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- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 6. |
- Parodis, I, et al.
(författare)
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Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus - distinct roles of BAFF and APRIL
- 2018
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Ingår i: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 27:9, s. 1470-1478
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/μl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1–15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.
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| 7. |
- Samuelsson, I, et al.
(författare)
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Myocardial infarctions, subtypes and coronary atherosclerosis in SLE: a case-control study
- 2021
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Ingår i: Lupus science & medicine. - : BMJ. - 2053-8790. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Patients with SLE have increased risk of myocardial infarction (MI). Few studies have investigated the characteristics of SLE-related MIs. We compared characteristics of and risk factors for MI between SLE patients with MI (MI-SLE), MI patients without SLE (MI-non-SLE) and SLE patients without MI (non-MI-SLE) to understand underlying mechanisms.MethodsWe identified patients with a first-time MI in the Karolinska SLE cohort. These patients were individually matched for age and gender with MI-non-SLE and non-MI-SLE controls in a ratio of 1:1:1. Retrospective medical file review was performed. Paired statistics were used as appropriate.ResultsThirty-four MI-SLE patients (88% females) with a median age of 61 years were included. These patients had increased number of coronary arteries involved (p=0.04), and ≥50% coronary atherosclerosis/occlusion was numerically more common compared with MI-non-SLE controls (88% vs 66%; p=0.07). The left anterior descending artery was most commonly involved (73% vs 59%; p=0.11) and decreased (<50%) left ventricular ejection fraction occurred with similar frequency in MI-SLE and MI-non-SLE patients (45% vs 36%; p=0.79). Cardiovascular disease (44%, 5.9%, 12%; p<0.001) and coronary artery disease (32%, 2.9%, 0%; p<0.001), excluding MI, preceded MI/inclusion more commonly in MI-SLE than in MI-non-SLE and non-MI-SLE patients, respectively. MI-SLE patients had lower plasma albumin levels than non-MI-SLE patients (35 (29–37) vs 40 (37–42) g/L; p=0.002).ConclusionIn the great majority of cases, MIs in SLE are associated with coronary atherosclerosis. Furthermore, MIs in SLE are commonly preceded by symptomatic vascular disease, calling for attentive surveillance of cardiovascular disease and its risk factors and early atheroprotective treatment.
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| 8. |
- Samuelsson, I, et al.
(författare)
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MYOCARDIAL INFARCTIONS, SUBTYPES, LOCATIONS AND CORONARY ATHEROSCLEROSIS IN SLE - A COMPARATIVE STUDY WITH MATCHED CONTROLS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 643-643
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Myocardial infarction (MI) is estimated to be 2- to 3-fold elevated in systemic lupus erythematosus (SLE) as compared to gender- and age-matched controls (1-2). Even though some risk factors have been purposed, mechanisms of increased MI incidence remains to be determined.Objectives:To explore underlying mechanisms, we compared MI characteristics and risk factors between SLE patients with MI (MI-SLE), MI patients without SLE (MI-nonSLE) and SLE patients without MI (nonMI-SLE).Methods:We performed retrospective medical file review including angiography and echocardiography reports in 34 MI-SLE patients, 34 MI-nonSLE patients and 34 nonMI-SLE patients – all individually matched for gender and age in a ratio of 1:1:1.Results:Median age was 61 years and 88% were females. MI-SLE patients had more coronary arteries involved (table 1; p=0.038), and ≥50% coronary atherosclerosis/occlusion at MI was numerically more common compared to MI-nonSLE controls (88% versus 66%; p=0.065). The left anterior descending artery was most frequently involved in both MI groups (73% versus 59%; p=0.11). Decreased (<50%) left ventricular ejection fraction occurred with similar frequency (45% versus 36%; p=0.79) in MI-SLE patients compared to MI-nonSLE patients. Cardiovascular disease (CVD) (44%, 5.9%, 12%; p<0.001) and coronary artery disease excluding MI (CAD, 32%, 2.9%, 0%; p<0.001) preceded MI/inclusion more commonly in MI-SLE than in MI-nonSLE and nonMI-SLE patients, respectively. MI-SLE patients differed from nonMI-SLE patients through lower plasma albumin levels (35 (29-37) versus 40 (37-42) g/L; p=0.002) and longer disease duration (22 (14-32) versus 14 (6.3-24) years; p=0.038).Conclusion:We demonstrate that non-procedural MIs in SLE are in 88% of cases associated with significant coronary atherosclerosis. Increased prevalence of CAD prior MI and higher number of coronary arteries involved at MI, suggest accelerated coronary atherosclerosis in SLE patients. This calls for attentive surveillance of CVD and early atheroprotective treatment in this patients group.References:[1]Hak AE et al. Systemic lupus erythematosus and the risk of cardiovascular disease: Results from the nurses’ health study. Arthritis and rheumatism 2009;61:1396-402.[2]Fischer LM et. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of first-time acute myocardial infarction. The American journal of cardiology 2004;93:198-200.Table 1.MI characteristicsMI-SLENtotalMI-nonSLENtotalP-valueECG findingsNSTEMI23 (72%)3221 (66%)321.0 STEMIPresence of atherosclerosis9 (28%)3211 (34%)32 0-VD3 (12%)2610 (35%)290.065 MI-CAD (≥1-VD)Number of involved arteries23 (88%)2619 (66%)29 0-VD3 (12%)2610 (35%)290.038 1-VD13 (50%)269 (31%)29 ≥2-VD10 (39%)2610 (35%)29Involvement of specific arteriesLMCA3 (12%)260 (0%)290.50 LAD19 (73%)2617 (59%)290.11 RCA7 (27%)269 (31%)290.75 Cx6 (23%)266 (21%)291.0Left ventricular ejection fraction <50%13 (45%)2912 (36%)330.79 ≥50%16 (55%)2921 (64%)330-VD = 0-Vessel disease. 1-VD = 1-Vessel disease. 2-VD = 2-Vessel disease. Cx = Circumflex artery. LAD = Left anterior descending artery. LMCA = Left main coronary artery. MI-CAD = MI with coronary artery disease. NSTEMI = Non-ST-elevation MI. RCA = Right coronary artery. STEMI = ST-elevation MI.Disclosure of Interests:Isak Samuelsson: None declared, Ioannis Parodis Grant/research support from: The author declare that he has no conflict of interest related to this work, Iva Gunnarsson Grant/research support from: The author declare that she has no conflict of interest related to this work, Agneta Zickert: None declared, Claes Hofman-Bang: None declared, Håkan Wallén Grant/research support from: The author declare that he has no conflict of interest related to this work, Elisabet Svenungsson Grant/research support from: The author declare that she has no conflict of interest related to this work
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| 9. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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