Genome‐wide association study of rheumatoid arthritis in the Spanish population: <i>KLF12</i> as a risk locus for rheumatoid arthritis susceptibility

Juliá, Antonio; Ballina, Javier; Cañete, Juan D.; Balsa, Alejandro; Tornero-Molina, Jesús; Naranjo, Antonio; Alperi-López, Mercedes; Erra, Alba; Pascual‐Salcedo, Dora; Barceló, P; Camps, Jordi; Marsal, Sara

doi:10.1002/art.23623

Cited by 101 publications

(78 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2B). More recently, KLF12 has been identified as a susceptibility gene for the autoimmune disorder rheumatoid arthritis (40), suggesting a mechanism by which IFN-␣ might precipitate a treatment course with exacerbated side effects relative to IFN-␤, as seen in multiple sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal system-based analysis of transcriptional responses to type I interferons

Pappas

Coppola

Gabatto

et al. 2009

Physiological Genomics

View full text Add to dashboard Cite

Type I interferons (IFNs) are pleiotropic cytokines that modulate both innate and adaptive immune responses. They have been used to treat autoimmune disorders, cancers, and viral infection and have been demonstrated to elicit differential responses within cells, despite sharing a single receptor. The molecular basis for such differential responses has remained elusive. To identify the mechanisms underlying differential type I IFN signaling, we used whole genome microarrays to measure longitudinal transcriptional events within human CD4 ϩ T cells treated with IFN-␣2b or IFN-␤1a. We identified differentially regulated genes, analyzed them for the enrichment of known promoter elements and pathways, and constructed a network module based on weighted gene coexpression network analysis (WGCNA). WGCNA uses advanced statistical measures to find interconnected modules of correlated genes. Overall, differential responses to IFN in CD4 ϩ T cells related to three dominant themes: migration, antigen presentation, and the cytotoxic response. For migration, WGCNA identified subtypespecific regulation of pre-mRNA processing factor 4 homolog B and eukaryotic translation initiation factor 4A2, which work at various levels within the cell to affect the expression of the chemokine CCL5. WGCNA also identified sterile ␣-motif domain-containing 9-like (SAMD9L) as critical in subtype-independent effects of IFN treatment. RNA interference of SAMD9L expression enhanced the migratory phenotype of activated T cells treated with IFN-␤ compared with controls. Through the analysis of the dynamic transcriptional events after differential IFN treatment, we were able to identify specific signatures and to uncover novel genes that may underpin the type I IFN response.human; T cell; cytokines; gene regulation INTERFERONS (IFNs) are pleiotropic molecules implicated in a wide range of cellular responses (44) and are Federal Drug Administration-approved therapeutics for the treatment of cancer, infection, and autoimmunity (49). Based on sequence homology and structure, IFNs are divided into three classes: types I, II, and III. Type I IFNs include IFN-␣ (15 known ␣-subtypes), IFN-␤, and IFN-, whereas type II IFN consists only of IFN-␥ and type III IFN consists only of IFN-. All type I IFNs activate a common cell surface receptor [the IFN receptor (IFNR)], which exists as two separate polypeptides (IFNAR1 and IFNAR2) with no intrinsic dimerization capacity (12). Binding of type I IFNs to IFNAR2, recruitment of IFNAR1, and stabilization of a heterotrimeric ligand/receptor complex activate members of the Jak1/tyrosine kinase 2 (Tyk2) and JAK/STAT pathways (12, 45). Phosphorylated STAT1/ STAT2 heterodimers form transcriptional activation complexes with IFN regulatory factor (IRF)9/p48, translocate to the nucleus, and drive the expression of numerous genes, including myxovirus resistance protein 1 (MX1), 2Ј,5Ј-oligoadenylate synthetase 1, and double-stranded RNA-activated protein kinase (EIF2AK2).Although type I IFNs share the same cognate receptor and und...

show abstract

Section: Discussionmentioning

confidence: 99%

Longitudinal system-based analysis of transcriptional responses to type I interferons

Pappas

Coppola

Gabatto

et al. 2009

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…Nonetheless, elucidating the genetics of these disorders is severely impeded by the existence of genetic heterogeneity. The genetic heterogeneity of RA have confirmed by whole genome association studies [9,10,32]. Thus the FCRL3 polymorphisms may play a different role in different ethnic populations because of diversity of genetic background.…”

Section: Discussionmentioning

confidence: 83%

Fc receptor–like 3 gene polymorphisms confer susceptibility to rheumatoid arthritis in a Chinese population

Yang

Zuo

et al. 2010

Human Immunology

View full text Add to dashboard Cite

“…2007b; WTCCC, 2007;Julià et al, 2008;Raychaudhuri et al, 2008;Gregersen et al, 2009;Kochi et al, 2010;Stahl et al, 2010). Some of the significant SNPs in the candidate RA-associated genes have shown consistent significance across diverse ethnic groups, while some other SNPs have not.…”

Section: Figure 1 Gwas Results and Plots In The Region Around Apom (A)mentioning

confidence: 99%

Common variants at the promoter region of theAPOMconfer a risk of rheumatoid arthritis

Jin

Yim

et al. 2011

Exp Mol Med

View full text Add to dashboard Cite

Although the genetic component in the etiology of rheumatoid arthritis (RA) has been consistently suggested, many novel genetic loci remain to uncover. To identify RA risk loci, we performed a genome-wide association study (GWAS) with 100 RA cases and 600 controls using Affymetrix SNP array 5.0. The candidate risk locus (APOM gene) was re-sequenced to discover novel promoter and coding variants in a group of the subjects. Replication was performed with the independent case-control set comprising of 578 RAs and 711 controls. Through GWAS, we identified a novel SNP associated with RA at the APOM gene in the MHC class III region on 6p21.33 (rs805297, odds ratio (OR) = 2.28, P = 5.20 × 10 -7). Three more polymorphisms were identified at the promoter region of the APOM by the re-sequencing. For the replication, we genotyped the four SNP loci in the independent case-control set. The association of rs805297 identified by GWAS was successfully replicated (OR = 1.40, P = 6.65 × 10 -5). The association became more significant in the combined analysis of discovery and replication sets (OR = 1.56, P = 2.73 × 10 -10). The individuals with the rs805297 risk allele (A) at the promoter region showed a significantly lower level of APOM expression compared with those with the protective allele (C) homozygote. In the logistic regressions by the phenotype status, the homozygote risk genotype (A/A) consistently showed higher ORs than the heterozygote one (A/C) for the phenotype-positive RAs. These results indicate that APOM promoter polymorphisms are significantly associated with the susceptibility to RA.

show abstract

Genome‐wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility

Cited by 101 publications

References 45 publications

Longitudinal system-based analysis of transcriptional responses to type I interferons

Longitudinal system-based analysis of transcriptional responses to type I interferons

Fc receptor–like 3 gene polymorphisms confer susceptibility to rheumatoid arthritis in a Chinese population

Common variants at the promoter region of theAPOMconfer a risk of rheumatoid arthritis

Contact Info

Product

Resources

About