Is Lupus Hereditary?

posted in Diagnosing Lupus on March 6, 2024 by

Gavin Abson

Updated August 17, 2024

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The Genetic Landscape: Is Lupus Hereditary? “Yes”

Over 180 genes have been identified that increase the risk of getting lupus. This partly explains why women are much more likely to get lupus than men. Understanding the hereditary nature of lupus is a complex journey. Let’s delve into the intricate world of genetics to unravel whether lupus is passed down through generations.

This blog on “Is Lupus Hereditary?” was edited and contributed to by Donald Thomas, MD; author of “The Lupus Encyclopedia.” Parts of this blog post come from “The Lupus Encyclopedia: A Comprehensive Guide for Patients and Health Care Providers, edition 2“

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Genetic Predisposition: A Key Player

While lupus is not directly inherited like some genetic conditions, there’s a substantial genetic component. Individuals with a family history of lupus may have a higher predisposition, indicating a link between genetics and susceptibility to the disease.

Genes are a set of instructions for everything that makes us who we are as individuals. Genes from our mothers and fathers decide if we are born with blue eyes or a big nose. Collections of genes are strung together in a twisted string (or strand) called DNA. DNA exists inside the nucleus (package found towards the middle of cells) and mitochondria of most cells in our body.

Mitochondria are structures in cells that produce energy. They contain small amounts of DNA handed down from the mother’s side of the family.

However, most DNA is located in the cell’s nucleus. The DNA contains the genetic code that tells each cell what substances to produce and how the cell should function. The DNA are packed inside the nucleus in chromosomes.

Each chromosome has two DNA strands braided around each other (this structure is called double-stranded DNA). For the DNA to produce important substances for the cell, many other enzymes and proteins (such as histones) are needed. These important elements are packaged along with the double-stranded DNA in a structure called a chromosome.

Lupus is More Common in Some Races and Ethnicities

Lupus tends to be more common in some ethnic and racial groups. Certain ethnic groups have a higher number of people affected by lupus than others. The best explanation for this is the genes passed down from each generation mixed with environmental factors and triggers (discussed later).

The Centers for Disease Control sponsored five large United States Registries to help answer the question of how many people have systemic lupus erythematosus (SLE) in the US. Native American and Native Alaskan women had the greatest chances for developing SLE. Approximately 27 out of every 10,000 Indigenous American women had SLE.

Here are the actual numbers by race, sex, and ethnicity. Out of every 100,000 people in each group, there were this many people in that group who had SLE “by the numbers”:

• 270 Native American /Native Alaskan women out of every 100,000
• 230 Black women
• 120 Hispanic women
• 85 White women
• 84 Asian/Pacific Islander women
• 54 Native American/Native Alaskan men out of every 100,000
• 27 Black men
• 18 Hispanic men
• 9 White men
• 11 Asian/Pacific Islander men

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A Note on the Data

Note that the above numbers underestimate the number of people with SLE. The registries used research classification criteria to define SLE, and many SLE patients do not meet research criteria. In addition, the registries were unable to include all health care facilities. Also, these numbers do not include those who have cutaneous lupus erythematosus without having SLE. There are approximately three to four people with cutaneous lupus for every one person with systemic lupus.

Another comment on the above numbers is that Dr. Thomas disagrees with lumping Asian and Pacific Islanders together. Asia Subcontinent individuals, East Asians, and Pacific Islanders have very different racial, ethnic, and genetic backgrounds. These really should have been split up, though the numbers would have been much smaller for each group, and the results most likely inaccurate.

Twins, Siblings, and Lupus

The importance of genetics is also evident in twins. Identical twins are born with the same genes. When an identical twin has SLE, there is a 25% chance that the other twin will also develop SLE. If lupus genes were the only cause, then 100% of identical twins with these genes would develop lupus. So, other factors must also play a role.

Fraternal (nonidentical) twins have a chance of developing lupus of only 5-8%. They do not have the same genes, and their genetic differences are like those of siblings born at different times to the same mother and father. Their chances of developing SLE are higher than those of people who do not have a sibling with SLE.

Familial Aggregation: Clusters in Families

Research suggests that lupus can occur in clusters within families. If a close relative, like a parent or sibling, has lupus, the risk for other family members also increases. This familial aggregation underscores the genetic influence on lupus susceptibility.

Having a sibling with SLE increases the risk of SLE even further. If someone has a sibling (who is not an identical twin) with SLE, that person is 30 times more likely to develop SLE than someone who does not have a sibling with SLE. If you have a sibling who has SLE, your chances of having SLE is around 2%. Sisters of SLE patients have as high as a 10% risk for SLE.

Around 25% of the chance of developing SLE is related to genetics; the other 75% comes from environmental triggers and other factors (like hormonal influences). Dr. Thomas often gets the question, “How can I keep my children and grandchildren from getting lupus?” There is growing evidence that people who practice lifestyle habits that avoid lupus triggers reduce their chance of developing lupus. Click on the link in the preceding sentence to learn these important habits.

Identified Lupus-Associated Genes

Scientists have identified certain genes linked to lupus, such as the HLA genes and several others affecting immune system regulation. These genes contribute to an individual’s susceptibility and can influence how the immune system functions.

When someone is born with lupus-related genes, we say they have a “genetic predisposition” for developing lupus, but the genes do not guarantee it. The lupus-causing genes contribute around 25% of the probability of getting lupus. The other 75% is due to other factors discussed below.

Some people with SLE have identifiable immune system abnormalities that play an important role in developing the disease. One of these involves complement proteins.

Genetic Complement Deficiencies and Lupus

Complements are immune system proteins. We regularly check blood complement levels in lupus patients, particularly the third and fourth complement levels (C3 and C4). C3 and C4 levels sometimes decrease when the immune system becomes active in SLE.

Complements (a shortened form for complement proteins) are abbreviated with “C” (for Complement) followed by a number. The number represents the order of discovery (C1 was discovered before C2).

If someone is born with a deficiency in some of these complements (especially C1q, C4, and C2), they have a high chance of having SLE. C1q and C4 are important for the body’s ability to eliminate bacteria. When harmful bacteria are present, C1q and C4 bind to the bacteria (a process called opsonization), alerting the immune system to get rid of them.

C1q and C4 are also crucial for eliminating our body’s dying cells. We continuously form new cells, and older cells die once they are no longer needed. C1q and C4 bind to these unneeded dying cells, alerting the immune system to dispose of them. However, these old cells remain if there is insufficient C1q or C4. Elements of these persistent, dying cells can stimulate the immune system to produce autoantibodies.

For example, if the immune system attacks molecules (antigens) from the dying cells’ nuclei, antinuclear antibodies (ANA) can form. Anti-double-stranded (anti-ds) DNA antibodies can develop against the dying cells’ own DNA, causing the immune system to attack the person’s body.

Prevalence of C1q Deficiency

It is rare to have C1q deficiency; less than 100 cases have been described as of 2022. Approximately 40% of these patients with C1q deficiency had lupus or a lupus-like disease. C1q-associated lupus usually presents in children with an average age of onset of 5 years. Since it is not tied to a sex chromosome, it affects both sexes equally. Discoid lupus and mouth sores occur more often. Arthritis and dsDNA antibodies appear less commonly than in other forms of SLE. Since C1q is vital in fighting off bacterial infections, frequent bacterial infections are often the most dangerous part of this genetic deficiency.

Genetic deficiencies in C4 can cause severe SLE onset at a younger age. These individuals can be identified by finding very low (sometimes zero) levels of C4 that persist even when their disease improves with treatment.

C2 works along with C4, so if there is not enough C2, clearance of dead cells does not happen, and the chance of developing SLE also increases.

Genetic Load and Lupus

People with a genetic lack of complements are rare. Since only one gene abnormality is involved, their lupus is a monogenic (one gene) disease. Monogenic SLE is rare, only occurring in 10% of SLE patients younger than ten. Most SLE patients have multiple lupus-related genes (polygenic SLE).

So far, doctors have found more than 180 lupus-related genes. Variants of these genes increase the chances of developing lupus. Some of these genes are very common, occurring in up to 30% of people without SLE. The more lupus-related genes someone inherits, the higher the likelihood of SLE.

Also, some genes are much more likely to cause lupus than others. Together, the number of lupus-related genes someone has plus the likelihood of their playing a role in that person’s developing lupus yield what is known as someone’s “genetic load.” People with a high genetic risk tend to be younger, have more severe disease with more organ damage, and test positive for more autoantibodies than people with low genetic risk.

Some lupus-related genes increase the risk for other autoimmune diseases such as Sjögren’s disease, scleroderma, vitiligo, Hashimoto’s thyroiditis, and rheumatoid arthritis. For example, genes called STAT4 and PTPN22 have been linked to lupus, rheumatoid arthritis, and diabetes type I. Genes are often named after the enzymes or chemical reactions they are associated with. Initials, like STAT, are used instead of the complete names, Signal Transducer and Activator of Transcription in the case of STAT, to simplify the name. It is common for people with lupus to have other family members with other autoimmune diseases. These shared genes help explain this.

Female Sex Chromosomes and Lupus

Each human body cell normally has 46 chromosomes, typically existing as 23 pairs. One chromosome of each pair comes from the mother, and one comes from the father. One of these chromosome pairs is composed of sex chromosomes. There are two types of sex chromosomes: Y and X. A female usually has just two X chromosomes (one from her mother and one from her father); a male usually has an X chromosome and a Y chromosome paired together (the X came from his mother, and the Y came from his father). With rare exceptions, being XX or XY decides whether a person is born as a female (XX) or male (XY).

Some genes linked to lupus, including IRAK1, TLR7, and MECP2, have been found on the X-chromosome. Because women have two X-chromosomes and men usually have only one, women are twice as likely to inherit these lupus-related genes.

Also, one of the X-chromosomes in women becomes inactive. However, this does not always occur in some women with SLE due to X-chormosome inactivation dysregulation. If both X-chromosomes are active, there is an even higher chance that the lupus genes on their extra X-chromosome will become active.

Trisomy-X and Lupus

Sometimes, the sex chromosomes do not transfer perfectly from generation to generation. One out of every 1,000 women is born with three X-chromosomes (XXX) instead of just two. Having this extra X-chromosome markedly increases the risk of developing SLE even further.

Klinefelter Syndrome and Lupus

Another example is the genetic disorder called Klinefelter syndrome (KS). KS occurs when a baby with XY sex chromosomes receives one or more extra X-chromosomes and is born as a baby identified as a boy. Most boys with KS are XXY (instead of the usual XY). However, other variations may also occur, such as receiving three X-chromosomes and one Y-chromosome. KS occurs in 1 out of 600 boys born. Boys with KS tend to be taller with little body hair, broad hips, narrow shoulders, smaller testicles, and are usually infertile. Men with KS are 15 times more likely to develop SLE. This increased risk is partially related to inheriting more lupus genes on the extra X-chromosome.

The Role of Genetics in Lupus Development

Lupus arises from a combination of genetic and environmental factors. Specific genes associated with lupus susceptibility, discussed above, have been identified. However, having these genes doesn’t guarantee that an individual will develop lupus; it merely increases the likelihood.

Unraveling the Environmental Puzzle

While genetics play a significant role, environmental factors also contribute to lupus development. Triggers like infections, hormonal changes, and exposure to certain medications or chemicals can activate lupus in genetically predisposed individuals.

Epigenetics: The Intersection of Genes and Environment

Epigenetics, the study of changes in gene activity that do not involve alterations to the genetic code, adds another layer to the lupus puzzle. Environmental factors can also modify gene expression, influencing the risk of developing lupus.

Before discussing lupus’s many potential environmental triggers, it is important to understand epigenetics. Many of these triggers are thought to cause epigenetic changes, which may cause lupus.

We already talked about how genes can lead to someone developing lupus. The collection of genes and DNA in our cells is called the “genome.” The term “genetics” refers to the study of these genes.

These DNA molecules supply the instructions for how each cell is to perform, but they do not work in isolation. Other molecules and structures surround each cell’s DNA (genome) to help the DNA function. Many of these structures (like histones and ribonucleic acid–RNA) exist in the chromosomes.

Chemical reactions occur with our DNA and these structures throughout our lives. Our DNA also reacts with other internal body molecules (like hormones) and external substances (like cigarette smoke) that enter our bodies. These reactions and interactions can change how the DNA functions. How the DNA is used and manipulated to create different types of proteins and other molecules is called epigenetics (epi- meaning “around” or “on the outside”).

Although each cell of the body has similar DNA, each cell type, such as a heart muscle cell or a skin cell, has different epigenetics at work, producing very different types of cells with very different functions (a heart muscle cell is very different from a skin cell though they have the same DNA).

A Simplified Way to Think About Epigenetics

One way to think of epigenetics is to imagine that the ingredients found in your kitchen are the DNA of your kitchen. You go into your kitchen in the morning and use a frying pan, bowls, spoons, and various ingredients to make a breakfast of oatmeal, eggs, and fresh orange juice. Later that day, you use different ingredients and utensils to bake a cake. You and the different utensils and cooking methods you used would be similar to epigenetic changes, while the different ingredients you selected would be similar to how only some parts of the DNA are used at a time. The end products (oatmeal and eggs instead of a cake) differ based on these epigenetics and the DNA used.

Similarly, though each cell of the body has similar DNA (the kitchen food ingredients), each cell type (such as a heart muscle cell or a skin cell) has different epigenetics at work (the cook, utensils, cooking methods), producing very different types of cells with very different functions (a heart muscle cell is very different from a skin cell, though they have the same DNA).

Lupus Triggers that Cause Epigenetic Changes

Sometimes, epigenetic changes can cause the DNA to produce unwanted results. For example, chemicals from smoking cigarettes, bad bacteria in the gut, or sun damage to the skin (each is a lupus trigger) can cause chemical structure changes in our DNA (such as methylation). Methylation is when environmental exposures cause a chemical structure, called a methyl group, to attach to DNA. We mention methylation only because it is a common epigenetic mechanism. However, you don’t have to understand methylation in detail. Epigenetic changes, like DNA methylation, can end up causing the DNA to act and function in such a way as to cause lupus (if the DNA contains lupus-related genes). Other epigenetic changes can involve the histones and RNA.

People with lupus commonly have autoantibodies against all these structures like DNA (anti-DNA and anti-chromatin). Examples of autoantibodies against the RNA component include anti-SSA, anti-RNP, and anti-Smith. Pointing out these autoantibodies illustrates how important these epigenetic components are in the development of lupus

What Are the Triggers?

Many things (such as diet, aging, hormones, sulfa drugs, and cigarettes) can cause epigenetic changes. In lupus and other autoimmune diseases, we consider these influences on epigenetics as “triggers.” They can trigger lupus-related genes to become active, causing the person to have lupus.

Epigenetic changes can last a person’s entire life and even be passed down to future generations. For example, someone born with lupus-related genes could get sun exposure and smoke cigarettes: these actions can cause epigenetic changes and potentially turn on the lupus genes, but they don’t always. While that person’s epigenetics may be affected, that person may never develop lupus. But suppose they have children: the altered epigenetics can be passed to the child, increasing their risk of lupus.

Environmental influences on our DNA, through epigenetics, help explain why, even though identical twins have the same genes, both twins do not necessarily develop lupus. Instead, something occurs in one of the twins (such as ultraviolet light damage, smoking, or a low vitamin D level), altering the DNA through this process of epigenetics and, in turn, causing lupus to develop.

The Complex Inheritance Pattern

Lupus doesn’t adhere to a simple inheritance pattern. Instead, it follows a complex polygenic inheritance (in most people with lupus), where multiple genes and environmental factors interact with each other. This complexity makes predicting lupus inheritance challenging.

Genetic Testing: A Tool for Insight

Genetic testing may provide insights into an individual’s susceptibility to lupus in the future. Currently (March 2024), genetic testing for lupus can only be done accurately in research facilities. Also, lupus-associated genes don’t guarantee disease development, highlighting the intricate interplay of genetics and environment.

Is Lupus Hereditary?

The answer lies in the intricate dance of genetics and environment. While familial patterns suggest a genetic influence, the complex interplay with environmental factors adds complexity. Understanding this dynamic is crucial for individuals with a family history of lupus and researchers working towards unraveling its genetic mysteries.

For more in-depth information on lupus and genetics:

Read more in The Lupus Encyclopedia, edition 2

Look up your symptoms, conditions, and medications in the Index of The Lupus Encyclopedia

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