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

Samuel E. Vaughn, Corinne Foley, Xiaoming Lu, Zubin H Patel, Erin Zoller, Albert F. Magnusen, Adrienne H. Williams, Julie T. Ziegler, Mary E. Comeau, Miranda C. Marion, Stuart B. Glenn, Adam Adler, Nan Shen, Swapan K. Nath, Anne M. Stevens, Barry I. Freedman, Betty P. Tsao, Chaim O. Jacob, Diane L. Kamen, Elizabeth E. BrownGary 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

Resultado de la investigación: Contribución a RevistaArtículo

14 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)450
PublicaciónFrontiers in Genetics
Volumen5
DOI
EstadoPublished - 2014
Publicado de forma externa

Huella dactilar

B-Lymphocytes
B-Cell Antigen Receptors
Haplotypes
Bayes Theorem
Systemic Scleroderma
Genome-Wide Association Study
COS Cells
3' Untranslated Regions
Autoimmunity
Epidermal Growth Factor Receptor
Systemic Lupus Erythematosus
Autoimmune Diseases
Rheumatoid Arthritis
Cell Survival
Logistic Models
Regression Analysis
Population

Citar esto

Vaughn, S. E., Foley, C., Lu, X., Patel, Z. H., Zoller, E., Magnusen, A. F., ... Kottyan, L. C. (2014). Lupus risk variants in the PXK locus alter B-cell receptor internalization. Frontiers in Genetics, 5, 450. https://doi.org/10.3389/fgene.2014.00450
Vaughn, Samuel E. ; Foley, Corinne ; Lu, Xiaoming ; Patel, Zubin H ; Zoller, Erin ; Magnusen, Albert F. ; Williams, Adrienne H. ; Ziegler, Julie T. ; Comeau, Mary E. ; Marion, Miranda C. ; Glenn, Stuart B. ; Adler, Adam ; Shen, Nan ; Nath, Swapan K. ; Stevens, Anne M. ; Freedman, Barry I. ; Tsao, Betty P. ; Jacob, Chaim O. ; Kamen, Diane L. ; Brown, Elizabeth E. ; Gilkeson, Gary S. ; Alarcón, Graciela S. ; Reveille, John D. ; Anaya, Juan-Manuel ; James, Judith A. ; Moser, Kathy L. ; Criswell, Lindsey A. ; Vilá, Luis M. ; Alarcón-Riquelme, Marta E. ; Petri, Michelle ; Scofield, R. Hal ; Kimberly, Robert P. ; Ramsey-Goldman, Rosalind ; Binjoo, Young ; Choi, Jeongim ; Bae, Sang Cheol ; Boackle, Susan A. ; Vyse, Timothy J. ; Guthridge, Joel M. ; Namjou, Bahram ; Gaffney, Patrick M. ; Langefeld, Carl D. ; Kaufman, Kenneth M. ; Kelly, Jennifer A. ; Harley, Isaac T W ; Harley, John B. ; Kottyan, Leah C. / Lupus risk variants in the PXK locus alter B-cell receptor internalization. En: Frontiers in Genetics. 2014 ; Vol. 5. pp. 450.
@article{bcef66ca5b9240eb820e4ecb27599f69,
title = "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.",
author = "Vaughn, {Samuel E.} and Corinne Foley and Xiaoming Lu and Patel, {Zubin H} and Erin Zoller and Magnusen, {Albert F.} and Williams, {Adrienne H.} and Ziegler, {Julie T.} and Comeau, {Mary E.} and Marion, {Miranda C.} and Glenn, {Stuart B.} and Adam Adler and Nan Shen and Nath, {Swapan K.} and Stevens, {Anne M.} and Freedman, {Barry I.} and Tsao, {Betty P.} and Jacob, {Chaim O.} and Kamen, {Diane L.} and Brown, {Elizabeth E.} and Gilkeson, {Gary S.} and Alarc{\'o}n, {Graciela S.} and Reveille, {John D.} and Juan-Manuel Anaya and James, {Judith A.} and Moser, {Kathy L.} and Criswell, {Lindsey A.} and Vil{\'a}, {Luis M.} and Alarc{\'o}n-Riquelme, {Marta E.} and Michelle Petri and Scofield, {R. Hal} and Kimberly, {Robert P.} and Rosalind Ramsey-Goldman and Young Binjoo and Jeongim Choi and Bae, {Sang Cheol} and Boackle, {Susan A.} and Vyse, {Timothy J.} and Guthridge, {Joel M.} and Bahram Namjou and Gaffney, {Patrick M.} and Langefeld, {Carl D.} and Kaufman, {Kenneth M.} and Kelly, {Jennifer A.} and Harley, {Isaac T W} and Harley, {John B.} and Kottyan, {Leah C.}",
year = "2014",
doi = "10.3389/fgene.2014.00450",
language = "English (US)",
volume = "5",
pages = "450",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",

}

Vaughn, SE, Foley, C, Lu, X, Patel, ZH, Zoller, E, Magnusen, AF, Williams, AH, Ziegler, JT, Comeau, ME, Marion, MC, Glenn, SB, Adler, A, Shen, N, Nath, SK, Stevens, AM, Freedman, BI, Tsao, BP, Jacob, CO, Kamen, DL, Brown, EE, Gilkeson, GS, Alarcón, GS, Reveille, JD, Anaya, J-M, James, JA, Moser, KL, Criswell, LA, Vilá, LM, Alarcón-Riquelme, ME, Petri, M, Scofield, RH, Kimberly, RP, Ramsey-Goldman, R, Binjoo, Y, Choi, J, Bae, SC, Boackle, SA, Vyse, TJ, Guthridge, JM, Namjou, B, Gaffney, PM, Langefeld, CD, Kaufman, KM, Kelly, JA, Harley, ITW, Harley, JB & Kottyan, LC 2014, 'Lupus risk variants in the PXK locus alter B-cell receptor internalization', Frontiers in Genetics, vol. 5, pp. 450. https://doi.org/10.3389/fgene.2014.00450

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

En: Frontiers in Genetics, Vol. 5, 2014, p. 450.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Lupus risk variants in the PXK locus alter B-cell receptor internalization

AU - Vaughn, Samuel E.

AU - Foley, Corinne

AU - Lu, Xiaoming

AU - Patel, Zubin H

AU - Zoller, Erin

AU - Magnusen, Albert F.

AU - Williams, Adrienne H.

AU - Ziegler, Julie T.

AU - Comeau, Mary E.

AU - Marion, Miranda C.

AU - Glenn, Stuart B.

AU - Adler, Adam

AU - Shen, Nan

AU - Nath, Swapan K.

AU - Stevens, Anne M.

AU - Freedman, Barry I.

AU - Tsao, Betty P.

AU - Jacob, Chaim O.

AU - Kamen, Diane L.

AU - Brown, Elizabeth E.

AU - Gilkeson, Gary S.

AU - Alarcón, Graciela S.

AU - Reveille, John D.

AU - Anaya, Juan-Manuel

AU - James, Judith A.

AU - Moser, Kathy L.

AU - Criswell, Lindsey A.

AU - Vilá, Luis M.

AU - Alarcón-Riquelme, Marta E.

AU - Petri, Michelle

AU - Scofield, R. Hal

AU - Kimberly, Robert P.

AU - Ramsey-Goldman, Rosalind

AU - Binjoo, Young

AU - Choi, Jeongim

AU - Bae, Sang Cheol

AU - Boackle, Susan A.

AU - Vyse, Timothy J.

AU - Guthridge, Joel M.

AU - Namjou, Bahram

AU - Gaffney, Patrick M.

AU - Langefeld, Carl D.

AU - Kaufman, Kenneth M.

AU - Kelly, Jennifer A.

AU - Harley, Isaac T W

AU - Harley, John B.

AU - Kottyan, Leah C.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.3389/fgene.2014.00450

DO - 10.3389/fgene.2014.00450

M3 - Article

C2 - 25620976

VL - 5

SP - 450

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

ER -