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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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| 2. |
- Grondal, G, et al.
(författare)
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Increased T-lymphocyte apoptosis/necrosis and IL-10 producing cells in patients and their spouses in Icelandic systemic lupus erythematosus multicase families
- 2002
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 11:7, s. 435-442
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate apoptosis and production of IL-10 in SLE patients, their spouses and first-degree relatives in Icelandic SLE multicase families. Previously, increased IL-10 production has been found in all three groups. As IL-10 has been found to induce apoptosis in SLE, the percentage of lymphocytes undergoing apoptosis was evaluated, as well as the possible correlation between apoptosis and IL-10 production. Apoptosis and IL-10 production were studied in SLE patients (n = 12) from SLE multicase families and their spouses (n = 12) and a matched control group of healthy individuals(n = 10). The proportion of T and B lymphocytes undergoing apoptosis at 0, 24, 48 and 72 h was detected by flow cytometry using Annexin V and PI staining and the rate of apoptosis was calculated. IL-10 production was studied simultaneously by ELISpot analysis of freshly isolated peripheral blood mononuclear cells. In addition, T lymphocyte apoptosis at t = 0 was investigated in a group of non-household first-degree relatives (n = 10) and controls (n = 10). Antinuclear and antilymphocyte antibodies were analysed in all the groups. The SLE patients as a group had a significantly increased percentage of T lymphocytes in apoptosis at 0 and 48 h and a significantly higher number of IL-10 producing cells as compared with the healthy controls (P = 0.03, 0.02 and 0.03, respectively). The spouses also had significantly increased percentage of T lymphocytes in apoptosis (t = 0) and a significantly higher number of IL-10-producing cells when compared with healthy controls (P = 0.01 and 0.02, respectively). There were no significant differences between the patients and their spouses. For apoptosis of B lymphocytes no difference was found between the groups. The SLE patients as a group had the highest rate of apoptosis. No correlation between the degree and rate of apoptosis and the number of IL-10-producing cells was detected. The first-degree relatives did not have increased percentage of T lymphocytes undergoing apoptosis at t = 0 compared with healthy controls. The SLE patients had higher titres of ANA compared with the other groups. No correlation was detected between the ANA titre and the percentage of lymphocytes undergoing apoptosis. There was no correlation between disease activity as measured by SLEDAI and apoptosis. In conclusion, our results suggest that environmental factors common to both SLE patients and their spouses are associated both with the increased apoptosis and increased spontaneousproduction of IL-10, thus providing support for the notion that both environmental and genetic factors influencing apoptosis are of importance for the development of SLE.
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| 3. |
- 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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| 5. |
- Olafsson, S, et al.
(författare)
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Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
- 2017
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 2, s. 24-
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Tidskriftsartikel (refereegranskat)abstract
- A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10−7, 4.3 × 10−9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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