Replication of recently identified systemic lupus erythematosus genetic associations: a case–control study

Suarez-Gestal, Marian; Calaza, Manuel; E, Endreffy; Pullmann, R; Ordi‐Ros, Josep; Sebastiani, Gian Domenico; Růžicková, Š; Santos, María José; Papasteriades, Chryssa; Marchini, Maurizio; Skopouli, Fotini N.; Suárez, Ana; Blanco, Francisco J.; D’Alfonso, Sandra; Bijl, Marc; Carreira, Patrícia; Witte, Torsten; Migliaresi, S.; Gómez-Reino, Juan J.; González, Antonio

doi:10.1186/ar2698

Cited by 132 publications

(115 citation statements)

References 27 publications

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“…Many SNPs are in the coding region, and .100 nonsynonymous variants have been annotated. Genome-wide association studies and more targeted candidate approaches have shown strong linkage of Tyk2 haplotypes or individual SNPs to systemic and organ-specific autoimmune diseases, namely systemic lupus erythematosus (SLE) (11)(12)(13)(14), multiple sclerosis (MS) (15)(16)(17)(18)(19), Crohn's disease (20)(21)(22), psoriasis (23), type 1 diabetes (24), endometriosis-related infertility (25), and primary biliary cirrhosis (26) (Table I). Interestingly, one rare MSassociated variant (rs34536443) is considered to be protective, whereas another (rs55762744) was recently identified as a risk allele (17).…”

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confidence: 99%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-α/β, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-α and IFN-γ signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context–dependent requirement for Tyk2 and the catalytic defect of the two disease-associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders.

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confidence: 99%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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“…9 Interestingly, another functional SNP in TYK2 was recently confirmed to confer susceptibility to systemic lupus erythematosus (SLE). 15 Comparing the MS-and SLE-associated TYK2 SNPs, that is, rs34536443 with rs2304256 in Haploview v.4Á1 (using the CEU individuals from the HapMap project phase 1, 2 and 3 (http://www. hapmap.org/ and http://www.ncbi.nlm.nih.gov/)), there was no evidence of linkage disequilibrium (LD) between these SNPs (r 2 ¼0.044).…”

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confidence: 99%

A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis

et al. 2009

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A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency¼0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P¼5Â10 À4 , odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P¼5.08Â10 À9 , OR 0.77) was shown.

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“…PXK domain containing serine/threonine kinase and act as modulator of Na, K-ATPase enzymatic and ion pump activities (Mao, 2005). It was identified as a novel candidate gene for systemic lupus erythematosus (SLE) from genomewide association studies (GWAS) in Caucasians (Suarez-Gestal, 2009). The association of PXK rs6445975 with SLE observed in Caucasians was not replication study in Hong Kong Chinese and Koreans (Kim, 2011;.…”

Section: Chromosome 3 41 Phox Homology (Px) Domain Kinase (Pxk) (3pmentioning

confidence: 99%

Genetics and Epigenetic in Systemic Lupus Erythematosus

AlFadhli¹

2012

Systemic Lupus Erythematosus

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Replication of recently identified systemic lupus erythematosus genetic associations: a case–control study

Abstract: Introduction We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci.

Cited by 132 publications

References 27 publications

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis

Genetics and Epigenetic in Systemic Lupus Erythematosus

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