Researchers have long speculated that arthritis is influenced by genetic factors [1]. With the advent of genome-wide association studies, the genetic risk factors contributing to multiple forms of arthritis have been identified [2, 3]. Now, diseases such as rheumatoid arthritis have as many as 100 or more genes linked to them [1]. This article will discuss three prominent forms of the disease–osteoarthritis (OA), rheumatoid arthritis (RA), and psoriatic arthritis (PsA)–and the strides that have been made in uncovering the genetic risk factors of arthritis.
Osteoarthritis is the most common form of arthritis [1]. Unfortunately, there is no cure for OA, furthering the importance of better understanding the genetics behind it [4]. Since 2005, several novel genetic loci contributing to OA onset have been reported [3]. One of the most pivotal studies of OA was arcOGEN, a genome-wide association study published in 2012 [3]. The experiment focused on patients suffering from either knee or hip OA [3]. It resulted in the identification of five significant loci for OA, as well as a gene-rich region in the 3p21 chromosome [5]. Since then, researchers have identified more candidate genes for OA, such as NCOA3, SULF2, and ALDH1A2 [3].
Despite the multiple genes contributing to osteoarthritis, genetic factors are more influential in a patient’s chance of developing rheumatoid arthritis [1]. Indeed, while RA affects about 0.5 to 1% of the world’s population, this prevalence rises to 2 to 4% among siblings of people with the condition [2]. The most influential genetic risk factor for this disease is located in the HLA, or human leukocyte antigen, locus [2]. More specifically, the sequence of amino acids referred to as the shared epitope (SE) alleles at positions 70 to 74 of the DRβ1 chain account for around 30 to 50% of a person’s genetic susceptibility to RA [2]. Other significant genes that have been isolated by GWAS studies include TRAF1/C5, PADI4, and CTLA4 [2]. Although researchers have pinpointed multiple loci associated with RA, the functional single nucleotide polymorphism (SNP) at many of these locations remains unknown [2]. To successfully mobilize genetic findings to help prevent future RA cases, more research on relevant SNPs will be necessary.
The genetic profile of psoriatic arthritis is similar to that of rheumatoid arthritis: HLA polymorphisms contribute to both conditions and are strongly linked with disease severity [6]. For instance, type I PsA patients carrying the HLA class I allele, HLA-Cw6, may experience more severe skin disease, while RA patients carrying SE alleles tend to present a more drastic phenotype and have a greater likelihood of developing extraarticular manifestations [6]. HLA genes can also influence how likely a patient is to develop PsA. A study by Yan and colleagues suggests that, among people with psoriasis, individuals with the HLA-C*06:02 allele were 67% less likely to develop psoriatic arthritis than patients without the allele [7].
While further experimentation is required on these points, these studies are certainly promising and reflect how far genetic studies have come in such a short time. With refined knowledge, researchers will be able to work towards developing treatments that, rather than respond to inflammation caused by genes, modify the genes to prevent arthritis development altogether [1].
References
[1] “Is Arthritis Hereditary?,” Cleveland Clinic, Updated June 17, 2019. [Online]. Available: https://health.clevelandclinic.org/is-arthritis-hereditary/.
[2] M. Bax et al., “Genetics of rheumatoid arthritis: what have we learned?,” Immunogenetics, vol. 63, p. 459-466, May 2011. [Online]. Available: https://doi.org/10.1007/s00251-011-0528-6.
[3] J. Loughlin, “Genetic contribution to osteoarthritis development: current state of evidence,” Current Opinion in Rheumatology, vol. 27, no. 3, p. 284-288, May 2015. [Online]. Available: https://doi.org/10.1097/BOR.0000000000000171.
[4] H. J. M. Kerkhof et al., “Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors,” Annuals of the Rheumatic Diseases, vol. 73, no. 12, p. 2116-2121, August 2013. [Online]. Available: https://doi.org/10.1136/annrheumdis-2013-203620.
[5] arcOGEN Consortium and arcOGEN Collaborators, “Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study,” Lancet, vol. 380, no. 9844, p. 815-823, September 2012. [Online]. Available: https://doi.org/10.1016/S0140-6736(12)60681-3.
[6] P. Y. P. C. Ho et al., “HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis,” Annals of the Rheumatic Disease, vol. 66, no. 6, p. 807-811, January 2007. [Online]. Available: https://doi.org/10.1136/ard.2006.064972.
[7] D. Yan et al., “Clinical and Genetic Risk Factors Associated with Psoriatic Arthritis among Patients with Psoriasis,” Dermatology and Therapy, vol. 8, p. 593-604, October 2018. [Online]. Available: https://doi.org/10.1097/BOR.0000000000000171.