International Psoriasis Council

Advancing Knowledge. Enhancing Care.

Advancing Knowledge. Enhancing Care.

Commentary: Genetic Meta-analysis Identified the Biological Mechanisms of Psoriasis Susceptibility

Helen Young, PhD, MBChB, FRCP

The University of Manchester

Manchester, United Kingdom

Bio

PUBLICATION

GWAS Meta-analysis of Psoriasis Identifies New Susceptibility Alleles Impacting Disease Mechanisms and Therapeutic Targets. Dand N, Stuart PE, Bowes J, et al. medRxiv [Preprint].  2023 Oct 5:2023.10.04.23296543.  doi: 10.1101/2023.10.04.23296543.  PMID: 37873414; PMCID: PMC10593001.

Why this article was chosen

Psoriasis, which affects approximately 60 million people worldwide, has a strong genetic component, with heritability estimated at 66%.1,2  Genetic studies have, to date, observed the strongest association within the MHC region on chromosome 6 and provided evidence for the IL23/IL17 pathway in disease pathogenesis.3-5  However, recently, Dand and colleagues completed a meta-analysis of 18 genome-wide association studies (GWAS) of psoriasis comprising 36,466 cases and 458,078 controls in which they identified 109 distinct psoriasis susceptibility loci, including 45 that had not been previously reported.

Commentary

Previous GWAS meta-analyses identified 65 genomic loci at which genetic variation is associated with psoriasis susceptibility in European ancestry populations, with 17 more reported in Asian ancestry populations.3,6-7  These have provided compelling evidence that a large proportion of genetic risk is attributable to the Major Histocompatibility Complex (MHC) class I allele HLA-C*06:02 and related antigen processing and presentation functions and established a key role for the IL-23/IL-17 axis in psoriasis pathogenesis, which has been mirrored by the effectiveness of biologic therapies targeting these cytokines.3-5  Nevertheless, important questions remain, including how and in which cell types the presence of risk-increasing alleles contribute to the development of psoriasis. Understanding these could better inform personalized medicine strategies and identify new therapeutic targets.8-10  Moreover, to date, GWAS meta-analyses of psoriasis have been relatively modest in size compared to those of other common diseases, where more extensive studies have detected genetic associations with small effects and discriminated between independent association signals within loci.11

In the present study, which represents the largest genetic study of psoriasis susceptibility undertaken to date, an international consortia of investigators from the United Kingdom, Europe, and North America report a meta-analysis of 18 case-control genome-wide association studies.  The increased statistical power of a sample size comprising more than 36,000 cases and 458,000 controls resulted in the authors identifying 45 new psoriasis susceptibility loci with genome-wide significant evidence of association.  In addition, a further five risk loci were observed for the first time at genome-wide significance in populations of European ancestry, thus representing a significant advance in understanding the genetic basis of psoriasis.

Other key findings include mapping newly reported association signals to fundamental processes of cell differentiation, proliferation, and trafficking, thus providing a causal link to established psoriasis pathomechanisms, including interferon response, T cell regulation, and keratinocyte hyperproliferation.  In addition, the current study identified two new psoriasis susceptibility loci harboring genes encoding therapeutic targets (including a subunit encoded by IL17RA, which is bound by high affinity by brodalumab and similarly, the aryl hydrocarbon receptor (AHR) is encoded by AHR targetted by the recently approved topical AHR agonist tapinarof.  Indeed, deleterious coding variants also identified potential new drug targets, including those encoded by STAP2, CPVL, and POU2F3.

Further data presented included a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants, highlighting a role for disrupting basic cellular machinery such as transcription and epigenetic modulation in regulating the inflammatory process in psoriasis.  These data, in conjunction with single-cell expression analyses, suggested that psoriasis genetic risk is mediated by cell types other than the established triad of T cells, dendritic cells, and keratinocytes and pointed to the participation in psoriasis pathogenesis of previously underappreciated cell types such as melanocytes.  Positive genetic correlations were also observed between psoriasis and 36 diseases and health-related traits, including evidence of a substantial shared genetic architecture with colitis, generalized pain, angina, and pulmonary disorders.  Significant genetic correlations were also observed with 11 lifestyle and quality of life traits.

In summary, this study represents a significant advance in our understanding of the genetic basis of psoriasis, which will underpin the next era of molecular studies in psoriasis and psoriasis therapeutics.

References

  1. National, Regional, and Worldwide Epidemiology of Psoriasis: Systematic Analysis and Modelling Study. Parisi R, Iskandar I Y K, Kontopantelis E, et al. BMJ. 2020;369:m1590.
  2. Psoriasis in Norwegian Twins: Contribution of Genetic and Environmental Effects. Grjibovski AM, Olsen AO, Magnus P, et al. J Eur Acad Dermatol Venereol. 2007 Nov;21(10):1337-43. doi: 10.1111/j.1468-3083.2007.02268.x. PMID: 17958839.
  3. Large Scale Meta-analysis Characterizes Genetic Architecture for Common Psoriasis Associated Variants. Tsoi L, Stuart P, Tian C, et al. Nat Commun. 2017;8:15382. https://doi.org/10/1038/ncomms15382.
  4. Psoriasis Bench to Bedside: Genetics Meets Immunology. Nair RP, Ding J, Duffin KC, et al. Arch Dermatol. 2009 Apr;145(4):462-4. doi: 10.1001/archdermatol.2009.73. PMID: 19380669; PMCID: PMC2739283.
  5. Genetics of Psoriasis. Mahil SK, Capon F, Barker JN. Dermatol Clin. 2015 Jan;33(1):1-11. doi: 10.1016/j.det.2014.09.001. PMID: 25412779.
  6. Exome-wide Association Study Reveals Novel Psoriasis Susceptibility Locus at TNFSF15 and Rare Protective Alleles in Genes Contributing to Type I IFN Signalling. Dand N, Mucha S, Tsoi LC, et al. Hum Mol Genet. 2017 Nov 1;26(21):4301-4313. doi: 10.1093/hmg/ddx328. PMID28973304; PMCID: PMC5886170.
  7. Genetic Signature to Provide Robust Risk Assessment of Psoriatic Arthritis Development in Psoriasis Patients. Patrick MT, Stuart PE, Raja K, et al. Nat Commun. 2018 Oct 9;9(1):4178. doi: 10.1038/s41467-018-06672-6. PMID: 30301895; PMCID: PMC6177414.
  8. Risk of Serious Adverse Events Associated with Biologic and Nonbiologic Psoriasis Systemic Therapy: Patients Ineligible vs Eligible for Randomized Controlled Trials. Garcia-Doval I, Carretero G, Vanaclocha F, et al. Arch Dermatol. 2012;148(4):463-470. doi:10.1001/archdermatol.2011.2768.
  9. Drug Survival Associated with Effectiveness and Safety of Treatment with Guselkumab, Ixekizumab, Secukinumab, Ustekinumab, and Adalimumab in Patients with Psoriasis. Yiu ZZN, Becher G, Kirby B, et al. JAMA Dermatol. 2022 Oct 1;158(10):1131-1141. doi: 10.1001/jamadermatol.2022.2909. Erratum in: JAMA Dermatol. 2022 Dec 1;158(12):1461. PMID: 35791876; PMCID: PMC9260644.
  10. The Support of Human Genetic Evidence for Approved Drug Indications. Nelson M, Tipney H, Painter J, et al. Nat Genet. 47, 856-860 (2015). https://doi.org/10.1038/ng.3314.
  11. Global Biobank Meta-analysis Initiative: Powering Genetic Discovery Across Human Dis Zhou W, Kanai M, Wu KH, et al. Cell Genom. 2022 Oct 12;2(10):100192. doi: 10.1016/j.xgen.2022.100192. PMID: 36777996; PMCID: PMC9903716.

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