The contribution of genetic variation to development of systemic lupus erythematosus
Creators: name: Jiang, Simon Hee-Tang
Publisher: name: The Australian National University
Year: 2015
Subjects: subject: Systemic lupus erythematosus
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Autoimmunity
subject: BANK1
subject: VANGL1
subject: Glomerulonephritis

description: Systemic lupus erythematosus is the prototypical autoimmune disease characterised by multi-organ involvement. Genetic variance is one of the most potent risk factors for development of lupus yet currently identified variants only account for 15% of genetic risk. Despite a strong genetic basis it does not follow Mendelian patterns of inheritance. A favoured hypothesis is that many common, mildly damaging variants combine to predispose to lupus. An alternative hypothesis is that few rare damaging variants cause disease. Single nucleotide and copy number variation have both been increasingly associated with a diverse range of diseases and this thesis investigates their contribution to lupus in isolation or in epistasis. This thesis describes the use of whole exome sequencing and SNP-chip arrays to identify genetic variants that associate with systemic lupus erythematosus. Using a combination of molecular tools we demonstrate the translational consequences of these variants and how the alterations to protein function may then disturb cellular function. In the final step of proof of causation we generate bespoke mouse models of the variants to demonstrate and test the effect of these variants in autoimmunity. Specifically we show that inheritance of a rare damaging mutation in BANK1 together with a second damaging rare mutation in one of three BANK1-interacting proteins: BLK, SAMSN1 or IRAK2, alters B cell responses to TLR ligands increasing secretion of the lupus-promoting cytokines IL-6 and IL-10. Introduction of the human BANK1W40C, BLKR131W and SAMSN1T198A variants in mice via CRISPR/Cas9 reveals the mutant alleles increase IL-6 production by B cells and cause lupus-like disease. These results provide support for digenic or oligogenic lupus, bespoke mouse models of human lupus, and novel targets for personalised intervention. Using a SNP-chip array a large intronic deletion in VANGL1 was identified that associated with glomerulonephritis in a cohort of SLE. Kidneys from Vangl1 deficient mice demonstrated spontaneous IgA and IgG deposition but were normal by light microscopy, with no evidence of systemic autoimmunity. B cell deficient Vangl1 mice, but not B cell sufficient Vangl1 mice, injected with wild type or Vangl1+/- serum demonstrated IgG deposition indicating a kidney intrinsic mechanism for the development of nephritis. This thesis identifies and demonstrates the contribution of rare single nucleotide variants functioning in systemic autoimmunity. The demonstration of the oligogenic contribution is a first for complex autoimmunity, as are many of the interactions and consequences of the mutations. Further, this thesis identifies genetic mechanisms through which organ-specific manifestations of lupus may occur – relatively common copy number variants in VANGL1 associates with increased risk of lupus nephritis.