Genetics and Lupus: 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 signs and 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. It, 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.

Genetics research shows that there isn’t a single gene that causes lupus. Instead, researchers have identified a bunch of different genetic variants that increase the relative risk of lupus a little bit.

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 the complexity of this 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 elevates and activates 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]

Genetic susceptibility plus a trigger = lupus

Most people with genetic variants linked to lupus will not end up with the disease.

In addition to genetic risk, many environmental factors increase the risk of developing lupus.

Environmental triggers of lupus include[ref]:

  • UV radiation
  • demethylating drugs such as Azacitidine or Decitabine
  • viral infections such as Epstein-Barr virus, parvovirus B19, and HERVs[ref]

 

Below is just a (partial) list of genes that have been studied in lupus patients. If you have lupus, I hope that understanding the genetic links can help you target the right solutions.


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 among individuals, and they are a big part of why people can respond differently to various pathogens. The HLA-DRB1 variant below is  positive in that it 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 developing 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 the 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 that 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.

Melatonin:

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

Lifestyle changes: Melatonin is your body’s natural immune modulator, produced in large amounts overnight.

Light at night in the blue wavelengths (~480nm) blocks melatonin production. It is why doctors recommend not using ‘screens’ for a couple of hours before bedtime. Think about it: before electricity, no human (or plant or animal) was ever exposed to light in the blue wavelengths at night. Firelight is shifted to the red end of the light spectrum.

There are a couple of lifestyle changes that can help you to increase your natural melatonin production. One option is to stop using electronics (TV, phone, tablets, laptops) at night and turn the house lights down low by using lamps. Another option is to get a pair of glasses that block 100% of blue light (the 100% part is important).

Sleeping in a dark room is also important. Light can come through your eyelids at night, impacting melatonin production. Get some good blackout curtains or shades, and make sure there aren’t any glowing green or blue indicator lights (like from a laptop charger) in your room at night.

Blocking blue light at night raises melatonin production by around 50% on average, which is significant.


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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.