Association analysis of GWAS and candidate gene loci in a Pakistani population with psoriasis

Munir, Saeeda; Rahman, Simeen Ber; Rehman, Sadia; Saba, Nusrat; Ahmad, Wasim; Nilsson, Staffan; Mazhar, Kehkashan; Naluai, Åsa Torinsson

doi:10.1016/j.molimm.2014.11.015

Cited by 33 publications

(36 citation statements)

References 28 publications

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“…MCPIP1 belongs to a 4-member family of CCCH-type zinc finger proteins. It is intriguing that polymorphisms in ZC3H12C (encoding MCPIP3) were identified in a GWAS study (50, 65). Similar to MCPIP1, MCPIP3 has endoribonuclease activity and curbs inflammatory responses in endothelial cells by suppressing NF-κB signaling (66).…”

Section: Discussionmentioning

confidence: 99%

MCPIP1/Regnase-1 Restricts IL-17A– and IL-17C–Dependent Skin Inflammation

Monin

Guðjónsson

Childs

et al. 2017

The Journal of Immunology

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The IL-17-family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti-IL-17A Abs were recently approved to treat human psoriasis. To date, little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. Here, we show that the endoribonuclease MCPIP1 (also known as Regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency (Zc3h12a+/−) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a+/− mice was associated with elevated expression of IL-17A- and IL-17C-dependent genes and also increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a+/− mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in non-hematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a+/−Il17ra−/− mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a+/−Il17a−/− and Zc3h12a+/−Il17c−/− mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits both IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a−/− keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, MCPIP1 is the first described negative regulator of IL-17C signaling.

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Section: Discussionmentioning

confidence: 99%

MCPIP1/Regnase-1 Restricts IL-17A– and IL-17C–Dependent Skin Inflammation

Monin

Guðjónsson

Childs

et al. 2017

The Journal of Immunology

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“…PRR9 encodes a protein of unknown function, with the highest expression levels in the skin , while LOR encodes loricrin, a component of the cornified cell envelope in terminally differentiated epidermal cells. Interestingly, association analyses in patients with psoriasis, an inflammatory skin disorder, have identified PRR9 as a susceptibility locus . Although this may represent overlap of disease risk loci between JIA and psoriasis, there is also the possibility that the JIA cohorts include psoriasis patients, given that ~20−25% of patients present with arthritis before skin disease, which is difficult to define in younger children.…”

Section: Discussionmentioning

confidence: 99%

Genome‐Wide Association Meta‐Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci

McIntosh

Marion

Sudman

et al. 2017

Arthritis & Rheumatology

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Objective Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)–negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes. Methods Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis. Results Meta-analysis showed evidence of association (P < 1 × 10−6) at 9 regions: PRR9_LOR (P = 5.12 × 10−8), ILDR1_CD86 (P = 6.73 × 10−8), WDFY4 (P = 1.79 × 10−7), PTH1R (P = 1.87 × 10−7), RNF215 (P = 3.09 × 10−7), AHI1_LINC00271 (P = 3.48 × 10−7), JAK1 (P = 4.18 × 10−7), LINC00951 (P = 5.80 × 10−7), and HBP1 (P = 7.29 × 10−7). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22. Conclusion This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

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“…The results of the study in South Indian Tamils suggest that IL4 (rs2243250) polymorphism is protective against psoriasis and the heterozygous C/T genotype demonstrated significant high IL-4 levels in blood (Indhumathi et al, 2017). In contrast, the rs2243250*C allele is associated with the increased risk of PS in another studies (Munir et al, 2015;Kim et al, 2007).…”

Section: Accepted Manuscriptmentioning

confidence: 93%