Lupus risk variants in the PXK locus alter B-cell receptor internalization

Samuel E Vaughn; Corinne Foley; Xiaoming Lu; Zubin H Patel; Erin E Zoller; Albert F Magnusen; Adrienne H Williams; Julie T Ziegler; Mary E Comeau; Miranda C Marion; Stuart B Glenn; Adam Adler; Nan Shen; Swapan Nath; Anne M Stevens; Barry I Freedman; Betty P Tsao; Chaim O Jacob; Diane L Kamen; Elizabeth E Brown; Gary S Gilkeson; Graciela S Alarcón; John D Reveille; Juan-Manuel Anaya; Judith A James; Kathy L Moser; Lindsey A Criswell; Luis M Vilá; Marta E Alarcón-Riquelme; Michelle Petri; R Hal Scofield; Robert P Kimberly; Rosalind Ramsey-Goldman; Young Binjoo; Jeongim Choi; Sang-Cheol Bae; Susan A Boackle; Timothy J Vyse; Joel M Guthridge; Bahram Namjou; Patrick M Gaffney; Carl D Langefeld; Kenneth M Kaufman; Jennifer A Kelly; Isaac T W Harley; John B Harley; Leah C Kottyan

doi:10.3389/fgene.2014.00450

Lupus risk variants in the PXK locus alter B-cell receptor internalization

Front Genet. 2015 Jan 8:5:450. doi: 10.3389/fgene.2014.00450. eCollection 2014.

Authors

Samuel E Vaughn¹, Corinne Foley², Xiaoming Lu³, Zubin H Patel¹, Erin E Zoller³, Albert F Magnusen³, Adrienne H Williams⁴, Julie T Ziegler⁴, Mary E Comeau⁴, Miranda C Marion⁴, Stuart B Glenn⁵, Adam Adler⁵, Nan Shen⁶, Swapan Nath⁵, Anne M Stevens⁷, Barry I Freedman⁸, Betty P Tsao⁹, Chaim O Jacob¹⁰, Diane L Kamen¹¹, Elizabeth E Brown¹², Gary S Gilkeson¹¹, Graciela S Alarcón¹³, John D Reveille¹⁴, Juan-Manuel Anaya¹⁵, Judith A James¹⁶, Kathy L Moser⁵, Lindsey A Criswell¹⁷, Luis M Vilá¹⁸, Marta E Alarcón-Riquelme¹⁹, Michelle Petri²⁰, R Hal Scofield²¹, Robert P Kimberly¹³, Rosalind Ramsey-Goldman²², Young Binjoo²³, Jeongim Choi²³, Sang-Cheol Bae²³, Susan A Boackle²⁴, Timothy J Vyse²⁵, Joel M Guthridge⁵, Bahram Namjou³, Patrick M Gaffney⁵, Carl D Langefeld⁴, Kenneth M Kaufman²⁶, Jennifer A Kelly⁵, Isaac T W Harley¹, John B Harley²⁶, Leah C Kottyan²⁶

Affiliations

¹ 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.
² Spelman College Atlanta, GA, USA.
³ Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
⁴ Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine Winston-Salem, NC, USA.
⁵ Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation Oklahoma City, OK, USA.
⁶ 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.
⁷ 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.
⁸ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine Winston-Salem, NC, USA.
⁹ Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA.
¹⁰ Department of Medicine, Keck School of Medicine, University of Southern California Los Angeles, CA, USA.
¹¹ Division of Rheumatology, Medical University of South Carolina Charleston, SC, USA.
¹² Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA ; Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
¹³ Department of Medicine, University of Alabama at Birmingham Birmingham, AL, USA.
¹⁴ Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston Houston, TX, USA.
¹⁵ Center for Autoimmune Disease Research, Universidad del Rosario Bogota, Colombia.
¹⁶ 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.
¹⁷ Rosalind Russell/Ephraim P Engleman Rheumatology Research Research Center, Department of Medicine, University of California, San Francisco San Francisco, CA, USA.
¹⁸ Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus San Juan, PR, USA.
¹⁹ 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.
²⁰ Department of Medicine, Johns Hopkins University School of Medicine Baltimore, MD, USA.
²¹ 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.
²² Division of Rheumatology, Feinberg School of Medicine, Northwestern University Chicago, IL, USA.
²³ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases Seoul, Korea.
²⁴ Division of Rheumatology, University of Colorado School of Medicine Aurora, CO, USA.
²⁵ Divisions of Genetics and Molecular Medicine and Immunology, King's College London London, UK.
²⁶ 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.

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.

Keywords: B cells; BCR; PXK; fine-mapping; lupus.

Abstract

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