| 1. |
- 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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| 2. |
- Johanneson, B, et al.
(författare)
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A comparison of genome-scans performed in multicase families with systemic lupus erythematosus from different population groups
- 1999
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 13, s. 137-
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE.
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| 3. |
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| 4. |
- Sigurdsson, S, et al.
(författare)
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Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus
- 2005
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 76:3, s. 528-37
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms ( SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes - the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes - we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P < 10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.
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| 5. |
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| 6. |
- Delgado-Vega, Angélica M., et al.
(författare)
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Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 8775-
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Tidskriftsartikel (refereegranskat)abstract
- In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D)J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level.
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| 8. |
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| 9. |
- Johansson, C. M., et al.
(författare)
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Characterization of a susceptibility locus for SLE, SLEB5, on chromosome 4p14-13
- 2006
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 64:3, s. 308-313
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus is a systemic autoimmune disorder of unknown aetiology but is most likely caused by an interaction between several genetic factors and the environment. In a previously published genome scan we presented linkage to a marker on chromosome 4p13 in Icelandic families. Fine mapping of the region has been performed using 10 multicase families from Iceland and the maximum two-point LOD score was given by marker D4S2974 (Z = 3.57, alpha = 1). Multipoint analyses of the markers in the region suggest a putative disease gene to be located between markers D4S405 and D4S2381. The maximum multipoint LOD score (Z = 3.76) was given for marker D4S2974 in combination with the novel repeat GT4C2. A family-specific haplotype was segregating with the disease in each of eight families although a founder haplotype could not be identified. Analysis of recombination events in the patients delimited the susceptibility locus to approximately 3 cM. The susceptibility locus identified probably contains a mutation that has been enriched in the Icelandic population but is less common in other populations. We also show that this region is not identical to a susceptibility locus for SLE located on 4p16 where we detect no linkage.
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| 10. |
- Kristjánsdóttir, Helga, 1966-, et al.
(författare)
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A study of the genetic basis of C4A protein deficiency. Detection of C4A gene deletion by long-range PCR and its associated haplotypes.
- 2004
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 33:6, s. 417-22
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Study the frequency of C4A gene deletions as the genetic basis of C4A protein deficiency (C4AQ0) and its associated haplotypes in Icelandic SLE families. Materials and methods: Nine multiplex SLE families were genotyped for C4A gene deletions using LR-PCR and MHC haplotypes were defined. Results: Of SLE patients, first- and second-degree relatives, 53,8%, 47,9% and 28,6% had C4AQ0, respectively. A C4A gene deletion is the genetic basis for C4AQ0 in 64,3% of SLE patients, 60,0% of first-degree and 50,0% of second-degree relatives. All individuals carrying haplotype B8-C4AQ0-C4B1-DR3 had a deletion and the deletion was also found on haplotypes B8-C4AQ0-C4B1-DR7 and B7-C4AQ0-C4B1-DR3. Conclusion: The study shows that a C4A gene deletion is the most common genetic basis for C4AQ0. It accounts for 2/3 of C4AQ0 and is found on different MHC haplotypes. 1/3 of C4AQ0 is due to other yet undefined genetic changes. The results thus demonstrate a heterogeneous genetic background for C4AQ0, giving further support for the hypothesis that C4AQ0 may be an independent risk factor for SLE.
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