Rheumatoid Arthritis Genes

Rheumatoid arthritis (RA) is a form of joint pain that is caused by an autoimmune response. About 1% of the population deals with the pain of RA.

What causes rheumatoid arthritis?

Rheumatoid arthritis is caused by an immune system attack on the joints, causing thickening and inflammation of the joint capsule. [ref]

While RA mainly attacks the joints in the fingers and toes, it can also cause problems with the larger joints and inflammation in organs such as the eyes, lungs, and blood vessels. RA can come and go in ‘attacks’.[ref]

Risk factors or potential environmental triggers for RA include: [ref]

  • cigarette smoking
  • silica dust exposure[ref]
  • periodontitis (and oral microbiome) [ref]
  • being overweight (increases the relative risk about 5%)
  • vitamin D deficiency

Is RA genetic?

Yes – and no.  Rheumatoid arthritis is thought to develop due to a combination of environmental triggers and genetic susceptibility. Not everyone with the genetic susceptibility will get RA. Likewise, not everyone exposed to the same environmental factors will end up with RA.

The heritability of RA is estimated to be 50-60%. ‘Heritability’ is a scientific term that refers to the genetic proportion of the risk. Thus, RA is both genetic and due to environmental and autoimmune factors. [ref]

Anticitrullinated Protein Antibodies

One test for RA looks at anticitrullinated protein antibodies (ACPA), which are found in between 55-91% of people with RA. The presence of ACPA alone can’t determine RA, though. A large study that looked at 40,000+ participants showed that 1% of people had elevated ACPA levels. Of those with high ACPA levels, about 22% had RA. [ref]

RA can be broken into two types: ACPA negative and ACPA positive.

Recent research shows that an oral bacteria, Porphyromonas gingivalis, is linked to the ACPA production. This bacteria cross-reacts with other bacteria and fungi (such as Candida and Aspergillus) as well as plants (rice, tomatoes, and soy) in producing the ACPA response. [ref]

From one study: “Our findings demonstrate, for the first time, that a monoclonal ACPA (CCP-Ab1) derived from RA patients cross-reacts not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA.“[ref]

 


Genetic variants linked to RA:


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Many studies over the past couple of decades have examined the genetic risk factors for RA. These can be broken into two main categories: [ref]

  1. Autoimmune immune-related genes (HLA, PTPN22)
  2. Inflammatory-pathway related genes (STAT4,  TRAF1/C5, TNFAIP3, CCR66)

 

Autoimmune related variants

HLA-DRB1*0401: serotype is linked to a much higher risk of RA and increased disease severity [ref]

Check your genetic data for rs660895 (tag for HLA-DRB1*0401) (23andMe v4; v5; AncestryDNA):

  • G/G: high risk of RA (~6-fold) [ref][ref]
  • A/G: increased risk of RA
  • A/A: typical risk

Members: Your genotype for rs660895 is .

 

PTPN22 gene: codes for protein tyrosine phosphatase non-receptor type 22, which moderates signaling through T-cells (keeps them from being overactive). It also interacts with PAD, which is an enzyme related to citrullination. [ref][ref]

Check your genetic data for rs2476601 (23andMe v4; AncestryDNA):

  • G/G: typical
  • A/G: increased thymic selection of T-cells; increased risk for RA in Caucasian and Middle Eastern-  but not African or Asian populations
  • A/A: increased thymic selection of T-cells; significantly increased risk for RA in Caucasian and Middle Eastern, but not African or Asian populations  [ref][ref][ref]

Members: Your genotype for rs2476601 is .

 

Inflammatory Related Variants

TRAF1/C5 gene: tumor necrosis factor-receptor associated factor 1/complement component 5

Check your genetic data for rs10818488 (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of RA (~2-fold) in Caucasian and African populations, but not Asians [ref]
  • A/G: increased risk of RA
  • G/G: typical or slightly decreased risk of RA [ref]

Members: Your genotype for rs10818488 is .

Check your genetic data for rs2900180 (23andMe v4; AncestryDNA):

  • T/T: increased risk of RA [ref]
  • C/T: increased risk of RA
  • CC: typical risk of RA

Members: Your genotype for rs2900180 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 RA
  • T/T: increased risk of RA[ref][ref] [ref]

Members: Your genotype for rs7574865 is .

TNFAIP3 gene: codes for TNF-alpha induced protein 3 which is a negative regulator of NF-κb. Genetic variants that decrease TNFAIP3 are linked to inflammation and autoimmune diseases through higher NF-κb.[ref]

Check your genetic data for rs6920220 (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of RA (~2-fold) [ref][ref]
  • A/G: increased risk of RA
  • G/G: typical

Members: Your genotype for rs6920220 is .

CCR6 gene: codes for C-C chemokine receptor type 6, which is involved in memory T-cells and the maturation of B cells [ref]

Check your genetic data for rs3093024 (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of RA, Asian population group [ref][ref][ref]
  • A/G: slightly increased risk of RA
  • G/G: typical risk of RA

Members: Your genotype for rs3093024 is .

ANG2 gene: codes for angiopoietin-2, a protein important in the creation of new blood vessels. More blood vessels are needed for RA due to the increased synovial lining of the joins and to bring in the inflammatory cells. [ref]

Check your genetic data for rs12674822 (AncestryDNA only):

  • T/T: increased risk of RA (2-fold)[ref]
  • G/T: increased risk of RA (2-fold)
  • G/G: typical risk

Members: Your genotype for rs12674822 is .

 


Lifehacks for RA:

Criteria for choosing these lifehacks: Quite a bit of research has been done on natural interventions for rheumatoid arthritis. Below are some of the studies – mainly chosen for being controlled trials in humans (instead of rats) that showed significant results. (In other words – there are a lot of marginally significant human studies and non-replicated animal studies.)

For everyone:

Avoid High Fructose Corn Syrup:
Daily consumption of HFCS sweetened beverages triples the risk of RA. The study included younger adults (age 20-30) who consumed beverages sweetened with high fructose corn syrup 5 times per week.[ref]

For people with variants related to inflammatory cytokines:

Curcumin:
Curcumin, a natural curcuminoid found in turmeric, has been shown to be beneficial in reducing inflammation in RA. It also may be helpful for periodontitis. [ref]  Here is a graphic explaining how curcumin prevents or reduces RA. (Creative Commons license)

Clinical trials on curcumin show that it is fairly effective. In fact, one trial using 500mg/day of curcumin showed it to be more effective than diclofenac, a prescription NSAID for arthritis pain. [ref] Other clinical trials also show that curcumin improves RA disease scores as well as decreasing CRP (a measure of inflammation). [ref][ref]

More omega-3s and less omega-6s:
Several studies show that increasing omega-3 intake is beneficial for RA (most studies used fish oil). Other studies point to decreasing the omega-6 to omega-3 ratio. [ref][ref][ref] Omega-3 fatty acids, such as DHA and EPA, are generally anti-inflammatory, while too much omega-6 may increase inflammation due to high arachidonic acid levels.

Pomegranates:
Pomegranate extract decreased pain and tenderness in joints in a controlled trial of RA patients. [ref]

Eat more chocolate?
I had to throw this one in since many articles on RA promote cocoa consumption, even though the research was all done in rats. Studies in animals show that a diet high in cocoa decreases autoimmune disease antibody concentrations. [ref]  Note that chocolate is a histamine intolerance trigger food for some people, so increasing your cocoa consumption may cause histamine or mast cell-related problems.


Related Articles and Topics:

Mast Cells: MCAS, Genetics, and Solutions
Mast cells are an important part of your innate immune system. They are front line defenders against pathogens and allergens. For some people, mast cells can be triggered too easily, giving allergy-like responses to lots of different substances.

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.

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.



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. 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.