Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris

Tsunemi, Yuichiro; Saeki, Hidehisa; Nakamura, Koichiro; Sekiya, Takashi; Hirai, Koichi; Fujita, Hideki; Asano, Noriko; Kishimoto, Megumi; Tanida, Yuka; Kakinuma, Takashi; Mitsui, Hiroshi; Tada, Yayoi; Wakugawa, Motoshi; Torii, Hideshi; Komine, Mayumi; Asahina, Akihiko; Tamaki, Kunihiko

doi:10.1016/s0923-1811(02)00072-5

Cited by 169 publications

(118 citation statements)

References 42 publications

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“…Following genome-wide linkage studies, evidence for psoriasis-associated variants segregating at 17q25 has been intriguing, albeit inconsistent in location and signal strength. [7][8][9] Recently, we have reported psoriasis-associated diplotypes at IL12B, confirming and extending the previous work by Tsunemi et al, 10 and predisposing/protective diplotypes at IL23R using a multi-staged, case-control design, scanning 25 215 genecentric single nucleotide polymorphisms (SNPs). 11 These results have been verified in four independent studies [12][13][14][15] and have paralleled association studies in related diseases.…”

Section: Introductionsupporting

confidence: 88%

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

García¹,

Chang²,

Brandon³

et al. 2008

Genes Immun

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Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (42800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR common ¼ 0.67; P comb ¼ 4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P Het ¼ 0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.

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Section: Introductionsupporting

confidence: 88%

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

García¹,

Chang²,

Brandon³

et al. 2008

Genes Immun

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“…The results from the previous studies as well as the current study demonstrate the effectiveness of ustekinumab across different ethnic populations with psoriasis. These findings may have been anticipated by genome-wide association studies that have demonstrated an association between psoriasis and polymorphisms of the genes that encode the shared p40 subunit of IL-12 and IL-23 (IL-12B), and ⁄ or one of the IL-23 receptor subunits 33 in white, 34 Japanese, 35 Chinese 36 and Thai 37 populations.…”

Section: Discussionmentioning

confidence: 82%

Efficacy and safety of ustekinumab in Japanese patients with moderate‐to‐severe plaque‐type psoriasis: Long‐term results from a phase 2/3 clinical trial

Igarashi

Kato

Kato³

et al. 2011

The Journal of Dermatology

187

156

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This phase 2 ⁄ 3, double-blind, placebo-controlled study was designed to assess the safety and efficacy of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis. Overall, 158 patients were randomized to receive ustekinumab 45 or 90 mg at weeks 0, 4, and every 12 weeks, or placebo with cross-over to ustekinumab at week 12. The primary end-point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 12. Physician's Global Assessment (PGA), Dermatology Life Quality Index (DLQI), Nail Psoriasis Severity Index and joint pain Visual Analog Scale (VAS) were also measured. At week 12, 59.4% and 67.7% of ustekinumab 45 and 90 mg patients achieved PASI 75, respectively, compared with 6.5% in the placebo group (P < 0.0001 each). PASI 75 responses were maintained through week 64 in 65.0% and 78.6% of the ustekinumabtreated patients, respectively. Placebo cross-over patients had similar responses to ustekinumab-treated patients. Significant improvements in PGA, DLQI and VAS scores were observed at week 12 and generally maintained over time. Adverse events during the placebo-controlled period were similar among groups (45 mg, 65.6%; 90 mg, 59.7%; placebo, 65.6%). Serious adverse events were observed in 0%, 4.8% and 6.3% of patients, respectively. Through week 72, similar rates and types of adverse events and serious adverse events were reported in patients receiving 45 and 90 mg. Rates of injection site reactions and antibodies to ustekinumab were low. Ustekinumab was efficacious and generally well-tolerated in Japanese patients with moderate-to-severe plaque-type psoriasis through 72 weeks. These results are consistent with those reported in the global, phase 3 studies.

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“…Tsunemi et al [27] found that a single nucleotide polymorphism in p40 was associated with psoriasis. This polymorphism was confirmed using genome-wide association studies and gene sequencing in additional independent cohorts [28••,29•].…”

Section: Il-23 Promotes Th17 Cell Survival and Proliferationmentioning

confidence: 99%

Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines

Fitch¹,

Harper²,

Skorcheva³

et al. 2007

Curr Rheumatol Rep

350

260

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T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases. Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells, and thus serves as a key master cytokine regulator for these diseases. In psoriasis, IL-23 is overproduced by dendritic cells and keratinocytes, and this cytokine stimulates Th17 cells within dermis to make IL-17A and IL-22. IL-22, in particular, drives keratinocyte hyperproliferation in psoriasis. Future targeting of these key cytokines is likely to lead to dramatic clinical improvement in patients with psoriasis. This review focuses on the numerous recent studies on the roles of IL-23 and Th17 cells in the pathogenesis of psoriasis.

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Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris

Cited by 169 publications

References 42 publications

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

Efficacy and safety of ustekinumab in Japanese patients with moderate‐to‐severe plaque‐type psoriasis: Long‐term results from a phase 2/3 clinical trial

Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines

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