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?

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 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]

Environmental factors:

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

Genetic variants linked to RA:

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)

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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 being 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:

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]

Lifehacks for people with variants related to inflammatory variants (TRAF1, STAT4, TFAIP, CCR6):

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 usually 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.

Omega-3 fatty acids are found in fish and seafood. Plant sources such as flaxseed and walnuts may be good for people without FADS1 variants.

Omega-6 fatty acids are abundant in many ‘vegetable’ oils including corn oil, soybean oil, safflower oil, and sunflower oil.

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.

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.