Gene–gene interactions in IL23/Th17 pathway contribute to psoriasis susceptibility in Chinese Han population

Wang, W.-J.; Xian, Yin; Zuo, Xian Bo; Cheng, Hui; Du, W.-D.; Zhang, F.-Y.; Yang, Sen; Zhang, X.-J.

doi:10.1111/j.1468-3083.2012.04683.x

Cited by 16 publications

(8 citation statements)

References 35 publications

(75 reference statements)

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“…Several studies have previously highlighted the importance of genes and haplotypes in both the IL-23 as well as the NF-B pathways in psoriasis (Nair et al, 2009;Safrany et al, 2011;Safrany et al, 2013) as well as in many other immune-mediated diseases; PsA (Di Meglio et al, 2013;Eiris et al, 2014;Nair et al, 2010;Cargill et al, 2007;Franke et al, 2010;Strange et al, 2010;Bowes et al, 2011;Liu et al, 2008;Popa et al, 2013;Wang et al, 2012;Capon et al, 2007), Crohn's disease (Chua et al, 2012;Dinu et al, 2012;Jung et al, 2012), inflammatory bowel disease (Duerr et al, 2006;Safrany et al, 2013), ankylosing spondylitis (Safrany et al, 2009), celiac disease and multiple sclerosis (Nunez et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

Nikamo

Lysell

Ståhle

2015

Journal of Investigative Dermatology

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Psoriasis is clinically heterogeneous, and symptoms can vary from mild almost cosmetic symptoms to severe disease requiring systemic therapy. Biomarkers predicting disease development are lacking. Herein we explored the genetic background in two polarized cohorts of carefully phenotyped patients with long-term follow-up: consistent mild phenotype (n=696) and severe disease course requiring systemic therapy (n=715). All patients were treated at the same dermatology department ensuring homogenous assessment. Genotyping included known psoriasis-associated variants, with special focus on the IL-23 and NF-κB pathways. A case-case study comparing severe and mild psoriasis phenotypes, controlling for age at disease onset and gender, revealed significant differences between the two groups for SNPs in IL23R, NFKB1, IL21, IL12B, NFKBIL1 and IL23A. HLA-C*06 associated equally in the mild and severe disease cohorts. Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis. No protective gene was identified in the mild cohort, suggesting that current screens have primarily identified psoriasis variants associated with a more severe phenotype. These results demonstrate the importance of careful phenotyping and long-term clinical follow-up in genetic studies.

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Section: Discussionmentioning

confidence: 97%

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

Nikamo

Lysell

Ståhle

2015

Journal of Investigative Dermatology

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“…The majority of identified psoriasis susceptibility genes are involved in the immune system. The activation of T-helper 17 (Th17) is currently in focus and is underscored by the genetic association to components in the Th17 pathway such as interleukin 23 receptor (IL23R), IL12B, and IL23A (Capon et al, 2007;Nair et al, 2010;Di Meglio et al, 2011;Wang et al, 2012;Popa et al, 2013), and by the compelling efficacy of therapies targeting this pathway. IL-22 is highly expressed by immune cells such as T cells in several chronic inflammatory conditions, including psoriasis (Zheng et al, 2007;Pan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Genetic Variants of the IL22 Promoter Associate to Onset of Psoriasis before Puberty and Increased IL-22 Production in T Cells

Nikamo

Cheuk

Lysell

et al. 2014

Journal of Investigative Dermatology

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Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and the exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset in patients between 0-9 (n=207), 10-20 (n=394), and 21-40 (n=468) years with healthy controls (n=1,529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (odds ratio=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in 80% higher promoter activity (P=0.012) compared with a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant produced 1.7 times more IL-22 compared with low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate the onset of psoriasis at an early age.

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“…Several significant SNPs have been identified in classic GWAS studies (Duerr et al, 2006; Hunter, 2007; Hunter et al, 2007; Scott et al, 2007). However, other SNPs of low frequencies which contribute to the complex traits remain hidden in the false negative results (Frayling et al, 2007; Willer et al, 2008; Sanna et al, 2008; Nair et al, 2009; Wang et al, 2013). To identify more novel susceptibility loci, large-scale GWAS is a costly and time-consuming approach.…”

Section: Discussionmentioning

confidence: 99%

Robust Reference Powered Association Test of Genome-Wide Association Studies

Wang

Meng

et al. 2019

Front. Genet.

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Genome-wide association studies (GWASs) have identified abundant genetic susceptibility loci, GWAS of small sample size are far less from meeting the previous expectations due to low statistical power and false positive results. Effective statistical methods are required to further improve the analyses of massive GWAS data. Here we presented a new statistic (Robust Reference Powered Association Test 1 ) to use large public database (gnomad) as reference to reduce concern of potential population stratification. To evaluate the performance of this statistic for various situations, we simulated multiple sets of sample size and frequencies to compute statistical power. Furthermore, we applied our method to several real datasets (psoriasis genome-wide association datasets and schizophrenia genome-wide association dataset) to evaluate the performance. Careful analyses indicated that our newly developed statistic outperformed several previously developed GWAS applications. Importantly, this statistic is more robust than naive merging method in the presence of small control-reference differentiation, therefore likely to detect more association signals.

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Gene–gene interactions in IL23/Th17 pathway contribute to psoriasis susceptibility in Chinese Han population

Abstract: Our results might be helpful for explaining the missing heritability of the psoriasis due to epistasis and provide a deep insight into the important role of the IL23/Th17 pathway in the pathogenesis of psoriasis.

Cited by 16 publications

References 35 publications

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

Genetic Variants of the IL22 Promoter Associate to Onset of Psoriasis before Puberty and Increased IL-22 Production in T Cells

Robust Reference Powered Association Test of Genome-Wide Association Studies

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