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- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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- Dahlqvist, Johanna, 1979-, et al.
(författare)
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Systematic identification of genomic elements that regulate FCGR2A expression and harbor variants linked with autoimmune disease
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083.
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Tidskriftsartikel (refereegranskat)abstract
- Background: FCGR2A binds antibody–antigen complexes to regulate the abundance of circulating and deposited complexes along with downstream immune and autoimmune responses. Although the abundance of FCRG2A may be critical in immune-mediated diseases, little is known about whether its surface expression is regulated through cis genomic elements and non-coding variants. In the current study, we aimed to characterize the regulation of FCGR2A expression, the impact of genetic variation and its association with autoimmune disease. Methods: We applied CRISPR-based interference and editing to scrutinize 1.7 Mb of open chromatin surrounding the FCGR2A gene to identify regulatory elements. Relevant transcription factors (TFs) binding to these regions were defined through public databases. Genetic variants affecting regulation were identified using luciferase reporter assays and were verified in a cohort of 1996 genotyped healthy individuals using flow cytometry. Results: We identified a complex proximal region and five distal enhancers regulating FCGR2A. The proximal region split into subregions upstream and downstream of the transcription start site, was enriched in binding of inflammation-regulated TFs, and harbored a variant associated with FCGR2A expression in primary myeloid cells. One distal enhancer region was occupied by CCCTC-binding factor (CTCF) whose binding site was disrupted by a rare genetic variant, altering gene expression. Conclusions: The FCGR2A gene is regulated by multiple proximal and distal genomic regions, with links to autoimmune disease. These findings may open up novel therapeutic avenues where fine-tuning of FCGR2A levels may constitute a part of treatment strategies for immune-mediated diseases.
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- Esberg, Anders, et al.
(författare)
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Oral Microbiota Profile in Patients with Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis
- 2022
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Microbiota has been associated with autoimmune diseases, with nasal Staphylococcus aureus being implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV). Little is known about the role of oral microbiota in AAV. In this study, levels of IgG antibodies to 53 oral bacterial species/subspecies were screened using immunoblotting in plasma/serum in pre-symptomatic AAV-individuals (n = 85), matched controls, and established AAV-patients (n = 78). Saliva microbiota from acute-AAV and controls was sequenced from 16s rDNA amplicons. Information on dental status was extracted from a national register. IgG levels against oral bacteria were lower in established AAV versus pre-AAV and controls. Specifically, pre-AAV samples had, compared to controls, a higher abundance of periodontitis-associated species paralleling more signs of periodontitis in established AAV-patients than controls. Saliva microbiota in acute-AAV showed higher within-sample diversity but fewer detectable amplicon-sequence variants and taxa in their core microbiota than controls. Acute-AAV was not associated with increased abundance of periodontal bacteria but species in, e.g., Arthrospira, Staphylococcus, Lactobacillus, and Scardovia. In conclusion, the IgG profiles against oral bacteria differed between pre-AAV, established AAV, and controls, and microbiota profiles between acute AAV and controls. The IgG shift from a pre-symptomatic stage to established disease cooccurred with treatment of immunosuppression and/or antibiotics.
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- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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- Schindler, Louise S., et al.
(författare)
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Associations between abdominal adipose tissue, reproductive span, and brain characteristics in post-menopausal women
- 2022
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Ingår i: NeuroImage. - : ELSEVIER SCI LTD. - 2213-1582. ; 36
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Tidskriftsartikel (refereegranskat)abstract
- The menopause transition involves changes in oestrogens and adipose tissue distribution, which may influence female brain health post-menopause. Although increased central fat accumulation is linked to risk of cardiometabolic diseases, adipose tissue also serves as the primary biosynthesis site of oestrogens post-menopause. It is unclear whether different types of adipose tissue play diverging roles in female brain health post-menopause, and whether this depends on lifetime oestrogen exposure, which can have lasting effects on the brain and body even after menopause. Using the UK Biobank sample, we investigated associations between brain characteristics and visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) in 10,251 post-menopausal females, and assessed whether the relationships varied depending on length of reproductive span (age at menarche to age at menopause). To parse the effects of common genetic variation, we computed polygenic scores for reproductive span. The results showed that higher VAT and ASAT were both associated with higher grey and white matter brain age, and greater white matter hyperintensity load. The associations varied positively with reproductive span, indicating more prominent associations between adipose tissue and brain measures in females with a longer reproductive span. The effects were in general small, but could not be fully explained by genetic variation or relevant confounders. Our findings indicate that associations between abdominal adipose tissue and brain health post-menopause may partly depend on individual differences in cumulative oestrogen exposure during reproductive years, emphasising the complexity of neural and endocrine ageing processes in females.
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