Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Dand, Nick; Mucha, Sören; Tsoi, Lam C.; Mahil, Satveer K.; Stuart, Philip E.; Arnold, Andreas; Baurecht, Hansjörg; Burden, A. D.; Duffin, Kristina Callis; Chandran, Vinod; Curtis, Charles; S, Das; Ellinghaus, David; Ellinghaus, Eva; Enerbäck, Charlotta; Esko, Tõnu; Gladman, Dafna D.; Griffiths, Christopher E.M.; Guðjónsson, Jóhann E.; Hoffman, Per; Homuth, Georg; Hüffmeier, Ulrike; Krueger, Gerald G.; Laudes, Matthias; Lee, Sang Hyuck; Lieb, Wolfgang; Lim, Henry W.; Löhr, Sabine; Mrowietz, Ulrich; Müller-Nurayid, Martina; Nöthen, Markus M.; Peters, Annette; Rahman, Proton; Reis, André; Reynolds, Nick J.; Rodríguez, Elke; Schmidt, Carsten Oliver; Spain, Sarah; Strauch, Konstantin; Tejasvi, Trilokraj; Voorhees, John J.; Warren, Richard B; Weichenthal, Michael; Weidinger, Stephan; Zawistowski, Matthew; Nair, Rajan P.; Capon, Francesca; Smith, Catherine; Trembath, Richard; Abecasis, Gonçalo R.; Elder, James T.; Franke, André; Simpson, Michael A.; Barker, Jonathan

doi:10.1093/hmg/ddx328

Cited by 45 publications

(37 citation statements)

References 72 publications

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“…In addition to informing the targets of biologic medications, genetic studies have opened new avenues for small molecule therapeutics. Following genetic association data highlighting TYK2 as a causal allele (31,32), an oral, selective Theme issue: Psoriasis inhibitor was developed, which has shown promising efficacy in phase II trials (57).…”

Section: Translation Of Genetic Discoveries Into Novel Therapeuticsmentioning

confidence: 99%

Psoriasis and Genetics

Dand¹,

Capon²,

Smith³

et al. 2020

Acta Derm Venerol

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Psoriasis has benefited greatly among dermatological conditions from genome-wide association studies (GWAS) of increasingly large, clinically well-described samples. Sixty-five regions of the genome have been linked to psoriasis risk in Europeans, with the largest contribution due to HLA-C*06:02, a variant of an important gene involved in immunity. Other regions implicate numerous immune and skin barrier processes in psoriasis development. Recent GWAS-based research has shown that genetics can help distinguish subgroups of psoriasis patients characterised by type (pustular vs. plaque psoriasis), development of joint disease or response to various drugs. This may help inform future tailored treatment strategies for individuals with psoriasis. Psoriasis is a common inflammatory skin disease caused by the interplay between multiple genetic and environmental risk factors. This review summarises recent progress in elucidating the genetic basis of psoriasis, particularly through large genome-wide association studies. We illustrate the power of genetic analyses for disease stratification. Psoriasis can be stratified by phenotype (common plaque versus rare pustular variants), or by outcome (prognosis, comorbidities, response to treatment); recent progress has been made in delineating the genetic contribution in each of these areas. We also highlight how genetic data can directly inform the development of effective psoriasis treatments.

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Section: Translation Of Genetic Discoveries Into Novel Therapeuticsmentioning

confidence: 99%

Psoriasis and Genetics

Dand¹,

Capon²,

Smith³

et al. 2020

Acta Derm Venerol

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“…In subsequent studies, haplotype analysis showed that the rs2304256 association in SLE and RA is likely driven by imperfect LD to the independent causal variants rs34536443 (P1104A), rs12720356 (I684S) or rs35018800 (A928V) [50]. A similar conclusion was reached in a study of systemic sclerosis patients and in a meta-analysis using exome arrays to identify psoriasis-associated rare variants [51,52]. Recently, a fine mapping analysis of causal variants for RA and IBD identified rs34536443 and rs12720356, but not rs2304256 [53].…”

Section: Discussionmentioning

confidence: 62%

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Rotival

Patin

et al. 2020

PLoS ONE

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TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.

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“…Genetic studies support its implication in autoimmune diseases and mycobacterial infections. Case-control and GWA studies have identified Tnfsf15 gene variants, such as rs6478108 alleles, that associate with increased susceptibility to psoriasis and psoriatic arthritis in populations of European descent (111, 112). Furthermore, alleles rs6478108 (T) and rs4979462 (T), have been found to increase susceptibility to both Primary Billiary Cholangitis (PBC) and CD, while protecting from leprosy (6, 113).…”

Section: Tl1a/dr3 In the Crossroads Of Systemic Inflammation: Associamentioning

confidence: 99%

TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity

2019

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TL1A and its functional receptor DR3 are members of the TNF/TNFR superfamilies of proteins. Binding of APC-derived TL1A to lymphocytic DR3 provides co-stimulatory signals for activated lymphocytes. DR3 signaling affects the proliferative activity of and cytokine production by effector lymphocytes, but also critically influences the development and suppressive function of regulatory T-cells. DR3 was also found to be highly expressed by innate lymphoid cells (ILCS), which respond to stimulation by TL1A. Several recent studies with transgenic and knockout mice as well as neutralizing or agonistic antibodies for these two proteins, have clearly shown that TL1A/DR3 are important mediators of several chronic immunological disorders, including Inflammatory Bowel Disease (IBD). TL1A and DR3 are abundantly localized at inflamed intestinal areas of patients with IBD and mice with experimental ileitis or colitis and actively participate in the immunological pathways that underlie mucosal homeostasis and intestinal inflammation. DR3 signaling has demonstrated a dichotomous role in mucosal immunity. On the one hand, during acute mucosal injury it exerts protective functions by ameliorating the severity of acute inflammatory responses and facilitating tissue repair. On the other hand, it critically participates in the pro-inflammatory pathways that underlie chronic inflammatory responses, such as those that take place in IBD. These effects are mediated through modulation of the relative mucosal abundance and function of Th1, Th2, Th17, Th9, and Treg lymphocytes, but also of all types of ILCs. Recently, an important role was demonstrated for TL1A/DR3 as potential mediators of intestinal fibrosis that is associated with the presence of gut inflammation. These accumulating data have raised the possibility that TL1A/DR3 pathways may represent a valid therapeutic target for chronic immunological diseases. Nevertheless, applicability of such a therapeutic approach will greatly rely on the net result of TL1A/DR3 manipulation on the various cell populations that will be affected by this approach.

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Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Cited by 45 publications

References 72 publications

Psoriasis and Genetics

Psoriasis and Genetics

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity

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