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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.

SUBMITTER: Vaughn SE

PROVIDER: S-EPMC4288052 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Vaughn Samuel E SE Foley Corinne C Lu Xiaoming X Patel Zubin H ZH Zoller Erin E EE Magnusen Albert F AF Williams Adrienne H AH Ziegler Julie T JT Comeau Mary E ME Marion Miranda C MC Glenn Stuart B SB Adler Adam A Shen Nan N Nath Swapan S Stevens Anne M AM Freedman Barry I BI Tsao Betty P BP Jacob Chaim O CO Kamen Diane L DL Brown Elizabeth E EE Gilkeson Gary S GS Alarcón Graciela S GS Reveille John D JD Anaya Juan-Manuel JM James Judith A JA Moser Kathy L KL Criswell Lindsey A LA Vilá Luis M LM Alarcón-Riquelme Marta E ME Petri Michelle M Scofield R Hal RH Kimberly Robert P RP Ramsey-Goldman Rosalind R Binjoo Young Y Choi Jeongim J Bae Sang-Cheol SC Boackle Susan A SA Vyse Timothy J TJ Guthridge Joel M JM Namjou Bahram B Gaffney Patrick M PM Langefeld Carl D CD Kaufman Kenneth M KM Kelly Jennifer A JA Harley Isaac T W IT Harley John B JB Kottyan Leah C LC

Frontiers in genetics 20150108

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-mapp ...[more]

PMID: 25620976

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Project description:Multiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the nonsynonymous SNPs rs1143679, rs1143678, and rs1143683) are associated with systemic lupus erythematosus (SLE). ITGAM encodes the protein CD11b, a subunit of the ?2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biologic functions of neutrophil Mac-1.Neutrophils from ITGAM-genotyped and -sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement-coated erythrocytes, serum-treated zymosan, heat-treated zymosan, and IgG-coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor ?-stimulated endothelial cells, was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry.Mac-1-mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the ?-propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fc? receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation.The nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE.

Dataset Information

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

Publications

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

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