| 1. |
- Saevarsdottir, S., et al.
(author)
-
Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
-
Journal article (peer-reviewed)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.
|
|
| 2. |
- Mikaelsdottir, E, et al.
(author)
-
Genetic variants associated with platelet count are predictive of human disease and physiological markers
- 2021
-
In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1, s. 1132-
-
Journal article (peer-reviewed)abstract
- Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Oddsson, Asmundur, et al.
(author)
-
Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
-
In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Journal article (peer-reviewed)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
|
|
| 7. |
|
|
| 8. |
- Ajore, Ram, et al.
(author)
-
Functional dissection of inherited non-coding variation influencing multiple myeloma risk
- 2022
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
-
Journal article (peer-reviewed)abstract
- Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
|
|
| 9. |
- Duran-Lozano, Laura, et al.
(author)
-
Germline variants at SOHLH2 influence multiple myeloma risk
- 2021
-
In: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 11:4
-
Journal article (peer-reviewed)abstract
- Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
- Halldorsson, K, et al.
(author)
-
CT after emergency surgery in penetrating trauma: a seven-year experience in a level I Nordic trauma center
- 2023
-
In: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 64:2, s. 684-689
-
Journal article (peer-reviewed)abstract
- Patients with severe penetrating trauma may require emergency surgery on arrival, and postoperative computed tomography (CT) can reveal significant additional injuries. Purpose To determine the utility of postoperative CT performed within 48 h of emergency surgery after penetrating trauma. Material and Methods Trauma registry data were retrieved over a seven-year period at a single level 1 trauma center. All patients aged ≥17 years, admitted with penetrating injury, who underwent urgent surgery and postoperative CT imaging within 48 h, were included. Pre- and intraoperative medical records were compared to CT findings. Age, sex, Injury Severity Score (ISS), New Injury Severity Score (NISS), 30-day mortality, injury mechanism, surgical intervention, and intensive care unit length of stay were extracted. Results Out of 1262 patients, 38 fulfilled the study criteria (36 men [94.7%], 2 women [5.3%]; mean age = 31.5 years. Stab wound (SW) was the most common injury mechanism (26/38, 68.4%) followed by gunshot wound (GSW; 10/38, 26.3%). Patients with GSWs were more severely injured than SW victims (median NISS = 34 [range = 3–75]; for GSWs = 34; for SWs = 26; P = 0.045). Out of 38 patients, 20 (52.6%) had additional findings at postoperative CT. Six patients (15.8%) had unidentified or underestimated findings at CT that were severe enough to warrant additional surgery or angiography. Conclusion Postoperative CT imaging after emergency surgery in penetrating trauma is an important tool in evaluating the injury panorama. Out of 38 patients, 6 (15.8%) had findings at postoperative CT that warranted additional surgical or angiographic intervention.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Poteser, M, et al.
(author)
-
Time Trends of Acrylamide Exposure in Europe: Combined Analysis of Published Reports and Current HBM4EU Studies
- 2022
-
In: Toxics. - : MDPI AG. - 2305-6304. ; 10:8
-
Journal article (peer-reviewed)abstract
- More than 20 years ago, acrylamide was added to the list of potential carcinogens found in many common dietary products and tobacco smoke. Consequently, human biomonitoring studies investigating exposure to acrylamide in the form of adducts in blood and metabolites in urine have been performed to obtain data on the actual burden in different populations of the world and in Europe. Recognizing the related health risk, the European Commission responded with measures to curb the acrylamide content in food products. In 2017, a trans-European human biomonitoring project (HBM4EU) was started with the aim to investigate exposure to several chemicals, including acrylamide. Here we set out to provide a combined analysis of previous and current European acrylamide biomonitoring study results by harmonizing and integrating different data sources, including HBM4EU aligned studies, with the aim to resolve overall and current time trends of acrylamide exposure in Europe. Data from 10 European countries were included in the analysis, comprising more than 5500 individual samples (3214 children and teenagers, 2293 adults). We utilized linear models as well as a non-linear fit and breakpoint analysis to investigate trends in temporal acrylamide exposure as well as descriptive statistics and statistical tests to validate findings. Our results indicate an overall increase in acrylamide exposure between the years 2001 and 2017. Studies with samples collected after 2018 focusing on adults do not indicate increasing exposure but show declining values. Regional differences appear to affect absolute values, but not the overall time-trend of exposure. As benchmark levels for acrylamide content in food have been adopted in Europe in 2018, our results may imply the effects of these measures, but only indicated for adults, as corresponding data are still missing for children.
|
|
| 19. |
|
|
| 20. |
|
|
