Genetics of Lupus: Understanding how your genes increase lupus risk

Getting diagnosed with lupus can be a frustrating experience. It sometimes seems that there are more questions than answers with this autoimmune disease!

This article dives into the genetic variants that increase the susceptibility to lupus — and hopefully sheds some light on what is going on with your body’s immune system.

Lupus, a complex autoimmune disease

Systemic lupus erythematosus, more commonly referred to as lupus or SLE, is a complex autoimmune disease that can affect many different organs of the body.

The Lupus Foundation of America estimates that 1.5 million people in the U.S. have lupus. It affects mainly women of childbearing age, although men and children can get lupus as well.[ref]

Ethnicity is an important risk factor as well.  African American women are at a three- to four-fold greater risk of lupus.[ref]

Common symptoms of lupus include:

  • fatigue
  • joint pain
  • a butterfly-shaped rash on the face
  • photosensitivity
  • headaches

As an autoimmune disease, the hyperactivation of the immune response causes excess proinflammatory cytokines. This, in turn, leads to the activation of immune factors such as B cells and T cells. [ref]

Is lupus genetic?

Lupus is thought to have both genetic and environmental components.

No single gene seems to cause lupus, but quite a few different genetic variants increase the risk of lupus.

The genetic component of lupus is estimated to be 25-40%.[ref] People with a close relative with lupus are at a 20-fold increased risk relative to the rest of the population.[ref]

The genetic variants associated with lupus paint a picture of why this is such a complex autoimmune disease.

  • Variants in the HLA genes impact the body’s immune response and increase the risk of autoimmune diseases.
  • B-cells are a type of white blood cell that matures in the bone marrow. Increased numbers of memory B-cells increase the risk of lupus and autoimmune diseases. Genetic variants in B-cell related genes are linked to an increased risk of lupus.[ref]
  • Genes in the interferon pathway point to the role that genetically increased interferon plays in lupus.[ref]

Interferon-α is a cytokine that cells release signaling a need for the immune system to be activated.

Generally, interferon is elevated and activated by viral pathogens. Interferon acts both as an immune signal and as a way to interfere (thus the name interferon) with viral replication. In lupus, interferon-α is often elevated, starting the cascade of autoimmune events.[ref]

Genes plus environment in lupus:

Many people with the genetic variants that are linked to lupus will never end up with the disease. In addition to genetic risk, there are a number of environmental factors that may trigger lupus.

Environmental triggers of lupus include[ref]:

  • UV radiation
  • demethylating drugs such as Azacitidine or Decitabine
  • viral infections such as Epstein-Barr virus


Below is just a partial list of genes that have been studied in reference to lupus. If you have lupus, my hope is that this list can help you start to research and understand your condition.

Genetic Variants Linked to Lupus

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HLA genes and the Major Histocompatibility Complex:

HLA-DQA1 Gene:

The HLA-DRB1 gene codes for a part of the innate immune response. The HLA genes vary widely amongst individuals, and they are a big part of why people can respond differently to various pathogens. The HLA-DRB1 variant below decreases susceptibility to several pathogens. On the flip side, the variant below increases the risk of certain autoimmune diseases including lupus.

Check your genetic data for rs2187668 (23andMe v4, v5; AncestryDNA):

  • T/T: likely to carry two copies of DRB1*0301, >2-fold increased risk of lupus[ref][ref]
  • C/T: likely to carry one copy of HLA-DRB1*0301, 2-fold increased risk of lupus
  • C/C: typical

Members: Your genotype for rs2187668 is .

TNXB gene:

The TNXB gene codes for a glycoprotein found in the connective tissue in joints, muscles, and skin. It is thought to play a role in regulating the production of certain types of collagen and elastin fibers.[ref] This TNXB variant is located in an area that may also be impacting the immune system by influencing the major histocompatibility complex.

Check your genetic data for rs1150754 (23andMe v4, v5; AncestryDNA):

  • T/T: 2-fold increased risk of lupus[ref]
  • C/T: 2-fold increased risk of lupus
  • C/C: typical

Members: Your genotype for rs1150754 is .

B Cells

BLK  gene: B lymphoid tyrosine kinase is an enzyme encoded by the BLK gene. This protein plays a role in the development of B-cells and in B-cell receptor signaling.[ref]  “The Role of B Cells in Lupus Pathogenesis” explains in great detail how B-cells are involved in lupus.

Check your genetic data for rs13277113 (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of lupus[ref][ref][ref][ref]
  • A/G: increased risk of lupus
  • G/G: typical

Members: Your genotype for rs13277113 is .

Check your genetic data for rs2248932 (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of lupus[ref][ref]
  • A/G: 2-fold increased risk of lupus
  • G/G: typical

Members: Your genotype for rs2248932 is .


Inflammatory cytokines:

TNF gene: codes for TNF-alpha, which regulates immune response

Check your genetic data for rs1800629  308G>A (23andMe v4, v5; AncestryDNA):

  • A/A: increased TNF-alpha, increased risk of lupus (European but not African populations)[ref][ref]
  • A/G: increased TNF-alpha,
  • G/G: typical

Members: Your genotype for rs1800629 is .

TNFAIP3 gene: codes for a protein that is important in stopping the signaling of NF-κB, an inflammatory cytokine (like an off-switch)

Check your genetic data for rs5029939 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/G: increased risk of lupus in European population
  • G/G: increased risk of lupus (>2-fold) in the European population[ref][ref]

Members: Your genotype for rs5029939 is .

STAT4 gene: codes for a protein that is important for activating other immune system genes in response to inflammatory cytokines (IL2, IL23, IFN-1, IL12).

Check your genetic data for rs7574865 (23andMe v4, v5; AncestryDNA):

  • G/G: typical risk
  • G/T: increased risk of discoid lupus
  • T/T: increased risk of discoid lupus [ref]

Members: Your genotype for rs7574865 is .

Check your genetic data for rs10181656 (23andMe v4; AncestryDNA):

  • C/C: typical risk
  • C/G: increased risk of lupus
  • G/G: increased risk of lupus[ref]

Members: Your genotype for rs10181656 is .

Interferon signaling Pathway:

A 2014 article in the Journal of Immunology offers an in-depth discussion of the role of interferon in lupus.

IRF5 gene: codes for an interferon regulatory factor which controls the activity of the gene[ref]

Check your genetic data for rs10954213 (23andMe v4; AncestryDNA):

  • G/G: typical risk
  • A/G: increased risk of lupus
  • A/A: increased risk of lupus[ref][ref][ref]

Members: Your genotype for rs10954213 is .

Check your genetic data for rs3807306 (23andMe v4; AncestryDNA):

  • G/G: typical risk
  • G/T: increased risk of  lupus
  • T/T: increased risk of  lupus (African and Caucasian populations)[ref][ref][ref]

Members: Your genotype for rs3807306 is .

IRF8 gene:

Check your genetic data for rs2280381 (23andMe v4, v5; AncestryDNA):

  • T/T: typical risk
  • C/T: typical risk of lupus
  • C/C: significantly decreased risk of lupus[ref]

Members: Your genotype for rs2280381 is .

The IFIH1 gene codes for an interferon-induced component that is critical for the body’s response to RNA viruses. IFIH1 is also known as MDA5.

Check your genetic data for rs1990760  (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased IFIH1, decreased risk of several RNA viruses, increased risk of lupus
  • T/T: increased IFIH1, decreased risk of several RNA viruses[ref] increased risk of lupus[ref]

Members: Your genotype for rs1990760 is .


Lifehacks for lupus:

The following are research-backed options that may help with lupus symptoms. Talk with your doctor – especially if you are on any medications – before adding in any immune system modifiers.


More than just a ‘sleep hormone’, melatonin is important in your immune system. It helps to increase the immune response against pathogens, but it also helps to moderate an overactive immune response.[ref]

Natural supplements:

A number of plant-based compounds can help to suppress the immune system in autoimmune diseases.[ref]

  • Curcumin: can help to regulate T-helper and T-regulatory cells in lupus[ref] Curcumin can also help regulate TNF-alpha levels[ref]
  • Andrographis: a herbal supplement that can help to regulate NF-κB in lupus[ref]

Things to avoid: 

The Johns Hopkins Lupus Center recommends avoiding sulfa antibiotics such as Bactrim and Septra. It also cautions against taking a lot of garlic, alfalfa sprouts, and echinacea.


Related Genes and Articles:

Rheumatoid Arthritis Genes
Rheumatoid arthritis is caused by an immune system attack on the joints, causing thickening and inflammation of the joint capsule. It is caused by a combination of genetic susceptibility and environmental triggers.

HLA-B27: Increased risk of autoimmune diseases
Our immune system does an awesome job (most of the time) of fighting off pathogenic bacteria and viruses. But to fight off these pathogens, the body needs to know that they are the bad guys. This is where the HLA system comes in.

TNF-Alpha: Higher innate levels of this inflammatory cytokine
Do you feel like you are always dealing with inflammation? Joint pain, food sensitivity, etc? Perhaps you are genetically geared towards a higher inflammatory response. Tumor necrosis factor (TNF) is an inflammatory cytokine that acts as a signaling molecule in our immune system.


Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.