ArticleFrontiers in genetics2014
Lupus risk variants in the PXK locus alter B-cell receptor internalization.
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Article in Frontiers in genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20citing papers in PubMed
3.8field-weighted citation impact, top 7% of its field
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.Human molecular genetics · 2018Trial
- Lymphocytes Change Their Phenotype and Function in Systemic Lupus Erythematosus and Lupus Nephritis.International journal of molecular sciences · 2024Review
- The 330 risk loci known for systemic lupus erythematosus (SLE): a review.Frontiers in lupus · 2024Article
- The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus.Current issues in molecular biology · 2023Review
- Systemic lupus erythematosus as a genetic disease.Clinical immunology (Orlando, Fla.) · 2022Article
- CASCADE: high-throughput characterization of regulatory complex binding altered by non-coding variants.Cell genomics · 2022Article
- Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans.Frontiers in immunology · 2022Review
- B Cells in Systemic Lupus Erythematosus: From Disease Mechanisms to Targeted Therapies.Rheumatic diseases clinics of North America · 2021Review
- Understanding the genetics of systemic lupus erythematosus using Bayesian statistics and gene network analysis.Clinical and experimental pediatrics · 2021Article
- Global discovery of lupus genetic risk variant allelic enhancer activity.Nature communications · 2021Article
- SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression.Nature communications · 2021Article
- Machine learning approaches to predict lupus disease activity from gene expression data.Scientific reports · 2019Article
- Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.Journal of autoimmunity · 2018Article
- Sex influences eQTL effects of SLE and Sjögren's syndrome-associated genetic polymorphisms.Biology of sex differences · 2017Article
- Updates in Lupus Genetics.Current rheumatology reports · 2017Review
- Genetics of eosinophilic esophagitis.Mucosal immunology · 2017Review
- Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice.PloS one · 2017Article
- Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus.G3 (Bethesda, Md.) · 2016Article
- Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.Nature genetics · 2015Article
- Pathogenesis of Systemic Sclerosis.Frontiers in immunology · 2015Review
Corrections and comments
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Authors and funding
47 authors at 20 institutions in 7 countries.
Samuel E VaughnImmunology 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.
Corinne FoleySpelman College Atlanta, GA, USA.
Xiaoming LuCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
Zubin H PatelImmunology 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.
Erin E ZollerCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
Albert F MagnusenCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
Adrienne H WilliamsCenter for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
Julie T ZieglerCenter for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
Mary E ComeauCenter for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
Miranda C MarionCenter for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
Stuart B GlennArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Adam AdlerArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Nan ShenImmunology 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.
Swapan NathArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Anne M StevensCenter for Immunity and Immunotherapies, Seattle Children's Research Institute Seattle, WA, USA ; Division of Rheumatology, Department of Pediatrics, University of Washington Seattle, WA, USA.
Barry I FreedmanDepartment of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine Winston-Salem, NC, USA.
Betty P TsaoDivision of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA.
Chaim O JacobDepartment of Medicine, Keck School of Medicine, University of Southern California Los Angeles, CA, USA.
Diane L KamenDivision of Rheumatology, Medical University of South Carolina Charleston, SC, USA.
Elizabeth E BrownDepartment of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA ; Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
Gary S GilkesonDivision of Rheumatology, Medical University of South Carolina Charleston, SC, USA.
Graciela S AlarcónDepartment of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
John D ReveilleRheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston Houston, TX, USA.
Juan-Manuel AnayaCenter for Autoimmune Disease Research, Universidad del Rosario Bogota, Colombia.
Judith A JamesArthritis 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.
Kathy L MoserArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Lindsey A CriswellRosalind Russell/Ephraim P Engleman Rheumatology Research Research Center, Department of Medicine, University of California, San Francisco San Francisco, CA, USA.
Luis M ViláDivision of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus San Juan, PR, USA.
Marta E Alarcón-RiquelmeArthritis 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.
Michelle PetriDepartment of Medicine, Johns Hopkins University School of Medicine Baltimore, MD, USA.
R Hal ScofieldArthritis 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.
Robert P KimberlyDepartment of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
Rosalind Ramsey-GoldmanDivision of Rheumatology, Feinberg School of Medicine, Northwestern University Chicago, IL, USA.
Young BinjooDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
Jeongim ChoiDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
Sang-Cheol BaeDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
Susan A BoackleDivision of Rheumatology, University of Colorado School of Medicine Aurora, CO, USA.
Timothy J VyseDivisions of Genetics and Molecular Medicine and Immunology, King's College London London, UK.
Joel M GuthridgeArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Bahram NamjouCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
Patrick M GaffneyArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Carl D LangefeldCenter for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
Kenneth M KaufmanCenter 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.
Jennifer A KellyArthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
Isaac T W HarleyImmunology 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.
John B HarleyCenter 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.
Leah C KottyanCenter 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.
Oklahoma Medical Research Foundation · USCincinnati Children's Hospital Medical Center · USHanyang University Seoul Hospital · KRUniversity of Alabama at Birmingham · USMedical University of South Carolina · USJohns Hopkins University · USKing's College London · GBNorthwestern University · USPfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research · ESRenji Hospital · CNSpelman College · USThe University of Texas Health Science Center at Houston · USUnited States Department of Veterans Affairs · USUniversidad del Rosario · COUniversity of California, Los Angeles · USUniversity of California, San Francisco · USUniversity of Cincinnati Medical Center · USUniversity of Colorado Denver · USUniversity of Oklahoma Health Sciences Center · USUniversity of Puerto Rico, Medical Sciences Campus · PR
Funding
University of Colorado Cancer Center Support Grant - Lung Cancer Patient-Derived Xenografts with Autologous Human Immune SystemsP30CA046934 · NCI · UNIVERSITY OF COLORADO DENVER · PI James V Degregori · 1988 to 2026
$117.0MTracking and Evaluation CoreU54GM104938 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI JUDITH A JAMES · 2013 to 2026
$68.2MColorado Clinical and Translational Sciences InstituteUL1TR001082 · NCATS · UNIVERSITY OF COLORADO DENVER · PI SOKOL, RONALD J. · 2013 to 2017
$48.0MLCenter for Clinical and Translational Science and TrainingUL1TR001425 · NCATS · UNIVERSITY OF CINCINNATI · PI HEUBI, JAMES E., KISSELA, BRETT M · 2015 to 2024
$37.5MStem Cell/Organoid and Genome Editing CoreP30DK078392 · NIDDK · CINCINNATI CHILDRENS HOSP MED CTR · PI LEE ARMISTEAD DENSON · 2007 to 2026
$24.4MColorado Clinical and Translational Science Institute (UL1)UL1TR000154 · NCATS · UNIVERSITY OF COLORADO DENVER · PI SOKOL, RONALD J. · 2012 to 2013
$20.4MProgram Project in the Genetics of SLEP01AR049084 · NIAMS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI KIMBERLY, ROBERT P. · 2002 to 2012
$12.7MThe Interplay of Sociodemographic and Genetic Factors in SLE Health DisparitiesP60AR053308 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI YELIN, EDWARD H · 2006 to 2016
$11.8MSOUTH CAROLINA CLINICAL & TRANSLATIONAL RESEARCH INSTITUTE (SCTR)UL1RR029882 · NCRR · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI BRADY, KATHLEEN T. · 2009 to 2011
$10.1MSequencingP01AI083194 · NIAID · OKLAHOMA MEDICAL RESEARCH FOUNDATION · PI KIMBERLY, ROBERT P. · 2009 to 2013
$9.6MROLE OF ANGPTL4, AN ANGIOGENIC MEDIATOR, IN ARTHRITISP30AR047363 · NIAMS · CINCINNATI CHILDRENS HOSP MED CTR · PI WAGNER, MICHAEL · 2001 to 2015
$9.2MLupus CohortR01AR043727 · NIAMS · JOHNS HOPKINS UNIVERSITY · PI PETRI, MICHELLE A · 1997 to 2015
$8.2MBLRD VA I01 BX001834NCATS NIH HHS UL1 TR000154NCATS NIH HHS UL1 TR001082NCATS NIH HHS UL1 TR001425NCI NIH HHS P30 CA046934NCRR NIH HHS UL1 RR029882NIAID NIH HHS K24 AI078004NIAID NIH HHS P01 AI083194NIAID NIH HHS R21 AI070304NIAID NIH HHS R37 AI024717NIAMS NIH HHS P01 AR049084NIAMS NIH HHS P30 AR047363NIAMS NIH HHS P60 AR053308NIAMS NIH HHS P60 AR062755NIAMS NIH HHS R01 AR043727NIAMS NIH HHS R01 AR043814NIAMS NIH HHS R21 AR065626NIDDK NIH HHS P30 DK078392NIDDK NIH HHS P30 DK090971NIGMS NIH HHS T32 GM063483NIGMS NIH HHS U54 GM104938
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.
Indexed as
B cellsBCRfine-mappinglupusPXK
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