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Rheumatoid Arthritis Genes: Root Causes

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.

This article explains RA, the different genes that increase susceptibility to RA, and possible solutions based on the genetic variants.

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 by about 5%)
  • vitamin D deficiency

Is rheumatoid arthritis genetic?

Rheumatoid arthritis is thought to develop due to a combination of environmental triggers and genetic susceptibility. Not everyone with 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 the oral bacteria, Porphyromonas gingivalis, is linked to 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]

Recently, another study pointed towards another microbial cause. The researchers found that a type of gut microbe, in the genus Subdoligranulum,  may be the culprit. These microbes bind to RA monoclonal antibodies, activate T cells, and induce serum RA–relevant IgG autoantibodies. The researchers believe that intestinal mucosa and resident gut bacteria are a driving factor in RA.[ref]

Environmental factors:

One recent study found that an environmental trigger for RA for military veterans was exposure to military waste disposal or burn pits. Both of those exposures caused a 5-fold increase in the risk for anti-CCP antibodies and RA.[ref]

Rheumatoid Arthritis Genotype Report:

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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. The studies below were chosen for controlled trials in humans rather than rats, which showed significant results. (In other words, there are a lot of marginally significant human studies and non-replicated animal studies.)

Lifehacks for everyone with RA:

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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 also 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.

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