How Do Genetics and Ethnicity Affect Lupus Risk?

Scientists studying the genetics of systemic lupus erythematosus (SLE) have learned a tremendous amount about this disease, who gets it, and why. Still, much remains to be learned. Among the questions researchers are trying to answer are:

• How much does lupus run in families?
• Why are certain ethnic groups—including people who are Black, Asian, Latinx, Native American, Native Hawaiian, and Pacific Islanders—two to threes times more likely than people who are White to develop the condition?
• Can genetics predict who is susceptible to lupus and, if so, prevent it?

The answers to these questions are likely to be complicated and involve many elements, including not only your genes but also hormones (especially estrogen) and environmental factors. While all these things are believed to be involved in the development of lupus, experts don’t yet understand their relationships or exactly what role each plays.

Genes Involved in Lupus

The genetic picture of lupus isn’t yet complete, but scientists have identified more than 60 genes that they believe influence a person’s risk of developing SLE. In particular, studies have shown that a class of genes called major histocompatibility complex (MHC) genes have an association with lupus. MHC genes’ functions include:

• Building your immune system’s response to certain infectious agents
• Creating a type of protein that deals with the immune system’s inflammatory response

Several other genes that work with MHC genes and the immune response are also implicated in lupus. They give instructions to cells for producing proteins that deal with:

• Sending signals to the immune system
• Identifying and attaching themselves to infectious agents
• Impairing the function of cell receptors in the immune system
• Function and development of B-cells and T-cells (white blood cells that are important to immunity) and certain antibodies 
• Secretion of inflammatory cells called cytokines
• Production of certain autoantibodies, including two called anti-Ro and anti-La 
• Increased immune system activation

Some of the proteins associated with these genes are implicated in numerous autoimmune and inflammatory conditions and may be tested for as indicators of these diseases, including:

• C-reactive protein
• Tumor necrosis factor α (TNF-α)
• Interleukin-10 (IL-10)

Each of the cells, receptors, and substances affected by these genetic abnormalities has a ripple effect on your immune system that contributes to the autoimmunity of lupus. Because some of these factors are also involved in other autoimmune diseases, it helps to explain why many people have more than one.

Monogenic Lupus

Most cases of lupus are believed to be caused by changes in multiple genes (called polygenic), but some are associated with single mutations, which is called monogenic. While a significant number of genes may cause SLE, the most common single-gene mutation is called a complement deficiency.  

A group of proteins called complement proteins have an important clean-up job after your immune system launches an attack. The deficiency means this clean-up isn’t done properly, which leaves behind networks of molecules that can damage your tissues. Complement proteins may also help in the production of cytokines.

Another monogenic cause is a mutation in a gene called PRKCD (for protein kinase c-δ). The deficiency caused by this mutation results in excessive amounts of T-cells and makes B-cells send improper signals to the immune system.

A few other known mutations are believed to cause monogenic lupus. No matter the cause, the end result is autoimmune activity against the organs. Monogenic lupus is thought to be rare and is often characterized by:

• Early onset, usually before age 5
• Higher disease severity
• Kidney damage
• Central nervous system involvement

Epigenetics

While genetic mutations appear to play an important role in the development of SLE, researchers believe they don’t tell the whole story. In part, that belief is based on findings in identical twins. When one twin has the disease, the chance the other will also have it is less than 60%. If it were truly genetic, that percentage would be higher.

Because more than 40% of identical twins don’t develop lupus when their twin does, it is likely that another type of genetic influence—which occurs after birth—is at play here. This genetic influence is called epigenetics.

You’re born with genetic mutations, but epigenetic changes can happen throughout your life and are influenced by environmental conditions (such as pollution or infection) or lifestyle factors (such as diet and smoking). The DNA itself doesn’t change, but different aspects may be turned “on” or “off” so that your genes give your cells different instructions.

Research suggests that several epigenetic mechanisms are at work in lupus, including:

• Overexpression of genes that regulate T-cells and other key immune cells
• Alterations in cytokine-related genes
• MicroRNA changes related to kidney and immune system function

Some epigenetic changes have been suggested as biomarkers to help diagnose lupus, monitor disease activity, and evaluate the risk of organ damage. So far, though, none of them have enough evidence behind them to be adopted by the medical community.

Prevalence in Families

Lupus does have a tendency to run in families. The evidence for that used to be largely anecdotal, but researchers have discovered some inherited tendencies, although without a clear pattern. According to the Lupus Foundation of America:

• In 20% of people who have lupus, a parent or sibling already has lupus or develops it later.
• About 5% of children born to a parent with lupus will develop the disease.
• Even in people with no lupus in their family history, other autoimmune diseases are more likely.

However, lupus isn’t generally inherited directly. Most of the time, people inherit a genetic predisposition—a mutation or set of mutations that increases their risk of developing SLE.

Not everyone with those genetic traits will end up with lupus, though. It likely takes the influence of certain environmental and hormonal conditions, possibly through epigenetic changes, to trigger the illness itself.

Prevalence in Black People and Other Ethnic Groups

While people of all ethnic backgrounds can develop lupus, some groups are more likely to not only have lupus but also have more severe disease. Some specific genetic changes aren’t present in certain ancestral lines, which may contribute to the different prevalence among ethnic groups. At the same time, most of the genetic risk factors are shared by everyone.

Groups with a higher rate of lupus than the general population include:

• People with African ancestry
• Certain Asian subpopulations
• Native Americans
• Native Hawaiians and other Pacific Islanders
• Mexicans, especially those descended from native populations

Particularly in Black and Latinx people, a serious complication of SLE called lupus nephritis is especially common and believed to be due to genetic differences unique to these groups. Lupus nephritis involves kidney damage and inflammation, and it can lead to kidney failure.

This condition is also more severe in people who are not of European descent. In addition, Black people tend to develop SLE at an earlier age and have more neurological symptoms.

In one study, Asians, Pacific Islanders, and Latinx participants were more likely to develop a serious lupus-related condition called antiphospholipid syndrome, which increases blood clotting and can lead to miscarriage, organ damage, and death.

While genes do seem to play a role in this, it’s also possible that environmental factors—such as higher poverty levels and lack of access to health care—contribute to the higher rates and more severe disease. Research into ethnic disparities is ongoing.

Prediction and Prevention

Since the early 2000s, thanks to the sequencing of the human genome, lupus research has been going at breakneck speed and researchers have learned a great deal, which has already led to better treatment strategies for different subtypes of the disease.

However, researchers have not yet been able to identify consistent enough genetic or epigenetic changes to unravel the remaining mysteries of lupus. Once they do, experts believe they’ll be able to predict:

• Who is susceptible to SLE
• Who is most likely to develop the condition
• How severe their disease is likely to be
• Which treatments are most likely to work for them

Once doctors can predict who is likely to get lupus, they may be able to take steps to delay or even prevent it entirely. In people who do develop it, a more targeted treatment plan could keep the disease from progressing, which could protect people from experiencing the disability, decline in quality of life, and fatal complications currently associated with SLE and lupus nephritis.

A Word From Verywell

Lupus research has come a long way thanks to advances in genetics research, but medical science still has a long way to go in understanding this complex and highly variable condition. Still, people who have lupus now are considerably better off than those who had it a generation ago, and the next generation is likely to fare better still.

If lupus runs in your family and you’re concerned about it turning up in you or someone you care about, you may be able to find comfort in the knowledge that the outlook is constantly improving for people who are living with SLE.