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Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases.

Nititham J, Taylor KE, Gupta R, Chen H, Ahn R, Liu J, Seielstad M, Ma A, Bowcock AM, Criswell LA, Stahle M, Liao W - Genes Immun. (2014)

Bottom Line: We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(-12), odds ratio (OR) = 1.23).Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(-5), OR = 1.15).Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Dermatology, University of California San Francisco, San Francisco, CA, USA [2] Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT
Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(-12), odds ratio (OR) = 1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(-5), OR = 1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs. Analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other AIDs. Overall, our findings identify novel candidate causal variants of TNFAIP3 in psoriasis and highlight the complex genetic architecture of this locus in autoimmune susceptibility.

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Association plots of psoriasis meta-analysis and conditional analysis in the TNFAIP3 region from 138.0Mb to 138.3MbThe blue diamond represents the top SNP from each analysis. The red, orange, and yellow colors represent the RegulomeDB categories of likely functionality: red (2a–2c), orange (3a–3b) and yellow (4–6). (A) Meta-analysis using a random effects model. (B) Meta-analysis conditioning on the top signal rs582757. (C) Meta-analysis conditioning on the top two signals rs582757 and rs6918329.
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Figure 1: Association plots of psoriasis meta-analysis and conditional analysis in the TNFAIP3 region from 138.0Mb to 138.3MbThe blue diamond represents the top SNP from each analysis. The red, orange, and yellow colors represent the RegulomeDB categories of likely functionality: red (2a–2c), orange (3a–3b) and yellow (4–6). (A) Meta-analysis using a random effects model. (B) Meta-analysis conditioning on the top signal rs582757. (C) Meta-analysis conditioning on the top two signals rs582757 and rs6918329.

Mentions: We performed a meta-analysis of the TNFAIP3 region, encompassing TNFAIP3 ± 250 kb, in five European ancestry psoriasis cohorts totaling 4,704 cases and 7,805 controls (Table 1). We optimized the density and accuracy of SNP imputation using a combined reference panel from the Division of Cancer Epidemiology and Genetics (DCEG)12 and 1000 Genomes phase 3resulting in 3,815variants that were analyzed (Supplementary Table 1). Association testing identified 43 variants whose significance exceeded a strict Bonferroni threshold of P< 1.3 × 10−5 (Table 2) and 49 variants whose significance exceeded an adjusted Bonferroni threshold of P < 5.3 × 10−5 that accounts for the linkage disequilibrium between nearby SNPs (see Materials and Methods). The most significant variant using a random-effects model was rs582757 (p =6.07 × 10−12, odds ratio (OR) = 1.23), which is located within an intron of TNFAIP3 (Figure 1A). This SNP is as significantly associated with psoriasis riskas the lead SNP reported in several previous GWA studies, rs610604 (p = 8.13 × 10−12, OR = 1.22).11, 13


Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases.

Nititham J, Taylor KE, Gupta R, Chen H, Ahn R, Liu J, Seielstad M, Ma A, Bowcock AM, Criswell LA, Stahle M, Liao W - Genes Immun. (2014)

Association plots of psoriasis meta-analysis and conditional analysis in the TNFAIP3 region from 138.0Mb to 138.3MbThe blue diamond represents the top SNP from each analysis. The red, orange, and yellow colors represent the RegulomeDB categories of likely functionality: red (2a–2c), orange (3a–3b) and yellow (4–6). (A) Meta-analysis using a random effects model. (B) Meta-analysis conditioning on the top signal rs582757. (C) Meta-analysis conditioning on the top two signals rs582757 and rs6918329.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4526682&req=5

Figure 1: Association plots of psoriasis meta-analysis and conditional analysis in the TNFAIP3 region from 138.0Mb to 138.3MbThe blue diamond represents the top SNP from each analysis. The red, orange, and yellow colors represent the RegulomeDB categories of likely functionality: red (2a–2c), orange (3a–3b) and yellow (4–6). (A) Meta-analysis using a random effects model. (B) Meta-analysis conditioning on the top signal rs582757. (C) Meta-analysis conditioning on the top two signals rs582757 and rs6918329.
Mentions: We performed a meta-analysis of the TNFAIP3 region, encompassing TNFAIP3 ± 250 kb, in five European ancestry psoriasis cohorts totaling 4,704 cases and 7,805 controls (Table 1). We optimized the density and accuracy of SNP imputation using a combined reference panel from the Division of Cancer Epidemiology and Genetics (DCEG)12 and 1000 Genomes phase 3resulting in 3,815variants that were analyzed (Supplementary Table 1). Association testing identified 43 variants whose significance exceeded a strict Bonferroni threshold of P< 1.3 × 10−5 (Table 2) and 49 variants whose significance exceeded an adjusted Bonferroni threshold of P < 5.3 × 10−5 that accounts for the linkage disequilibrium between nearby SNPs (see Materials and Methods). The most significant variant using a random-effects model was rs582757 (p =6.07 × 10−12, odds ratio (OR) = 1.23), which is located within an intron of TNFAIP3 (Figure 1A). This SNP is as significantly associated with psoriasis riskas the lead SNP reported in several previous GWA studies, rs610604 (p = 8.13 × 10−12, OR = 1.22).11, 13

Bottom Line: We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(-12), odds ratio (OR) = 1.23).Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(-5), OR = 1.15).Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Dermatology, University of California San Francisco, San Francisco, CA, USA [2] Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT
Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(-12), odds ratio (OR) = 1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(-5), OR = 1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs. Analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other AIDs. Overall, our findings identify novel candidate causal variants of TNFAIP3 in psoriasis and highlight the complex genetic architecture of this locus in autoimmune susceptibility.

Show MeSH
Related in: MedlinePlus