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. 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 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 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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