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PXK and Lupus: Novel Immunobiology for a Lupus-Risk Gene

Vaughn, Samuel
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447690650

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Immunology.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. There is a strong evidence for genetics playing an important role in the development of disease. Genetic association studies have begun to identify many SLE-associated genetic loci, yet for very few of these loci is the specific pathogenic mechanism of disease described. We undertook a genetic fine-mapping study of the PXK locus, which our group had previously identified as being associated with SLE. In the course of performing the fine-mapping study, we also developed a streamlined analytic approach. By using existing genetic analysis software suites, linking them with small Linux scripts and parallel processing multiple statistical models simultaneously, we were able to greatly facilitate our genetic analysis. For the PXK locus, we identify a 257kb haplotype associated with SLE. The strongest association was found at rs6445972 with P < 4.62 × 10-10, OR 0.81 (0.75–0.86). We confirmed this finding with Bayesian analysis, confirming a 95% credible set consisting of 172 variants. We found one association at the locus. In addition to the genetic fine-mapping results, we also demonstrate that PXK colocalizes with the B cell antigen receptor (BCR) following BCR-crosslinking. shRNA-mediated knockdown of PXK resulted in delayed BCR internalization. Cell lines derived from patients carrying the SLE-associated risk variant displayed a delay in BCR internalization. Given the role for BCR internalization in B cell fate determination and survival, our results support new candidate mechanisms for SLE-disease risk, including BCR trafficking and BCR-mediated B cell activation.
John Harley, M.D. Ph.D. (Committee Chair)
Fred Finkelman, M.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
William Ridgway, Ph.D. (Committee Member)
Stephanie Ware, M.D. Ph.D. (Committee Member)
235 p.
Immunology
Lupus; PXK; B cells; BCR; fine-mapping

Recommended Citations

Citations

  • Vaughn, S. (2015). PXK and Lupus: Novel Immunobiology for a Lupus-Risk Gene [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447690650

    APA Style (7th edition)

  • Vaughn, Samuel. PXK and Lupus: Novel Immunobiology for a Lupus-Risk Gene. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447690650.

    MLA Style (8th edition)

  • Vaughn, Samuel. "PXK and Lupus: Novel Immunobiology for a Lupus-Risk Gene." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447690650

    Chicago Manual of Style (17th edition)

ucin1447690650
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© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.