Lupus risk variants in the PXK locus alter B-cell receptor internalization
Samuel E Vaughn1, Corinne Foley2, Xiaoming Lu3
1Immunology 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.
Frontiers in Genetics
|January 27, 2015
Summary
Genetic variants in PXK increase lupus risk by decreasing B-cell antigen receptor internalization. This study identifies a new mechanism for autoimmunity linked to intracellular trafficking regulation.
Area of Science:
- Genetics
- Immunology
- Autoimmune Diseases
Background:
- Genome-wide association studies link PXK variants to autoimmune diseases like lupus.
- The precise mechanism by which PXK influences lupus pathophysiology remains unclear.
- PXK's role in epidermal growth factor receptor trafficking is known, but its function in autoimmunity is undefined.
Purpose of the Study:
- To investigate the mechanism underlying the association between PXK variants and lupus risk.
- To perform fine-mapping analysis in a multi-ancestral lupus cohort.
- To identify the causal variant and understand its functional impact on B cells.
Main Methods:
- Fine-mapping analysis in a large, multi-ancestral study of lupus patients and controls.
- Statistical analyses including stepwise logistic regression and Bayesian analysis.
- Functional studies assessing PXK's role in B-cell antigen receptor (BCR) internalization.
Main Results:
- A common 257kb haplotype containing a single causal variant in PXK was identified, associated with lupus risk in European populations.
- The strongest association was with rs6445972 (P < 4.62 × 10(-10)).
- PXK influences BCR internalization rate, and individuals with the risk haplotype show decreased BCR internalization, impacting B cell fate.
Conclusions:
- PXK variants confer lupus risk through altered BCR internalization, a novel mechanism in autoimmunity.
- Intracellular trafficking regulation is highlighted as a genetically influenced pathway in human autoimmunity.
- This study provides a candidate mechanism for PXK's role in lupus pathogenesis.
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