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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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Related in: MedlinePlus

Haplotype analysis of the top 2 SNPs from conditional analysis(A) Shaded boxes represent the minor allele. (B) An LD plot shows that with an r2 of 0.29 and D′=0.58, the top two SNPs are not in strong LD with each other.
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Figure 2: Haplotype analysis of the top 2 SNPs from conditional analysis(A) Shaded boxes represent the minor allele. (B) An LD plot shows that with an r2 of 0.29 and D′=0.58, the top two SNPs are not in strong LD with each other.

Mentions: Haplotype analysis of the top two independent risk variants, rs582757 and rs6918329, identified four main haplotypes present within the European population (Figure 2). H2, the most detrimental risk haplotype containing the minor alleles of both SNPs, had a frequency of 23% in the European population and conferred a psoriasis odds ratio of 1.23. Haplotype H4, containing the minor allele of rs582757 but major allele of rs6918329, had a frequency of 8% and conferred a psoriasis odds ratio of 1.16.


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)

Haplotype analysis of the top 2 SNPs from conditional analysis(A) Shaded boxes represent the minor allele. (B) An LD plot shows that with an r2 of 0.29 and D′=0.58, the top two SNPs are not in strong LD with each other.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Haplotype analysis of the top 2 SNPs from conditional analysis(A) Shaded boxes represent the minor allele. (B) An LD plot shows that with an r2 of 0.29 and D′=0.58, the top two SNPs are not in strong LD with each other.
Mentions: Haplotype analysis of the top two independent risk variants, rs582757 and rs6918329, identified four main haplotypes present within the European population (Figure 2). H2, the most detrimental risk haplotype containing the minor alleles of both SNPs, had a frequency of 23% in the European population and conferred a psoriasis odds ratio of 1.23. Haplotype H4, containing the minor allele of rs582757 but major allele of rs6918329, had a frequency of 8% and conferred a psoriasis odds ratio of 1.16.

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