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.

Pathogenesis of Systemic Sclerosis

“…Paraxylene–Orthoxylene domain containing serine/threonine kinase is a protein that plays a role in the ligand-induced internalization, degradation, and trafficking of epidermal growth factors. Variation in PXK is association with SLE susceptibility where it is found to alter B-cell receptor internalization ( 131 ). PXK rs2176082 and rs4681851 are associated with SSc and rs2176082 has association for ACA positivity.…”

Genetics of eosinophilic esophagitis

“…STAT6 is a transcription factor that is activated by the allergy-associated cytokines IL-4 and IL-13 and possibly IL-33. 52–56 Esophageal epithelial cell lines have intact STAT6 signaling, 57–59 and STAT6 drives the expression of many of the genes in the EoE transcriptome. 7,58,60 Indeed, STAT6 had a critical and established role in the pathophysiology of EoE before its identification as an EoE-risk locus.…”

Sex influences eQTL effects of SLE and Sjögren’s syndrome-associated genetic polymorphisms

“…Regarding functional consequences of the PXK region SNP, one study has reported that it influenced the rate of BCR internalization, and that subjects carrying the risk haplotype had a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate [ 52 ]. CTSB encodes Cathepsin B, a lysosomal cysteine protease with a poorly studied function, but which potentially may play a role in protein turnover [ 53 ].…”