November 10, 2020

Lupus affects individuals differently, from disease symptoms to responses to treatments.  Lupus patients of African ancestry often show significantly greater severity of lupus and respond to lupus drugs differently than lupus patients of European ancestry.

In a collaboration among investigators at RILITE Foundation led by Dr. Peter Lipsky and Wake Forest School of Medicine led by Dr. Carl Langefeld, Dr Kate Owen, the lead investigator of this study, employed novel “big data” analysis to collect all of the genetic variants associated with lupus, identify the most likely risk genes, assemble them into functional pathways, identify those lupus-associated pathways with DNA variation more common in African or European ancestries, and predict drugs that might therefore be more effective in each ancestral group. Together, these collaborators hypothesized that although everyone has the same genes, some of the clinical differences are due to small differences in the DNA for groups of genes that show varied activity across the two populations. They hope to use the differences in these groups of genes to enable researchers to make more effective drugs for all lupus patients.

This work was supported in part by grants from the Lupus Research Alliance as well as the Impact Award through the Lupus Research Program (LRP) within the Department of Defense – a program that the Lupus Research Alliance advocated to create – and the NIH. These results were published in the American Journal of Human Genetics.

Dr. Langefeld’s lab uses results from analyses of the Immunochip, a technology designed to pinpoint the regions and specific variation in the DNA of our chromosomes that are important in human immune disorders. Chromosomes are the biochemical structures that contain our DNA – our genetic material. They feature millions of naturally occurring variations, some of which may be linked to disease. Over a hundred such chromosomal regions and genetic variations have been linked to lupus. Importantly, the genetic variations that have been linked to lupus are not necessarily found in all lupus patients and some appear to be more or less common in different ancestries (e.g. European or African ancestry). This newest study aimed to identify these differences in hopes of better understanding the varied biological processes involved with lupus. Knowing which biological processes are influenced by lupus-linked genetic variations could lead to more effective treatments. Building upon the identified lupus-linked genetic variations in people of African descent and European descent, these researchers identified the genetic variations that were similar and differed between the two groups of people. They then examined the cellular processes controlled by those genetic variations. These processes are happening in our cells all the time to keep our bodies safe, and include things like inflammation and other immune responses.

There were 23 processes that were more frequent in lupus patients of African ancestry and 20 processes more frequent in those of European ancestry. There were 45 lupus-associated processes found in lupus patients across both ancestries. The processes more common in lupus patients of African ancestry were involved in the breakdown of proteins and the adaptive immune system — the arm of the immune system that makes antibodies and remembers germs it has been exposed to in the past. This made sense, since doctors have observed that lupus in this group of people is driven by an increase in the number of B cells that make autoantibodies that can cause tissue damage. In contrast, the processes more common in lupus patients of European ancestry were involved in inflammation and the innate immune system, the body’s first line of defense against anything foreign.

Dr. Langefeld commented: “The risk to developing lupus and its severity results from a combination of environmental factors interacting with genetic susceptibility. Thus, socioeconomic factors, such as access to care, are important contributors to clinical differences in lupus and cannot be ignored. By better understanding the genetic differences among lupus populations, as we are attempting to do, we may ultimately be able to create more personalized treatments strategies.”

RILITE Foundation President and rheumatologist Dr. Peter Lipsky,  noted “Focusing on biological processes, rather than individual genes, can give us a greater understanding of how the disease develops and progresses and can uncover more targets for drug development.”

Different drugs are used to target these different biological processes when treating lupus, so another strength of this study is in identifying drugs that could be more effective in one population or the other. For example, a drug already approved by the FDA for use in treating a type of cancer, bortezomib, reduces the breakdown of proteins that normally occurs in the body, and may thus be a good therapeutic option for lupus patients of African ancestry. Siponimod is an FDA-approved treatment for multiple sclerosis; it prevents inflammation, and thus may be particularly well suited to use in lupus patients with European ancestry.

The authors note that the design of Immunochip was heavily influenced by studies primarily of European populations, and only contains genetic regions already thought to be important in inflammatory and autoimmune disorders. Thus, it does not survey all of our DNA. Furthermore, they emphasize that the identified processes may be more common in specific ancestries but would not necessarily apply to every lupus patient. However, these findings are valuable as they suggest that different processes or paths can lead to lupus, some of which show different frequencies across different ancestries. And their identification of the genetic differences underlying the respective pathways may help serve as a foundation for more personalized therapies. Finally, this study highlights the importance of research designs inclusive of multiple ancestries in order to better serve all patient populations.