Researchers have shown that rare genetic mutations are a major cause of lupus


In a world first, researchers from The Australian National University (ANU) have shown previously ignored rare genetic mutations are a major cause of lupus.

The discovery is set to change our understanding of the causes of disease and potentially save lives.

Lupus is an autoimmune disease that has no cure.

Systemic Lupus Erythematosus (SLE [MIM 152700]) is a chronic inflammatory disease characterized by a loss of tolerance to self-antigens and the production of high titers of autoantibodies directed against native DNA and other cellular constituents.

Approximately 90% of individuals affected with SLE are female, predominately of childbearing age. SLE patients can present with a wide spectrum of clinical manifestations involving multiple organ systems.

The prevalence of SLE in the U.S. is estimated between 0.05% and 0.1% of the population;

The disease disproportionately affects African Americans (prevalence estimates: 0.009%, white men; 0.066%, white women; 0.038%, African-American men; and 0.282%, African-American women) 1.

About one-half of SLE patients will manifest the more severe complications of the disease, which can include nephritis, central nervous system vasculitis, pulmonary hypertension, interstitial lung disease, and stroke.

Lupus nephritis (LN) is among the most common clinical complication of SLE, occurring in up to 74% percent of patients and accounting for significant morbidity and mortality particularly among ethnic minorities 2.

The current paradigm is that LN results from immune complex deposition in the renal glomeruli leading to complement activation, chronic inflammation and renal insufficiency defined by histopathology and the presence of proteinuria and cellular casts.

Multiple lines of indirect evidence support a genetic etiology in SLE and LN. Twin studies estimated that the rate of SLE concordance in monozygotic twins is 24%-35%, compared to 2%–5% in dizygotic twin pairs 3,4.

Familial aggregation studies in SLE show that 10%-12% of patients with SLE have first or second degree family members with the disease, compared to < 1% of controls 5,6. In SLE, the sibling risk ratio (λS) is estimated to be between 20 and 40 7.

In addition, a genetic component to the susceptibility of LN is supported by an over-representation of LN among children with SLE, familial aggregation of end-stage renal disease (ESRD) among African Americans with LN 8 and linkage studies of LN 9.

Recently, more direct evidence for the role of genetic variation in the pathogenesis SLE and LN has emerged.

Until 2007, only a handful of candidate gene polymorphisms had been convincingly implicated is SLE risk.

Remarkable technological advances such as high-throughput genotyping, the completion of the human genome sequence and the International HapMap Project and parallel development of analytic and bioinformatic methods have occurred.

Funding from the Alliance for Lupus Research has facilitated the development of the International Consortium on Systemic Lupus Erythematosus Genetics (SLEGEN; Collaborations between industry (e.g., Genentech) and academic institutions facilitated pooling of patient samples and leveraged recent technological advances to permit genome-wide searches for genetic polymorphisms predisposing to SLE and its complications.

These efforts and those of many individual researchers have triggered an explosion of discoveries on the genetics of SLE.

In spite of the complex genetic architecture of SLE, these discoveries demonstrate that a broad array of pathways underlines the genetic heterogeneity of SLE. Currently, the number of validated genetic regions predisposing to SLE is approximately 30.

Current follow up efforts are now focused on precisely identifying the causative genetic variants and their effects, and the biological mechanisms through which they predispose to SLE. Research in LN has not attained the same level of maturity as it has in SLE.

For example, no large-scale genome-wide association study (GWAS) for LN has been published. Consistent with the pre-GWAS era, the literature on LN genetics is remarkable for the lack of strength and consistency of associations of variants across different study designs and diverse populations.

The role of other forms of genetic variation is an exciting new frontier. Some copy number variants have already been shown to be important for SLE 10.

Epigenetic variation, (i.e., heritable change in genome function that occur without a change in DNA sequence) is clearly involved in the pathogenesis of SLE 11.

Such change may be the result of environmental exposures and can have a profound impact on gene expression.

Given its potential importance, epigenomics has recently been included on the NIH Roadmap (

These new findings are creating new hypothesis about mechanisms of disease that may be potential therapeutic targets, and will revolutionize our knowledge of SLE.

Genetic Connections - Key Genes that appear in multiple autoimmune diseases.

It targets the body’s healthy tissue, causing inflammation, damage and pain.

Until now, the exact cause of the disease has been poorly understood.

That’s changed thanks to a genetic breakthrough by ANU researchers Dr. Simon Jiang, Dr. Vicki Athanasopoulos, and Professor Carola Vinuesa.

Dr. Jiang has spent six years analysing the genetic instructions locked in DNA which lead to the disease.

“We have shown for the first time how rare gene variants that occur in less than one percent of the population cause lupus and how these variants drive the disease in the body,” said Dr. Jiang, from the Centre for Personalised Immunology, an NHMRC Centre for Research Excellence at ANU.

“Until now, it was thought that these rare variants played a negligible role in human autoimmunity and related autoimmune diseases.

“We’ve shown how most lupus patients harbour those so-called rare gene variants and how these rare gene variants cause immune cells to no longer work properly.

“When the cells no longer work, your immune system struggles to distinguish viruses and bacteria from self, leading to lupus.”

The finding makes way for life-saving personalised treatment for lupus and other autoimmune diseases.

“There is huge potential for targeted treatment,” said Dr. Jiang.

“I’ve already started treating people who have these rare gene mutations with targeted therapies instead of bombarding their immune system with non-specific treatments that have lots of side effects – which is the current mainstay of therapy.

“And because the genes we have worked on are linked to other autoimmune diseases, our discovery could also be applied to conditions like rheumatoid arthritis and type 1 diabetes.”

The finding may also help identify and predict how severe an individual’s lupus is.

Lupus is a disease that can be very hard to diagnose. You can have a lot of illnesses that look like lupus, smell like lupus, but we can’t formally call it lupus.

“It now will only take a few weeks to get a patient’s genome sequence. We can look at how the immune system is behaving, take blood tests and with genome sequencing we can fit the pieces together and see if it is lupus.”

Dr. Jiang says the discovery is a personal victory because he has seen so many people suffering from lupus.

“When I was a junior doctor, I had a patient in her 40s who died because of an autoimmune condition and we just could not figure out what was wrong.

That shouldn’t happen and it affected me a lot. I’d like to think if she came to me nowadays I’d be able to do something different. I hope I’d be able to save her life.”

More information: Simon H. Jiang et al. Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus, Nature Communications (2019). DOI: 10.1038/s41467-019-10242-9

Journal information: Nature Communications
Provided by Australian National University


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