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Farias, Fabiana H. G.
Alternative names
Publications (9 of 9) Show all publications
Sandling, J. K., Pucholt, P., Hultin-Rosenberg, L., Farias, F. H. G., Kozyrev, S. V., Eloranta, M.-L., . . . Rönnblom, L. (2021). Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing. Annals of the Rheumatic Diseases, 80(1), 109-117
Open this publication in new window or tab >>Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
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2021 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 1, p. 109-117Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE.

METHODS: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS).

RESULTS: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes.

CONCLUSIONS: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.

Place, publisher, year, edition, pages
BMJ Publishing Group LtdBMJ PUBLISHING GROUP, 2021
Keywords
autoimmunity, genetic, lupus erythematosus, polymorphism, systemic
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-434591 (URN)10.1136/annrheumdis-2020-218636 (DOI)000607296800028 ()33037003 (PubMedID)
Funder
Swedish Research Council, 2018-02399Swedish Research Council, 2018-02535Swedish Heart Lung FoundationSwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2021-02-10 Created: 2021-02-10 Last updated: 2024-01-15Bibliographically approved
Farias, F. H. G., Dahlqvist, J., Kozyrev, S. V., Leonard, D., Wilbe, M., Abramov, S., . . . Lindblad-Toh, K. (2019). A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. European Journal of Human Genetics, 27, 432-441
Open this publication in new window or tab >>A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

National Category
Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-368313 (URN)10.1038/s41431-018-0297-x (DOI)000458626500013 ()30459414 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Rheumatism AssociationKnut and Alice Wallenberg Foundation
Note

These authors contributed equally: Johanna Dahlqvist, Sergey V. Kozyrev, Dag Leonard, Maria Wilbe

Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2020-10-26Bibliographically approved
Abramov, S., Kozyrev, S. V., Farias, F. H. G., Dahlqvist, J., Leonard, D., Wilbe, M., . . . Lindblad-Toh, K. (2018). The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing. Paper presented at Conference on Changing the Face of Modern Medicine - Stem Cell and Gene Therapy, OCT 16-19, 2018, Lausanne, SWITZERLAND. Human Gene Therapy, 29(12), A44-A44
Open this publication in new window or tab >>The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing
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2018 (English)In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A44-A44Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-373072 (URN)000453707700143 ()
Conference
Conference on Changing the Face of Modern Medicine - Stem Cell and Gene Therapy, OCT 16-19, 2018, Lausanne, SWITZERLAND
Available from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-01-11Bibliographically approved
Ardesjö-Lundgren, B., Tengvall, K., Bergvall, K., Farias, F. H. G., Wang, L., Hedhammar, Å., . . . Andersson, G. (2017). Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs. Veterinary dermatology (Print), 28(4), 377-e88
Open this publication in new window or tab >>Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs
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2017 (English)In: Veterinary dermatology (Print), ISSN 0959-4493, E-ISSN 1365-3164, Vol. 28, no 4, p. 377-e88Article in journal (Refereed) Published
Abstract [en]

Background

Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome‐wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin‐2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities.

Objectives

The main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD‐affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location.

Animals/Methods

Skin biopsies were collected from nine CAD‐affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology.

Results

We observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding‐partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed.

Conclusion

Plakophilin‐2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.

National Category
Veterinary Science
Identifiers
urn:nbn:se:uu:diva-333703 (URN)10.1111/vde.12441 (DOI)000407137900010 ()28386956 (PubMedID)
Funder
Swedish Research Council, 521-2012-2826, 221-2009-1689, 524-2012-7053EU, European Research Council, 310203
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2020-10-01Bibliographically approved
Tengvall, K., Kozyrev, S., Kierczak, M., Bergvall, K., Farias, F. H. G., Ardesjö-Lundgren, B., . . . Lindblad-Toh, K. (2016). Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs. BMC Genetics, 17(1), Article ID 97.
Open this publication in new window or tab >>Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs
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2016 (English)In: BMC Genetics, E-ISSN 1471-2156, Vol. 17, no 1, article id 97Article in journal (Refereed) Published
Abstract [en]

Background

Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2.

Results

Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10−7) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10−5), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region.

Conclusions

Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.

Keywords
PKP2, Atopic dermatitis, Genetic association, Luciferase reporter assay, Cell type-specific enhancers, Dog, Plakophilin 2, Eczema
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-299868 (URN)10.1186/s12863-016-0404-3 (DOI)000378844000003 ()27357287 (PubMedID)
Funder
Swedish Research Council, 521-2012-2826Swedish Research Council Formas, 221-2009-1689EU, European Research Council, 310203EU, FP7, Seventh Framework Programme, GA-201370
Available from: 2016-07-28 Created: 2016-07-28 Last updated: 2024-01-17Bibliographically approved
Wilbe, M., Kozyrev, S. V., Farias, F. H. G., Bremer, H. D., Hedlund, A., Pielberg, G. R., . . . Lindblad-Toh, K. (2015). Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease. PLOS Genetics, 11(6), Article ID e1005248.
Open this publication in new window or tab >>Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease
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2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 6, article id e1005248Article in journal (Refereed) Published
Abstract [en]

The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAM-TOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-259123 (URN)10.1371/journal.pgen.1005248 (DOI)000357341600014 ()26057447 (PubMedID)
Funder
Swedish Research Council FormasSwedish Research Council, 80576801, 70374401Swedish Foundation for Strategic Research
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2018-01-11Bibliographically approved
Farias, F., Wilbe, M., Dahlqvist, J., Leonard, D., Kozyrev, S., Pielberg, G., . . . Lindblad-Toh, K. (2014). High-Throughput Sequencing of 219 Candidate Genes for Identification of SLE-Associated Risk Variants. Paper presented at American College of Rheumatology (ACR/ARHP) Annual Meeting, 14-19 November 2014, Boston, USA. Arthritis & Rheumatology, 66(S10), S1170-S1170, Article ID 2673.
Open this publication in new window or tab >>High-Throughput Sequencing of 219 Candidate Genes for Identification of SLE-Associated Risk Variants
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2014 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S1170-S1170, article id 2673Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-246742 (URN)000344384905350 ()
Conference
American College of Rheumatology (ACR/ARHP) Annual Meeting, 14-19 November 2014, Boston, USA
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2016-01-15Bibliographically approved
Tengvall, K., Kierczak, M., Bergvall, K., Olsson, M., Frankowiack, M., Farias, F. H. G., . . . Lindblad-Toh, K. (2013). Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis. PLOS Genetics, 9(5), e1003475
Open this publication in new window or tab >>Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 5, p. e1003475-Article in journal (Refereed) Published
Abstract [en]

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-205345 (URN)10.1371/journal.pgen.1003475 (DOI)000320030000005 ()
Note

Correction in: PLoS Genetics, vol. 11(12):e1005740. doi:10.1371/journal.pgen.1005740

Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2022-01-28Bibliographically approved
Mathioudaki, A., Nordin, J., Karlsson, Å., Murén, E., Hultin-Rosenberg, L., Bianchi, M., . . . Meadows, J.The sex-stratified genetic architecture of ankylosing spondylitis.
Open this publication in new window or tab >>The sex-stratified genetic architecture of ankylosing spondylitis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sexual dimorphism is an emerging feature of ankylosing spondylitis (AS), a chronic rheumatic condition affecting up

to three times more men than women. Using 691 individuals from a Swedish case-control cohort, we revealed that

sex biases are also a hallmark of AS genetic predisposition, and that this multifactorial disease is in part driven by

both rare and common variants. We identified SNPs via the targeted re-sequencing of 7 270 coding and non-coding

loci, and assessed novel patterns of association with both single marker and aggregate loci SKAT tests. The male

specific RUNX3 locus (including rs7414934, OR=2.58, p=1.7x10-5) and female specific MICB SKAT locus (27

variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. Multiple risk variants from

each locus were shown to be functionally active in immune (Jurkat), skin (HaCat) and bone (SaOS-2) cell lines.

Differential patterns of genetic predisposition may point to alternative disease mechanisms in male and female

patients. Genetic and functional analyses demonstrated that risk alleles should not be considered in isolation and that

associated variants would likely affect gene regulation across multiple tissues. This work illustrates the need to

consider the contribution of sex to the genetics of AS and the duality that individual loci may play in the key clinical outcomes of disease.

Keywords
ankylosing spondylitis, SKAT, RUNX3, MICB
National Category
Genetics
Research subject
Molecular Genetics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-390455 (URN)
Available from: 2019-08-10 Created: 2019-08-10 Last updated: 2019-09-24
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