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

Nat Commun. 2019 May 17;10(1):2201. doi: 10.1038/s41467-019-10242-9.

Authors

Simon H Jiang^{1

2

3}, Vicki Athanasopoulos^{4

5}, Julia I Ellyard^{4

5}, Aaron Chuah^{5

6}, Jean Cappello^{4

5}, Amelia Cook^{4

5}, Savit B Prabhu^{4

5

7}, Jacob Cardenas⁸, Jinghua Gu⁸, Maurice Stanley^{4

5}, Jonathan A Roco^{4

5}, Ilenia Papa⁴, Mehmet Yabas^{4

9}, Giles D Walters^{4

5

10}, Gaetan Burgio⁴, Kathryn McKeon^{4

5}, James M Byers^{4

5}, Charlotte Burrin⁴, Anselm Enders^{4

5}, Lisa A Miosge⁴, Pablo F Canete^{4

5}, Marija Jelusic¹¹, Velibor Tasic¹², Adrian C Lungu¹³, Stephen I Alexander^{5

14}, Arthur R Kitching^{5

15}, David A Fulcher^{4

5

16}, Nan Shen¹⁷, Todor Arsov^{4

5

17}, Paul A Gatenby¹⁶, Jeff J Babon¹⁸, Dominic F Mallon¹⁹, Carmen de Lucas Collantes²⁰, Eric A Stone²¹, Philip Wu^{5

22}, Matthew A Field^{5

6}, Thomas D Andrews^{5

6

23}, Eun Cho^{5

6}, Virginia Pascual⁸, Matthew C Cook^{4

5

16

17}, Carola G Vinuesa^{24

25

26}

Affiliations

¹ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Acton, 2601, ACT, Australia. [email protected].
² Centre for Personalised Immunology, NHMRC Centre for Research Excellence, Acton, 2601, Australia. [email protected].
³ Department of Renal Medicine, The Canberra Hospital, Garran, 2601, ACT, Australia. [email protected].
⁴ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Acton, 2601, ACT, Australia.
⁵ Centre for Personalised Immunology, NHMRC Centre for Research Excellence, Acton, 2601, Australia.
⁶ Genome Informatics Laboratory, John Curtin School of Medical Research, Acton, 2601, ACT, Australia.
⁷ Paediatric Biology Center, Translational Health Science and Technology Institute, Faridabad, 121001, Haryana, India.
⁸ Baylor Medical Institute, Houston, 77030, Texas, USA.
⁹ Department of Genetics and Bioengineering, Trakya University, Edirne, 22030, Turkey.
¹⁰ Department of Renal Medicine, The Canberra Hospital, Garran, 2601, ACT, Australia.
¹¹ Department of Paediatric Rheumatology and Immunology, University of Zagreb School of Medicine, Zagreb, 10000, Croatia.
¹² University Children's Hospital, Medical School, Skopje, 1000, Macedonia.
¹³ Department of Pediatric Nephrology, Fundeni Clinical Institute, Bucharest, 022328, Romania.
¹⁴ Westmead Children's Hospital, Westmead, 2145, NSW, Australia.
¹⁵ Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, 3168, VIC, Australia.
¹⁶ Department of Immunology, The Canberra Hospital, Garran, 2601, ACT, Australia.
¹⁷ China Australia Centre for Personalised Immunology, Renji Hospital Shanghai, JiaoTong University Shanghai, Huangpu Qu, 200333, China.
¹⁸ Walter and Eliza Hall Institute, Parkville, 3052, VIC, Australia.
¹⁹ Immunology PathWest Fiona Stanley Hospital, Murdoch, 6150, WA, Australia.
²⁰ Department of Pediatric Nephrology, Children's University Hospital Niño Jesús, Madrid, 28009, Spain.
²¹ Research School of Biology and Research School of Finance, Actuarial Studies and Statistics, Acton, 2601, ACT, Australia.
²² Australian Phenomics Facility, ANU, Acton, 2601, ACT, Australia.
²³ National Computational Infrastructure, ANU, Acton, 2601, ACT, Australia.
²⁴ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Acton, 2601, ACT, Australia. [email protected].
²⁵ Centre for Personalised Immunology, NHMRC Centre for Research Excellence, Acton, 2601, Australia. [email protected].
²⁶ China Australia Centre for Personalised Immunology, Renji Hospital Shanghai, JiaoTong University Shanghai, Huangpu Qu, 200333, China. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Adolescent
Adult
Animals
B-Lymphocytes / cytology
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Case-Control Studies
Cell Line
Cell Nucleus / immunology
Cell Nucleus / metabolism
Child
Disease Models, Animal
Exome Sequencing
Female
Gene Frequency
Genetic Predisposition to Disease*
HEK293 Cells
Healthy Volunteers
Humans
Interferon Regulatory Factors / immunology
Interferon Regulatory Factors / metabolism
Interferon Type I / immunology
Interferon Type I / metabolism
Lupus Erythematosus, Systemic / blood
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / immunology
Male
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation, Missense
src-Family Kinases / genetics*
src-Family Kinases / metabolism

Substances

Adaptor Proteins, Signal Transducing
BANK1 protein, human
IRF5 protein, human
Interferon Regulatory Factors
Interferon Type I
Irf5 protein, mouse
Membrane Proteins
B lymphoid kinase, mouse
BLK protein, human
src-Family Kinases