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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.

SUBMITTER: Jiang SH 

PROVIDER: S-EPMC6525203 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Jiang Simon H SH   Athanasopoulos Vicki V   Ellyard Julia I JI   Chuah Aaron A   Cappello Jean J   Cook Amelia A   Prabhu Savit B SB   Cardenas Jacob J   Gu Jinghua J   Stanley Maurice M   Roco Jonathan A JA   Papa Ilenia I   Yabas Mehmet M   Walters Giles D GD   Burgio Gaetan G   McKeon Kathryn K   Byers James M JM   Burrin Charlotte C   Enders Anselm A   Miosge Lisa A LA   Canete Pablo F PF   Jelusic Marija M   Tasic Velibor V   Lungu Adrian C AC   Alexander Stephen I SI   Kitching Arthur R AR   Fulcher David A DA   Shen Nan N   Arsov Todor T   Gatenby Paul A PA   Babon Jeff J JJ   Mallon Dominic F DF   de Lucas Collantes Carmen C   Stone Eric A EA   Wu Philip P   Field Matthew A MA   Andrews Thomas D TD   Cho Eun E   Pascual Virginia V   Cook Matthew C MC   Vinuesa Carola G CG  

Nature communications 20190517 1


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  ...[more]

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