The Genetics of Psoriatic Arthritis and Psoriasis

Having First-Degree Relatives With the Conditions May Increase Your Risk

Genetic Research
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A genetic predisposition and a triggering event are thought to cause certain types of arthritis. For example, researchers have determined that about 40 percent of people with psoriasis or psoriatic arthritis have a family history of the diseases involving first-degree relatives. Family studies have shown that psoriatic arthritis is 55 times more likely to develop in first-degree relatives of people with the disease compared to unrelated controls.

In genetic studies, the term concordance refers to the degree of similarity in a set of twins regarding the presence or absence of a disease or trait. The concordance rate for psoriatic arthritis (30 percent) is significantly higher than for psoriasis (7 percent). Twin studies in psoriasis have demonstrated a high rate of concordance among identical twins versus fraternal twins.  

Identifying genes that are associated with susceptibility to a specific disease is no small task. It may involve:

  • Familial aggregation studies: Looking for clustering of a disease within families.
  • Segregation analysis: Determining whether a major gene is connected to the distribution of a specific phenotypic trait (i.e, an observable trait).
  • Linkage analysis: Identifying the association of heritability between genes based on their location on a chromosome.
  • Association analysis: Uncovering relationships from data, in this case, finding candidate genes or genome regions that contribute to a specific disease.
  • Functional studies to characterize the genes: Studying natural variation or experimental functional disruptions that affect genes, chromosomes, and more.

Sound complicated and confusing? It is, as can be the nomenclature. But, let's peek at what has been found.

HLA (Human Leukocyte Antigen)

The discovery of MHC (major histocompatibility complex) on chromosome 6 was pivotal to studying genetic factors in psoriatic arthritis.

Several genetic factors have been identified. There is a well-known association between the HLA (human leukocyte antigen) region of MHC recognized as HLA-C, and specifically HLA-Cw6, and susceptibility to psoriasis. The association with HLA-Cw6 is slightly weaker in psoriatic arthritis, where HLA-B27 is more strongly associated (especially in people with spinal manifestations of psoriatic arthritis), as is HLA-B38 and HLA-B39. HLA-Cw6 is associated with an earlier onset of psoriasis (less than 40 years old) as well as more severe disease. Of other HLA antigens, it is known that HLA-B13, HLA-B17, HLA-B57, and HLA-Cw*0602 occur more frequently in people with psoriatic arthritis compared to the general population.

The following alleles (one of two or more alternate forms of a gene that develop by mutation, found at the same location on a chromosome) were found to be significantly associated with psoriatic arthritis compared to psoriasis: B*8, B*27, B*38, and C*06. There also are HLA haplotypes (a group of genes that were inherited together from a single parent) associated with psoriatic arthritis: B*18, C*07, B*27, B38, and B*8.

While HLA-B27 is said to have the highest predictive value of psoriatic arthritis versus psoriasis, it is not a certainty. The frequency of HLA-B27 is higher in ankylosing spondylitis and reactive arthritis compared to psoriatic arthritis. It is also worth mentioning that many people who have psoriasis and one of the spondyloarthropathies are negative for HLA-B27. Also, many people with psoriatic arthritis who are positive for HLA-B27 do not exhibit spinal involvement.

Some studies have shown an association between psoriatic arthritis and HLA-DR4, an antigen that is known to be associated with rheumatoid arthritis. The alleles differ between the two conditions, however, with HLA-DRB1*0401 being less frequent in people with psoriatic arthritis who are positive for HLA-DRB1*04 than among people with rheumatoid arthritis. The reverse is true for HLA-DRB1*0402, which is more frequent in psoriatic arthritis than rheumatoid arthritis. Other genes within the MHC region have been studied as well.

GWAS (Genome-Wide Association Scans)

Genome-wide association scans (GWAS) analyze common genetic variants among different people in an effort to ascertain if any variant is associated with a trait. According to Best Practice & Research: Clinical Rheumatology (2014), 36 genes have reached genome-wide significance and they account for about 22% of psoriasis heritability. Genes identified by GWAS that are considered prominent in psoriasis include:  HLA-Cw6, IL12B, IL23R, IL23A, TNIP1, TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and ERAP1. Genes identified by GWAS that are prominent in psoriatic arthritis include: HLA-B/C, HLA-B, IL-12B, IL-23R, TNIP1, TRAF3IP2, FBXL19, and REL.

Bottom Line

If you have a family member with psoriatic arthritis, learning that studies have shown a 55 times higher likelihood of developing the condition may, understandably, be worrisome. Arm yourself with the right knowledge—perhaps you have misconceptions about the condition that facts can help set straight, reducing your worry. And, of course, keep open communication with your health care professional. 

Sources:

Analysis of familial aggregation studies with complex ascertainment schemes. Matthews AG et al. Stat Med. 2008 October 30; 27(24): 5076–5092.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562890/

Genetics of Psoriatic Arthritis. Best Practice & Research: Clinical Rheumatology. O'Rielly DD et al. 2014 Oct;28(5):673-85.
http://www.ncbi.nlm.nih.gov/pubmed/25488777

Pathogenesis of Psoriatic Arthritis. UptoDate. Gladman and Ritchlin. Reviewed May 2016.
https://www.uptodate.com/contents/pathogenesis-of-psoriatic-arthritis

Genetics of Psoriasis and Psoriatic Arthritis. Indian Journal of Dermatology. V. Chandran. 2010 Apr-Jun.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887520/

Psoriatic Arthritis. Pathogenesis. Genetic Factors. Kelley's Textbook of Rheumatology. Chapter 77. Ninth edition. Elsevier.

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