Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus

Simon H. Jiang; Vicki Athanasopoulos; Julia I. Ellyard; Aaron Chuah; Jean Cappello; Amelia Cook; Savit B. Prabhu; Jacob Cardenas; Jinghua Gu; Maurice Stanley; Jonathan A. Roco; Ilenia Papa; Mehmet Yabas; Giles D. Walters; Gaetan Burgio; Kathryn McKeon; James M. Byers; Charlotte Burrin; Anselm Enders; Lisa A. Miosge; Pablo F. Canete; Marija Jelusic; Velibor Tasic; Adrian C. Lungu; Stephen I. Alexander; Arthur R. Kitching; David A. Fulcher; Nan Shen; Todor Arsov; Paul A. Gatenby; Jeff J. Babon; Dominic F. Mallon; Carmen de Lucas Collantes; Eric A. Stone; Philip Wu; Matthew A. Field; Thomas D. Andrews; Eun Cho; Virginia Pascual; Matthew C. Cook; Carola G. Vinuesa

doi:10.1038/s41467-019-10242-9

Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus

Simon H. Jiang^*, Vicki Athanasopoulos, Julia I. Ellyard, Aaron Chuah, Jean Cappello, Amelia Cook, Savit B. Prabhu, Jacob Cardenas, Jinghua Gu, Maurice Stanley, Jonathan A. Roco, Ilenia Papa, Mehmet Yabas, Giles D. Walters, Gaetan Burgio, Kathryn McKeon, James M. Byers, Charlotte Burrin, Anselm Enders, Lisa A. MiosgePablo F. Canete, Marija Jelusic, Velibor Tasic, Adrian C. Lungu, Stephen I. Alexander, Arthur R. Kitching, David A. Fulcher, Nan Shen, Todor Arsov, Paul A. Gatenby, Jeff J. Babon, Dominic F. Mallon, Carmen de Lucas Collantes, Eric A. Stone, Philip Wu, Matthew A. Field, Thomas D. Andrews, Eun Cho, Virginia Pascual, Matthew C. Cook, Carola G. Vinuesa

^*Corresponding author for this work

School of Medicine and Psychology

Research output: Contribution to journal › Article › peer-review

84 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

Original language	English
Article number	2201
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10242-9
Publication status	Published - 1 Dec 2019

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Jiang, S. H., Athanasopoulos, V., Ellyard, J. I., Chuah, A., Cappello, J., Cook, A., Prabhu, S. B., Cardenas, J., Gu, J., Stanley, M., Roco, J. A., Papa, I., Yabas, M., Walters, G. D., Burgio, G., McKeon, K., Byers, J. M., Burrin, C., Enders, A., ... Vinuesa, C. G. (2019). Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nature Communications, 10(1), Article 2201. https://doi.org/10.1038/s41467-019-10242-9

@article{51289f4ae8774c6ab8dbdf7f39632464,

title = "Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus",

abstract = "Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.",

author = "Jiang, {Simon H.} and Vicki Athanasopoulos and Ellyard, {Julia I.} and Aaron Chuah and Jean Cappello and Amelia Cook and Prabhu, {Savit B.} and Jacob Cardenas and Jinghua Gu and Maurice Stanley and Roco, {Jonathan A.} and Ilenia Papa and Mehmet Yabas and Walters, {Giles D.} and Gaetan Burgio and Kathryn McKeon and Byers, {James M.} and Charlotte Burrin and Anselm Enders and Miosge, {Lisa A.} and Canete, {Pablo F.} and Marija Jelusic and Velibor Tasic and Lungu, {Adrian C.} and Alexander, {Stephen I.} and Kitching, {Arthur R.} and Fulcher, {David A.} and Nan Shen and Todor Arsov and Gatenby, {Paul A.} and Babon, {Jeff J.} and Mallon, {Dominic F.} and {de Lucas Collantes}, Carmen and Stone, {Eric A.} and Philip Wu and Field, {Matthew A.} and Andrews, {Thomas D.} and Eun Cho and Virginia Pascual and Cook, {Matthew C.} and Vinuesa, {Carola G.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10242-9",

language = "English",

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Jiang, SH , Athanasopoulos, V , Ellyard, JI, Chuah, A, Cappello, J, Cook, A, Prabhu, SB, Cardenas, J, Gu, J, Stanley, M , Roco, JA, Papa, I, Yabas, M, Walters, GD, Burgio, G, McKeon, K, Byers, JM, Burrin, C, Enders, A, Miosge, LA, Canete, PF, Jelusic, M, Tasic, V, Lungu, AC, Alexander, SI, Kitching, AR, Fulcher, DA, Shen, N, Arsov, T, Gatenby, PA, Babon, JJ, Mallon, DF, de Lucas Collantes, C, Stone, EA, Wu, P, Field, MA, Andrews, TD, Cho, E, Pascual, V, Cook, MC & Vinuesa, CG 2019, 'Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus', Nature Communications, vol. 10, no. 1, 2201. https://doi.org/10.1038/s41467-019-10242-9

TY - JOUR

T1 - Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus

AU - Jiang, Simon H.

AU - Athanasopoulos, Vicki

AU - Ellyard, Julia I.

AU - Chuah, Aaron

AU - Cappello, Jean

AU - Cook, Amelia

AU - Prabhu, Savit B.

AU - Cardenas, Jacob

AU - Gu, Jinghua

AU - Stanley, Maurice

AU - Roco, Jonathan A.

AU - Papa, Ilenia

AU - Yabas, Mehmet

AU - Walters, Giles D.

AU - Burgio, Gaetan

AU - McKeon, Kathryn

AU - Byers, James M.

AU - Burrin, Charlotte

AU - Enders, Anselm

AU - Miosge, Lisa A.

AU - Canete, Pablo F.

AU - Jelusic, Marija

AU - Tasic, Velibor

AU - Lungu, Adrian C.

AU - Alexander, Stephen I.

AU - Kitching, Arthur R.

AU - Fulcher, David A.

AU - Shen, Nan

AU - Arsov, Todor

AU - Gatenby, Paul A.

AU - Babon, Jeff J.

AU - Mallon, Dominic F.

AU - de Lucas Collantes, Carmen

AU - Stone, Eric A.

AU - Wu, Philip

AU - Field, Matthew A.

AU - Andrews, Thomas D.

AU - Cho, Eun

AU - Pascual, Virginia

AU - Cook, Matthew C.

AU - Vinuesa, Carola G.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

AB - Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

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U2 - 10.1038/s41467-019-10242-9

DO - 10.1038/s41467-019-10242-9

M3 - Article

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2201

ER -

Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus

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