At the heart of lupus is a genetic puzzle – a puzzle that has recently revealed a bit more of the complex causes and symptoms of SLE.  Understanding the relationship between lupus and genetics is crucial to finding answers about why it affects each person so differently and in the end perhaps the key to its eventual cure.

 

• Introduction: The 30-second Overview
• The “Family Tree” of Lupus
• Autoimmunity and the Search for Lupus Genes
• In Conclusion

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Introduction: The 30-second Overview

The genetics of lupus is complex!  Lupus is not considered a typical genetic disease, though researchers estimate that genetics accounts for about 40% to 60% of the risk factors associated with SLE.  Environmental factors, like ultraviolet light, infections and other stresses accounting for the other roughly 50%.

We know that genetics plays a significant role in at least three ways:

1. Specific genes can help predict which individuals are more likely to get lupus than others;
2. Genetics help explain why symptoms are so different from one person to the next, and
3. Genes can even be the cause for why different patients respond so differently to standard medications.

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Some Quick Facts About Lupus and Genetics: 

• There is no such thing as a “lupus gene.”
  • However, there are over 180 genetic regions or “loci” that have been associated with increased risk for developing lupus.
  • The more of these problematic genes a person has, the more likely they are to develop lupus.
• Having a close family relative with lupus increases the risk of a person developing it themselves.
  • However, even the identical twin of a person living with lupus is only 25% likely to have lupus themselves.
• Many of the genes that increase the risk for lupus are found on two chromosomes: Chromosome 6 and the X chromosome.
  • This provides a genetic basis for the fact that 9 times more women than men develop SLE.  Women usually have two X chromosomes, while men usually have only one.
• Genetics is a major reason behind the statistics for why certain ethnic groups (Black, Asian, Hispanic, Native American, Pacific Islanders, and others) are 2 to 3 times more likely to develop lupus than those who are White or have European ancestry.

Want to learn more?  Read on!

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The “Family Tree” of Lupus

As mentioned earlier, research has shown that lupus does run in families … sort of.

The thing is that lupus does not follow the classic Mandelian family inheritance patterns that determine things such as hair color, eye color or blood type.  Lupus also does not follow the inheritance rules of truly genetic diseases like cycle cell anemia or cystic fibrosis – conditions that clearly run in people’s families.

Here are some statistics on lupus in families:

• About 5% of children with a parent with lupus will develop lupus.
• Siblings of those with lupus are at a 20 to 30 times higher risk for developing SLE compared to those who do not.  However, since lupus is a relatively rare condition in general, that comes to only about a 2% chance for other siblings to develop lupus.
• If the siblings are nonidentical twins, that increases from 5% to 8%.
• Even an identical twin to a person with lupus only has a 25% chance of developing lupus themselves. That means 75% of the time, even for two people with identical genetics, only one will develop lupus.

So, why is the genetics of lupus so difficult to predict?  Well, that requires a bit more genetics to answer!

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Autoimmunity and the Search for Lupus Genes

Even after the completion of the Human Genome Project in 2001, it has been challenging to estimate the number of genes coded in human DNA.  The current estimate is that between 20,000 and 25,000 protein-coding genes provide the blueprint for everything that our cells do – including regulating the immune system.  There are at least that many “genes” that either regulate how the other 25,000 work or they have unknown functions.  All these genes are organized into 46 separate chromosomes (23 inherited from each parent).

As mentioned earlier, there are about 180 genes that seem to be most involved in lupus and this number is bound to get larger as more research is done.  As with most things that have to do with lupus, things get complicated quickly because these genes can interact and express themselves in incredibly diverse (heterogeneous) ways that lead to all types of SLE.  Almost all instances of lupus are due to the combination of multiple genes (polygenic lupus), while a few rare forms of lupus seem to originate from the mutation of just one gene (monogenic lupus).  This would be a good time to explore these in a bit more detail.

 

Polygenic Lupus

It is clear that lupus is very rarely associated to just one specific gene.  It is the result of a combination of many genetic factors (termed polygenic risk factors) that are associated across several locations places among the 46 chromosomes that make up the human genome.

One of the areas of the human genome where these genes were first recognized was on chromosome 6 – called the major histocompatibility complex (MHC) genes.  These genes are responsible for coding the immune system’s response to certain infections, particularly bacteria, creating proteins that promote the many aspects of the inflammatory response.

One part of these MHC genes, called the human leukocyte antigen (HLA) genes was first associated with lupus in the 1970s.  Each gene in the HLA region is associated with different types of autoantibodies and they reflect different clinical symptoms of lupus:  some are more common to those with discoid lupus, others with lupus nephritis, etc.

Some of these genes code for the production of chemicals that may be familiar as biomarkers in blood tests that you have had.  These include C-reactive protein, tumor necrosis factor alpha (TNF-a) and interleukin-10 (IL-10).  Each is a protein that is coded by a gene and if any or all are incorrectly produced by cells, lupus might be the result.

What does this all mean?

• The more “lupus genes” a person has, the more likely they will develop lupus.
• Also, the more “lupus genes” a person has, the more severe are the symptoms they experience.
• Just think of all the possible combinations of the 180+ problematic genes that we know exist so far.  It is a bit easier to appreciate how different and complex each person’s lupus can be!

Yet, there is also research on a few forms of lupus seem to be caused by just one genetic mutation – the so-called monogenic versions of SLE.  These are very rare, but they are important because they may hold the key to understanding genetic aspects of the other, more common forms of lupus.

Monogenic Lupus

The most common example of a lupus-like condition caused by single-gene is a condition called, complement deficiency.  This is most prevalent in child-onset lupus – though still rare at only about 10% of these patients.  They are also most often associated with skin involvement.

There are many forms of complement and they are important in making sure the body does not mistake its own dead cells for being foreign invaders. They basically tell the body to not over-react.  The suggestion is that these patients actually have fewer genes to produce a specific type of complement, and when this happens, the body over-reacts, and creates autoantibodies against its own dead cells, which then leads to an autoimmune response.

In 2022, a study made headlines suggested that a specific gene, called the TLR7 gene, could potentially be a lupus triggering gene.  TLR7 refers to a protein called Toll-like receptor 7, which the body normally produces to recognize certain pathogens, mostly RNA viruses.  Mutations in this gene are thought to over-activate the immune system – encouraging the production of B cells and their autoantibodies.

Epigenetics

To complicate things further, another layer of genetic control over the expression of a person’s DNA is the field of study called, epigenetics.  This is a relatively new frontier in lupus research that combines what we know about genetics with the environmental factors that regulate how that genetics is expressed.  In this case, there is not a specific mutation or problem with the DNA of the gene itself, but rather the DNA is hidden by special proteins whose job it is to turn genes “on” and “off.”

There are many factors that can turn genes “on” when they should be “off” and vice versa.  These have been associated to environmental factors like pollution, bodily trauma and mental stress.  Because these can be caused by social problems like poverty, unemployment or homelessness, it may explain how socioeconomic status might lead to the development of lupus.

This may explain why it is uncommon for identical twins to both develop lupus.

A more detailed description of epigenetics can be found in the KFL blog article, “Lupus and Epigenetics.”

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In Conclusion

Even though lupus is not considered a classic genetic disease, it is significantly affected by a person’s genetics in ways that are still not well-understood and difficult to comprehend.  Yet, as research continues, scientists are discovering what drives the complex relationships between specific genes the resulting autoimmune and inflammatory responses in lupus.

It is currently not possible to directly change a patient’s DNA in order to eliminate these problems at the genetic level.  However, advances are happening at a rapid pace and it is increasingly likely that some combination of genetic and epigenetic therapies will be developed that could eventually lead to a cure.  That is the hope for lupus and its genetic connection!

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References

Brown, G.J., Cañete, P.F., Wang, H., Medhavy, A., Bones, J., Roco, J.A., He, Y., Qin, Y., Cappello, J., Ellyard, J.I., Bassett, K., Shen, Q., Burgio, G., Zhang, Y., Turnbull, C., Meng, X., Wu, P., Cho, E., Miosge, L.A., Adrews, T.D., & Vinuesa, C.G. (2022). TLR& gain-of-function genetic variation causes human lupus. Nature, 605, 349-356. https://doi.org/10.1038/s41586-022-04642-z

Demkova, K., Morris, D.L., & Vyse, T.J. (2023). Genetics of SLE: Does this explain susceptibility and severity across racial groups? Rheumatology, 62(1), i15-i21. https://academic.oup.com/rheumatology/article/62/Supplement_1/i15/6965625

Guerra, S. G., Vyse, T. J., & Cunninghame Graham, D. S. (2012). The genetics of lupus: a functional perspective. Arthritis Research & Therapy, 14(3), 211. https://doi.org/10.1186/ar3844

Harley, I.T., & Sawalha, A.H. (2022). Systemic lupus erythematosus as a genetic disease, Clinical Immunology,(236). e.108953. https://www.sciencedirect.com/science/article/abs/pii/S152166162200033X

Klimi, E. (2022). Lupus genetics. Systemic Lupus Erythematosus – Pathogenesis and Management.  https://www.intechopen.com/chapters/82979

Lo, M. (2018, June 4). Insights gained from the study of pediatric systemic lupus erythematosus.  Frontiers of Immunology. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01278/full

Moha, C., & Putterman, C. (2015). Genetics and the pathogenesis of systemic lupus erythematosus and lupus nephritis. Nature Reviews: Nephrology, 11. 329-341. https://www.nature.com/articles/nrneph.2015.33

Ramos, P. S., Brown, E. E., Kimberly, R. P., & Langefeld, C. D. (2010). Genetic factors predisposing to systemic lupus erythematosus and lupus nephritis. Seminars in Nephrology, 30(2), 164–176. https://doi.org/10.1016/j.semnephrol.2010.01.007

Scofield, R.H. (2020, May 5). Systemic lupus erythematosus (SLE) genetics. Medscape. https://emedicine.medscape.com/article/1884084-overview

Tangtanatakul, P., Lei, Y., & Jaiwan, K. (2024). Association of genetic variation on X chromosome with systemic lupus erythematosus in both Thai and Chinese populations. Lupus Science & Medicine, 11. e001061. doi: 10.1136/lupus-2023-001061

Thomas, D. (2024, March 6). The genetic landscape: Is lupus hereditary? “Yes.” The Lupus Encyclopedia. https://www.lupusencyclopedia.com/is-lupus-hereditary/

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Author: Greg Dardis, MS      

Professor Dardis was formerly the Chair of the Science Department at Marylhurst University and is currently an Assistant Professor at Portland State University and the American College of Healthcare Sciences.  His focus has been human biology and physiology with an interest in  autoimmunity.  Professor Dardis is also a former President of the Board of Directors of Kaleidoscope Fighting Lupus.

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