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

Jiang, Simon, Athanasopoulos, Vicki, Ellyard, Julia, Chuah, Aaron, Cappello, Jean, Cook, Amelia, Prabhu, Savit B., Cardenas, Jacob, Gu, Jinghua, Stanley, Maurice, Roco, Jonathan A., Papa, Ilenia, Yabas, Mehmet, Walters, Giles D., Burgio, Gaetan, McKeon, Kathryn, Byers, James M., Burrin, Charlotte, Enders, Anselm, Miosge, Lisa A., Canete, Pablo F., Jelusic, Marjia, Tasic, Velibor, Lungu, Adrian C., Alexander, Stephen I., Kitching, Arthur R., Fulcher, David, Shen, Nan, Arsov, Todor, Gatenby, Paul A., Babon, Jeff J., Mallon, Dominic F., de Lucas Collantes, Carmen, Stone, Eric A., Wu, Philip, Field, Matt, Andrews, Thomas D., Cho, Eun, Pascual, Virginia, Cook, Matthew, and Vinuesa, Carola G. (2019) Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nature Communications, 10. 2201.

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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.

Item ID: 58320
Item Type: Article (Research - C1)
ISSN: 2041-1723
Copyright Information: Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0
Funders: National Health and Medical Research Council (NHMRC)
Date Deposited: 16 Jul 2019 23:49
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110706 Immunogenetics (incl Genetic Immunology) @ 50%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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