| 1. |
- Abelson, Anna-Karin, et al.
(author)
-
STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
- 2009
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 68:11, s. 1746-1753
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
|
|
| 2. |
- Delgado-Vega, Angélica M., et al.
(author)
-
Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein
- 2012
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:7, s. 1219-1226
-
Journal article (peer-reviewed)abstract
- ObjectivesTo perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE).MethodsGenotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor. B (NFkB) binding.ResultsFine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NF kappa B-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR = 2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life.ConclusionsThese results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.
|
|
| 3. |
- Löfgren, Sara E., et al.
(author)
-
Promoter Insertion/Deletion in the IRF5 Gene Is Highly Associated with Susceptibility to Systemic Lupus Erythematosus in Distinct Populations, But Exerts a Modest Effect on Gene Expression in Peripheral Blood Mononuclear Cells
- 2010
-
In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 37:3, s. 574-578
-
Journal article (peer-reviewed)abstract
- Objective. We examined the genetic association of the promoter insertion/deletion (indel) in IRF5 gene with systemic lupus erythematosus (SLE) in distinct populations and assessed its role in gene expression. Methods. Four IRF5 polymorphisms were genotyped in 1488 SLE patients and 1466 controls. Gene expression was analyzed by quantitative real-time PCR using RNA from peripheral blood mononuclear cells (PBMC). Results. The promoter indel and rs2070197 had independent genetic effects, which accounted for the association of rs2004640 and rs10954213. Gene expression analysis revealed that rs10954213 exerted the greatest influence on IRF5 transcript levels. Conclusion. We corroborated the association of the promoter indel with SLE in 5 different populations and revealed that rs10954213 is the main single-nucleotide polymorphism responsible for altered IRF5 expression in PBMC.
|
|
| 4. |
- Oparina, Nina Y., et al.
(author)
-
PXK locus in systemic lupus erythematosus : fine mapping and functional analysis reveals novel susceptibility gene ABHD6
- 2015
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:3
-
Journal article (peer-reviewed)abstract
- Objectives To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease. Methods Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs. Results Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans. Conclusions These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.
|
|
