.affiliation: Spelman College Atlanta, GA, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Foley
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Lu
authors.affiliation: Immunology Graduate Program and Medical Scientist Training Program, University of Cincinnati College of Medicine Cincinnati, OH, USA ; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Zubin H
authors.initials: ZH
authors.lastname: Patel
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Zoller
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Albert F
authors.initials: AF
authors.lastname: Magnusen
authors.affiliation: Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Williams
authors.affiliation: Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Ziegler
authors.affiliation: Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Comeau
authors.affiliation: Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
authors.forename: Miranda C
authors.initials: MC
authors.lastname: Marion
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Glenn
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Adler
authors.affiliation: Immunology Graduate Program and Medical Scientist Training Program, University of Cincinnati College of Medicine Cincinnati, OH, USA ; Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Swapan
authors.initials: S
authors.lastname: Nath
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute Seattle, WA, USA ; Division of Rheumatology, Department of Pediatrics, University of Washington Seattle, WA, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Stevens
authors.affiliation: Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine Winston-Salem, NC, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California Los Angeles, CA, USA.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Division of Rheumatology, Medical University of South Carolina Charleston, SC, USA.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Kamen
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA ; Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.affiliation: Division of Rheumatology, Medical University of South Carolina Charleston, SC, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.affiliation: Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.affiliation: Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston Houston, TX, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.affiliation: Center for Autoimmune Disease Research, Universidad del Rosario Bogota, Colombia.
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA ; Department of Medicine, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.affiliation: Rosalind Russell/Ephraim P Engleman Rheumatology Research Research Center, Department of Medicine, University of California, San Francisco San Francisco, CA, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus San Juan, PR, USA.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Vilá
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA ; Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucia Granada, Spain.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine Baltimore, MD, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA ; Department of Medicine, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA ; United States Department of Veterans Affairs Medical Center Oklahoma City, OK, USA.
authors.forename: R Hal
authors.initials: RH
authors.lastname: Scofield
authors.affiliation: Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University Chicago, IL, USA.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
authors.forename: Young
authors.initials: Y
authors.lastname: Binjoo
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
authors.forename: Jeongim
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Division of Rheumatology, University of Colorado School of Medicine Aurora, CO, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Boackle
authors.affiliation: Divisions of Genetics and Molecular Medicine and Immunology, King's College London London, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Bahram
authors.initials: B
authors.lastname: Namjou
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; United States Department of Veterans Affairs Medical Center Cincinnati, OH, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Immunology Graduate Program and Medical Scientist Training Program, University of Cincinnati College of Medicine Cincinnati, OH, USA ; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Isaac T W
authors.initials: IT
authors.lastname: Harley
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; United States Department of Veterans Affairs Medical Center Cincinnati, OH, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; United States Department of Veterans Affairs Medical Center Cincinnati, OH, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
keywords: B cells; BCR; PXK; fine-mapping; lupus