Publications by authors named "Per Eriksson"

311 Publications

The proteome of the human endolymphatic sac endolymph.

Sci Rep 2021 Jun 4;11(1):11850. Epub 2021 Jun 4.

Department of Chemistry - BMC, Analytical Chemistry, Uppsala University, Uppsala, Sweden.

The endolymphatic sac (ES) is the third part of the inner ear, along with the cochlea and vestibular apparatus. A refined sampling technique was developed to analyse the proteomics of ES endolymph. With a tailored solid phase micro-extraction probe, five ES endolymph samples were collected, and six sac tissue biopsies were obtained in patients undergoing trans-labyrinthine surgery for sporadic vestibular schwannoma. The samples were analysed using nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) to identify the total number of proteins. Pathway identification regarding molecular function and protein class was presented. A total of 1656 non-redundant proteins were identified, with 1211 proteins detected in the ES endolymph. A total of 110 proteins were unique to the ES endolymph. The results from the study both validate a strategy for in vivo and in situ human sampling during surgery and may also form a platform for further investigations to better understand the function of this intriguing part of the inner ear.
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http://dx.doi.org/10.1038/s41598-021-89597-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178308PMC
June 2021

Successful Treatment of AA Amyloidosis in Ankylosing Spondylitis Using Tocilizumab: Report of Two Cases and Review of the Literature.

Front Med (Lausanne) 2021 26;8:661101. Epub 2021 Apr 26.

Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden.

Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis.
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http://dx.doi.org/10.3389/fmed.2021.661101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107218PMC
April 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

Relative survival after aortic valve surgery in patients with bicuspid aortic valves.

Heart 2021 Feb 23. Epub 2021 Feb 23.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Objectives: The objective of this cohort study was to analyse long-term relative survival in patients with bicuspid aortic valve (BAV) who underwent aortic valve surgery.

Methods: We studied 865 patients with BAVs who participated in three prospective cohort studies of elective, open-heart, aortic valve surgery at the Karolinska University Hospital, Stockholm, Sweden, between 2007 and 2020. The expected survival for the age, sex and calendar year-matched general Swedish population was obtained from the Human Mortality Database. The Ederer II method was used to calculate relative survival, which was used as an estimate of cause-specific survival.

Results: No differences were found in the observed versus expected survival at 1, 5, 10 or 12 years: 99%, 94%, 83% and 76% vs 99%, 93%, 84% and 80%, respectively. The relative survival at 1, 5, 10 and 12 years was 100% (95% CI 99% to 100%), 101% (95% CI 99% to 103%), 99% (95% CI 95% to 103%) and 95% (95% CI 87% to 102%), respectively. The relative survival at the end of follow-up tended to be lower for women than men (86% vs 95%). The mean follow-up was 6.3 years (maximum 13.3 years).

Conclusions: The survival of patients with BAV following aortic valve surgery was excellent and similar to that of the general population. Our results suggest that the timing of surgery according to current guidelines is correct and provide robust long-term survival rates, as well as important information about the natural history of BAV in patients following aortic valve surgery.
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http://dx.doi.org/10.1136/heartjnl-2020-318733DOI Listing
February 2021

Pre- and postoperative left atrial and ventricular volumetric and deformation analyses in severe aortic regurgitation.

Cardiovasc Ultrasound 2021 Feb 14;19(1):14. Epub 2021 Feb 14.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Background: The impact of volume overload due to aortic regurgitation (AR) on systolic and diastolic left ventricular (LV) indices and left atrial remodeling is unclear. We assessed the structural and functional effects of severe AR on LV and left atrium before and after aortic valve replacement.

Methods: Patients with severe AR scheduled for aortic valve replacement (n = 65) underwent two- and three-dimensional echocardiography, including left atrial strain imaging, before and 1 year after surgery. A control group was selected, and comprised patients undergoing surgery for thoracic aortic aneurysm without aortic valve replacement (n = 20). Logistic regression analysis was used to assess predictors of impaired left ventricular functional and structural recovery, defined as a composite variable of diastolic dysfunction grade ≥ 2, EF < 50%, or left ventricular end-diastolic volume index above the gender-specific normal range.

Results: Diastolic dysfunction was present in 32% of patients with AR at baseline. Diastolic LV function indices and left atrial strain improved, and both left atrial and LV volumes decreased in the AR group following aortic valve replacement. Preoperative left atrial strain during the conduit phase added to left ventricular end-systolic volume index for the prediction of impaired LV functional and structural recovery after aortic valve replacement (model p < 0.001, accuracy 70%; addition of left atrial strain during the conduit phase to end-systolic volume index p = 0.006).

Conclusions: One-third of patients with severe AR had signs of diastolic dysfunction. Aortic valve surgery reduced LV and left atrial volumes and improved diastolic indices. Left atrial strain during the conduit phase added to the well-established left ventricular end-diastolic dimension for the prediction of impaired left ventricular functional and structural recovery at follow-up. However, long-term follow-up studies with hard endpoints are needed to assess the value of left atrial strain as predictor of myocardial recovery in aortic regurgitation.
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http://dx.doi.org/10.1186/s12947-021-00243-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883437PMC
February 2021

The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals.

Sci Rep 2021 Jan 12;11(1):632. Epub 2021 Jan 12.

Institute of Health and Wellbeing, University of Glasgow, Room 111, Public Health, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK.

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.
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http://dx.doi.org/10.1038/s41598-020-79964-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804422PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Host Range of Influenza A Virus H1 to H16 in Eurasian Ducks Based on Tissue and Receptor Binding Studies.

J Virol 2021 02 24;95(6). Epub 2021 Feb 24.

Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

Dabbling and diving ducks partly occupy shared habitats but have been reported to play different roles in wildlife infectious disease dynamics. Influenza A virus (IAV) epidemiology in wild birds has been based primarily on surveillance programs focused on dabbling duck species, particularly mallard (). Surveillance in Eurasia has shown that in mallards, some subtypes are commonly (H1 to H7 and H10), intermediately (H8, H9, H11, and H12), or rarely (H13 to H16) detected, contributing to discussions on virus host range and reservoir competence. An alternative to surveillance in determining IAV host range is to study virus attachment as a determinant for infection. Here, we investigated the attachment patterns of all avian IAV subtypes (H1 to H16) to the respiratory and intestinal tracts of four dabbling duck species ( and spp.), two diving duck species ( spp.), and chicken, as well as to a panel of 65 synthetic glycan structures. We found that IAV subtypes generally showed abundant attachment to colon of the duck species, mallard, and Eurasian teal (), supporting the fecal-oral transmission route in these species. The reported glycan attachment profile did not explain the virus attachment patterns to tissues but showed significant attachment of duck-originated viruses to fucosylated glycan structures and H7 virus tropism for Neu5Gc-LN. Our results suggest that ducks play an important role in the ecology and epidemiology of IAV. Further knowledge on virus tissue attachment, receptor distribution, and receptor binding specificity is necessary to understand the mechanisms underlying host range and epidemiology of IAV. Influenza A viruses (IAVs) circulate in wild birds worldwide. From wild birds, the viruses can cause outbreaks in poultry and sporadically and indirectly infect humans. A high IAV diversity has been found in mallards (), which are most often sampled as part of surveillance programs; meanwhile, little is known about the role of other duck species in IAV ecology and epidemiology. In this study, we investigated the attachment of all avian IAV hemagglutinin (HA) subtypes (H1 to H16) to tissues of six different duck species and chicken as an indicator of virus host range. We demonstrated that the observed virus attachment patterns partially explained reported field prevalence. This study demonstrates that dabbling ducks of the genus are potential hosts for most IAV subtypes, including those infecting poultry. This knowledge is useful to target the sampling of wild birds in nature and to further study the interaction between IAVs and birds.
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http://dx.doi.org/10.1128/JVI.01873-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094940PMC
February 2021

De novo lupus nephritis during treatment with belimumab.

Rheumatology (Oxford) 2020 Dec 20. Epub 2020 Dec 20.

Rheumatology/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping.

Objective: In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting.

Methods: Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2).

Results: We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).

Conclusion: Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.
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http://dx.doi.org/10.1093/rheumatology/keaa796DOI Listing
December 2020

High-Frequency Ultrasound of Multiple Arterial Areas Reveals Increased Intima Media Thickness, Vessel Wall Appearance, and Atherosclerotic Plaques in Systemic Lupus Erythematosus.

Front Med (Lausanne) 2020 9;7:581336. Epub 2020 Oct 9.

Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

Despite improved therapies and management, patients with systemic lupus erythematosus (SLE) still have increased risks of cerebrovascular and cardiovascular disease. High-frequency ultrasound (US) provides an opportunity to distinguish atherosclerosis from inflammation in the vessels. We hypothesized that an extended US protocol may add information regarding vascular affection in SLE. Sixty patients (52 women, 8 men; mean age 43.2 ± 11.3 years) with SLE characterized by either lupus nephritis (LN; = 20), antiphospholipid syndrome (APS; = 20), or skin and joint involvement ( = 20) as well as matched healthy controls ( = 60) were included. Intima-media thickness (IMT), assessment of vessel walls, and plaque occurrence were recorded using high-frequency US (GE Logic E9) in common carotid, internal carotid, brachiocephalic, subclavian, axillary, common femoral, and proximal superficial femoral arteries as well as in the aortic arch. For the entire SLE group, IMT was increased in the internal carotid artery (0.52 ± 0.17 vs. 0.45 ± 0.09 mm, = 0.004), the common femoral artery (0.57 ± 0.23 vs. 0.49 ± 0.11 mm, < 0.01), the subclavian artery (0.58 ± 0.19 vs. 0.53 ± 0.13 mm, = 0.02), and the aortic arch (1.21 ± 0.63 vs. 0.98 ± 0.25 mm, = 0.002) compared to controls. These differences were primarily observed in the APS and LN groups compared to controls. Vessels with increased IMT ≥0.9 mm had a smooth, medium echogenic appearance in areas free of atherosclerotic plaques. Atherosclerotic plaques were detected in 15/60 patients (25%) as compared to 2/60 of the controls (3%). Plaques were predominantly (67%) located in the carotid bifurcation. Multivariate analysis revealed influence of age on IMT in all vessel areas. Furthermore, in the common femoral artery, sagittal abdominal diameter, diastolic blood pressure, and cholesterol all showed association with increased IMT. In the internal carotid artery, male sex and presence of Raynaud phenomenon influenced IMT. Among SLE patients without presence of plaques, an extended US protocol revealed increased wall thickness with predominantly medium echogenic appearance highlighting possibly inflammation or early atherosclerosis. The appearance of vessel walls has not previously been studied in detail. An increased number of plaques were found in SLE compared to age- and sex-matched healthy controls. We found similar risk factors for increased IMT and occurrence of plaques, possibly indicating atherosclerotic mechanisms rather than inflammation.
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http://dx.doi.org/10.3389/fmed.2020.581336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581856PMC
October 2020

Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease Do Not Associate with Measures of Sub-Clinical Atherosclerosis: Results from the IMPROVE Study.

Genes (Basel) 2020 10 22;11(11). Epub 2020 Oct 22.

Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden.

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study ( = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels ( < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMT and c-IMT ( = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development.
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http://dx.doi.org/10.3390/genes11111243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690395PMC
October 2020

Cigarette smoking patterns preceding primary Sjögren's syndrome.

RMD Open 2020 Sep;6(3)

Division of Rheumatology, Department of Medicine Solna, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjögren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.

Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.

Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.

Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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http://dx.doi.org/10.1136/rmdopen-2020-001402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547543PMC
September 2020

Tunica-Specific Transcriptome of Abdominal Aortic Aneurysm and the Effect of Intraluminal Thrombus, Smoking, and Diameter Growth Rate.

Arterioscler Thromb Vasc Biol 2020 11 10;40(11):2700-2713. Epub 2020 Sep 10.

Department of Molecular Medicine and Surgery (M.L.L., R.H., C.V., M.K., J.R.), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Objective: There is no medical treatment to prevent abdominal aortic aneurysm (AAA) growth and rupture, both of which are linked to smoking. Our objective was to map the tunica-specific pathophysiology of AAA with consideration of the intraluminal thrombus, age, and sex, and to subsequently identify which mechanisms were linked to smoking and diameter growth rate. Approach and Results: Microarray analyses were performed on 246 samples from 76 AAA patients and 13 controls. In media and adventitia, there were 5889 and 2701 differentially expressed genes, respectively. Gene sets related to adaptive and innate immunity were upregulated in both tunicas. Media-specific gene sets included increased matrix disassembly and angiogenesis, as well as decreased muscle cell development, contraction, and differentiation. Genes implicated in previous genome-wide association studies were dysregulated in media. The intraluminal thrombus had a pro-proteolytic and proinflammatory effect on the underlying media. Active smoking resulted in increased inflammation, oxidative stress, and angiogenesis in all tissues and enriched lipid metabolism in adventitia. Processes enriched with active smoking in control aortas overlapped to a high extent with those differentially expressed between AAAs and controls. The AAA diameter growth rate (n=24) correlated with T- and B-cell expression in media, as well as lipid-related processes in the adventitia.

Conclusions: This tunica-specific analysis of gene expression in a large study enabled the detection of features not previously described in AAA disease. Smoking was associated with increased expression of aneurysm-related processes, of which adaptive immunity and lipid metabolism correlated with growth rate.
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http://dx.doi.org/10.1161/ATVBAHA.120.314264DOI Listing
November 2020

Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome.

Rheumatology (Oxford) 2021 02;60(2):837-848

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.

Objectives: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.

Methods: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.

Results: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS.

Conclusion: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.
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http://dx.doi.org/10.1093/rheumatology/keaa367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850528PMC
February 2021

Molecular Imaging of Inflammation in a Mouse Model of Atherosclerosis Using a Zirconium-89-Labeled Probe.

Int J Nanomedicine 2020 14;15:6137-6152. Epub 2020 Aug 14.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, BioClinicum, Karolinska Institutet, Stockholm, SE 17176, Sweden.

Background: Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions.

Materials And Methods: Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 (Zr). The targeting potential of this probe was compared with unspecific Zr-HSA and F-FDG in an experimental model of atherosclerosis ( mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls.

Results: PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of Zr-Mal-HSA in the atherosclerotic lesions of mice. The maximum standardized uptake values (SUV) for Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (<0.05) in mice than in control WT mice, whereas no difference in SUV was observed for F-FDG in the same animals. Zr-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher (<0.01) for mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher (<0.001) for Zr-Mal-HSA compared with unspecific Zr-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of Zr-Mal-HSA in the aortas of mice than in WT mice (9.4±1.4 vs 0.8±0.3%; <0.001).

Conclusion: Zr radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of mice, as demonstrated by quantitative in vivo PET/MRI. Zr-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis.
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http://dx.doi.org/10.2147/IJN.S256395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434576PMC
November 2020

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis.

Cells 2020 07 16;9(7). Epub 2020 Jul 16.

Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, 171 77 Stockholm, Sweden.

Calcific aortic valve stenosis (CAVS) is a common age-related disease characterized by active calcification of the leaflets of the aortic valve. How innate immune cells are involved in disease pathogenesis is not clear. In this study we investigate the role of the pattern recognition receptor Toll-like receptor 7 (TLR7) in CAVS, especially in relation to macrophage subtype. Human aortic valves were used for mRNA expression analysis, immunofluorescence staining, or ex vivo tissue assays. Response to TLR7 agonist in primary macrophages and valvular interstitial cells (VICs) were investigated in vitro. In the aortic valve, TLR7 correlated with M2 macrophage markers on mRNA levels. Expression was higher in the calcified part compared with the intermediate and healthy parts. TLR7 cells were co-stained with M2-type macrophage receptors CD163 and CD206. Ex vivo stimulation of valve tissue with the TLR7 ligand imiquimod significantly increased secretion of IL-10, TNF-α, and GM-CSF. Primary macrophages responded to imiquimod with increased secretion of IL-10 while isolated VICs did not respond. In summary, in human aortic valves TLR7 expression is associated with M2 macrophages markers. Ex vivo tissue challenge with TLR7 ligand led to secretion of immunomodulatory cytokine IL-10. These results connect TLR7 activation in CAVS to reduced inflammation and improved clearance.
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http://dx.doi.org/10.3390/cells9071710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407122PMC
July 2020

Promoter anchored interaction landscape of THP-1 macrophages captures early immune response processes.

Cell Immunol 2020 09 12;355:104148. Epub 2020 Jun 12.

KTH Royal Institute of Technology, School of Chemistry, Biotechnology and Health, Science for Life Laboratory, Tomtebodavägen 23A, 171 65 Stockholm, Sweden. Electronic address:

Macrophages are highly plastic immune cells with temporally distinct transcriptome changes upon lipopolysaccride (LPS) activation. However, to what extent transcriptome reprogramming is mediated via spatial chromatin looping is not well studied. We generated high resolution chromatin interaction maps for LPS-stimulated THP-1 macrophages (0 and 2 h) using capture Hi-C. Success of LPS stimulation was validated with transcriptome sequencing. Circa 2900 genes changed their interaction profile upon LPS stimulation and those gaining interactions were enriched for LPS response relevant processes, suggesting a substantial role for distal regulation. Immune and cardiovascular risk variants were enriched within the interacting regions, thereby providing insights into macrophage biology.
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http://dx.doi.org/10.1016/j.cellimm.2020.104148DOI Listing
September 2020

FADS1 (Fatty Acid Desaturase 1) Genotype Associates With Aortic Valve FADS mRNA Expression, Fatty Acid Content and Calcification.

Circ Genom Precis Med 2020 06 12;13(3):e002710. Epub 2020 May 12.

Department of Medicine Solna, Unit of Cardiovascular Medicine (O.P., G.A., M.C., P.E., M.B.), Karolinska Institutet, Stockholm.

Background: Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within the gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS. encodes a rate-limiting enzyme for ω-3 and ω-6 fatty acid metabolism. The aim of this study was to decipher the local transcriptomic and lipidomic consequences of rs174547 in tricuspid aortic valves from patients with AS.

Methods: Expression quantitative trait loci study was performed using data from Illumina Human610-Quad BeadChip, Infinium Global Screening Arrays, and Affymetrix Human Transcriptome 2.0 arrays in calcified and noncalcified aortic valve tissue from 58 patients with AS (mean age, 74.2; SD, 5.9). Fatty acid content was assessed in aortic valves from 25 patients with AS using gas chromatography. 5 and 6 desaturase activity was assessed by the product-to-precursor ratio.

Results: The minor C-allele of rs174547, corresponding to the protective genotype for AS, was associated with higher FADS2 mRNA levels in calcified valve tissue, whereas FADS1 mRNA and other transcripts in proximity of the single nucleotide polymorphism were unaltered. In contrast, the FADS1 5-desaturase activity and the FADS2 6-desaturase activity were decreased. Finally, docosahexaenoic acid was decreased in calcified tissue compared with non-calcified tissue and C-allele carriers exhibited increased docosahexaenoic acid levels. Overall desaturase activity measured with ω-3 fatty acids was higher in C-allele carriers.

Conclusions: The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.
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http://dx.doi.org/10.1161/CIRCGEN.119.002710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299231PMC
June 2020

Hearing outcome after myringoplasty in Sweden: A nationwide registry-based cohort study.

Clin Otolaryngol 2020 05 20;45(3):357-363. Epub 2020 Feb 20.

Department of Clinical Sciences, Otorhinolaryngology, Umeå University, site Sundsvall, Umeå, Sweden.

Objectives: To present hearing results after successful primary myringoplasty surgeries registered in the Swedish Quality Registry for Myringoplasty and to evaluate the chance of hearing improvement and the risk of hearing loss.

Design: A retrospective nationwide cohort study based on prospectively collected registry data between 2002 and 2012.

Settings: Registry data from secondary and tertiary hospitals performing myringoplasty.

Participants: Patients with healed tympanic membrane after primary myringoplasty surgery performed from 2002 to 2012 in Sweden.

Main Outcome Measures: Postoperative hearing results, hearing gain and air-bone gap (ABG).

Results: In 2226 myringoplasties, air conduction audiograms were recorded, and the average preoperative pure tone average (PTA ) of the group was 28.5 dB, which improved postoperatively to 19.6 dB with an average of 8.8 dB improvement. Bone conduction was measured for 1476 procedures. Closure of the ABG to 10 dB or less was achieved in 51% of the ears and to less than 20 dB in 89% of the ears. Sixty-one percent of patients with preoperatively deteriorated hearing experienced improved hearing, but 3% of all patients experienced deteriorated hearing. After the surgery, 93% of the patients were satisfied.

Conclusions: Hearing results after successful myringoplasty surgery are often favourable, but although the tympanic membrane is healed, hearing improvement is not guaranteed, and hearing deterioration can also occur.
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http://dx.doi.org/10.1111/coa.13506DOI Listing
May 2020

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve.

Front Cardiovasc Med 2019 17;6:182. Epub 2019 Dec 17.

Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden.

Thoracic aortic aneurysm (TAA) is the progressive enlargement of the aorta due to destructive changes in the connective tissue of the aortic wall. Aneurysm development is silent and often first manifested by the drastic events of aortic dissection or rupture. As yet, therapeutic agents that halt or reverse the process of aortic wall deterioration are absent, and the only available therapeutic recommendation is elective prophylactic surgical intervention. Being born with a bicuspid instead of the normal tricuspid aortic valve (TAV) is a major risk factor for developing aneurysm in the ascending aorta later in life. Although the pathophysiology of the increased aneurysm susceptibility is not known, recent studies are suggestive of a transformation of aortic endothelium into a more mesenchymal state i.e., an endothelial-to-mesenchymal transition in these individuals. This process involves the loss of endothelial cell features, resulting in junction instability and enhanced vascular permeability of the ascending aorta that may lay the ground for increased aneurysm susceptibility. This finding differentiates and further emphasizes the specific characteristics of aneurysm development in individuals with a bicuspid aortic valve (BAV). This review discusses the possibility of a developmental fate shared between the aortic endothelium and aortic valves. It further speculates about the impact of aortic endothelium phenotypic shift on aneurysm development in individuals with a BAV and revisits previous studies in the light of the new findings.
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http://dx.doi.org/10.3389/fcvm.2019.00182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928128PMC
December 2019

PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.

Circ Res 2020 02 2;126(5):571-585. Epub 2020 Jan 2.

From the Department of Molecular Medicine and Surgery, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden (U.R., B.E.S., S.R., A.R., M.L., M.K., U.H., L.M.).

Rationale: PCSKs (Proprotein convertase subtilisins/kexins) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix remodeling, and mitogens.

Objective: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall.

Methods And Results: Genetic analyses revealed association of intronic variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions versus healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localized to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB (platelet-derived growth factor subunit B) and MMP (matrix metalloprotease) 2/MMP14. Here, PCSK6 was shown to colocalize and cointeract with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6 versus control mice revealed suppression of contractile SMC markers, extracellular matrix remodeling enzymes, and cytokines/receptors. Pcsk6 mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro leads to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB (platelet-derived growth factor BB)-induced cell proliferation and particularly migration.

Conclusions: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling. Visual Overview: An online visual overview is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316063DOI Listing
February 2020

Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi.

Int J Mol Sci 2019 Dec 3;20(23). Epub 2019 Dec 3.

Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH (HMGU), 85764 Neuherberg, Germany.

In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind this adverse outcome. Neonatal male NMRI mice were administered ketamine (7.5 mg kg) and irradiated (whole-body, 100 mGy or 200 mGy, Cs) one hour after ketamine exposure on postnatal day 10. The control mice were injected with saline and sham-irradiated. The hippocampi were analyzed using label-free proteomics, immunoblotting, and Golgi staining of CA1 neurons six months after treatment. Mice co-exposed to ketamine and low-dose radiation showed alterations in hippocampal proteins related to neuronal shaping and synaptic plasticity. The expression of brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and postsynaptic density protein 95 were significantly altered only after the combined treatment (100 mGy or 200 mGy combined with ketamine, respectively). Increased numbers of basal dendrites and branching were observed only after the co-exposure, thereby constituting a possible reason for the displayed alterations in behavior. These data suggest that the risk of radiation-induced neurotoxic effects in the pediatric population may be underestimated if based only on the radiation dose.
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http://dx.doi.org/10.3390/ijms20236103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929167PMC
December 2019

Vascular ultrasound for monitoring of inflammatory activity in Takayasu arteritis.

Clin Physiol Funct Imaging 2020 Jan 10;40(1):37-45. Epub 2019 Nov 10.

Department of Clinical Physiology, University Hospital, Linköping, Sweden.

Background: Takayasu arteritis (TA) is a rare large-vessel arteritis that primarily affects the aorta and its major branches. The aim of this study was to describe the value of high frequency ultrasound for monitoring of inflammatory activity.

Methods: Twenty-five patients, range 11-71 years, diagnosed with TA were investigated with duplex ultrasound (DUS) including follow-up studies. Twenty-five healthy controls were also investigated. Nine patients had newly diagnosed active TA. Sixteen patients had stable/inactive disease at baseline DUS, and TA was diagnosed median 4·5 years previously. Intima-media thickness (IMT), vessel and lumen diameter were measured in the carotid arteries, central neck arteries and the aortic arch. The vessel walls were studied qualitatively. The Takayasu ultrasound index was created for inflammatory activity scoring.

Results: Intima-media thickness in common carotid artery (CCA) was (median and 25-75 percentile parenthetic) 2·3 mm (1·7-2·9) in clinically active TA, 1·2 mm (1·1-1·6) in clinically stable TA (P<0·001) and 0·5 mm (0·5-0·6) in healthy controls (P<0·001). Clinically active TA had prominent increase in IMT and/or increased vessel diameter, and/or intramural arteries, and/or hypoechogenic areas interpreted as oedema in the vessel wall. TA in clinical remission was characterized by increased IMT with medium to high echogenicity with or without fibrotic stripes. The Takayasu ultrasound index was higher in patients with active disease versus treated disease, 2·55 (1·60-3·05) versus 1·30 (1·00-1·58), (P = 0·003).

Conclusion: DUS is an excellent tool to monitor inflammatory changes in the vessel wall in TA. Further DUS studies in larger patient populations are warranted.
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http://dx.doi.org/10.1111/cpf.12601DOI Listing
January 2020

Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia.

J Mol Cell Cardiol 2019 12 15;137:1-8. Epub 2019 Sep 15.

Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression.

Materials And Methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP.

Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart.

Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.
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http://dx.doi.org/10.1016/j.yjmcc.2019.09.003DOI Listing
December 2019

Elevated free secretory component in early rheumatoid arthritis and prior to arthritis development in patients at increased risk.

Rheumatology (Oxford) 2020 05;59(5):979-987

Department of Rheumatology, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Objectives: Considering growing evidence of mucosal involvement in RA induction, this study investigated circulating free secretory component (SC) in patients with either recent-onset RA or with ACPA and musculoskeletal pain.

Methods: Two prospective cohorts were studied: TIRA-2 comprising 452 recent-onset RA patients with 3 years of clinical and radiological follow-up, and TIRx patients (n = 104) with ACPA IgG and musculoskeletal pain followed for 290 weeks (median). Blood donors and three different chronic inflammatory diseases served as controls. Free SC was analysed by sandwich ELISA.

Results: Serum levels of free SC were significantly higher in TIRA-2 patients compared with TIRx and all control groups (P < 0.01). Among TIRx patients who subsequently developed arthritis, free SC levels were higher compared with all control groups (P < 0.05) except ankylosing spondylitis (P = 0.74). In TIRA-2, patients with ACPA had higher baseline levels of free SC compared with ACPA negative patients (P < 0.001). Free SC status at baseline did not predict radiographic joint damage or disease activity over time. In TIRx, elevated free SC at baseline trendwise associated with arthritis development during follow-up (P = 0.066) but this disappeared when adjusting for confounders (P = 0.72). Cigarette smoking was associated with higher levels of free SC in both cohorts.

Conclusion: Serum free SC levels are increased in recent-onset RA compared with other inflammatory diseases, and associate with ACPA and smoking. Free SC is elevated before arthritis development among ACPA positive patients with musculoskeletal pain, but does not predict arthritis development. These findings support mucosal engagement in RA development.
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http://dx.doi.org/10.1093/rheumatology/kez348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850007PMC
May 2020

Effect of Treatment on Damage and Hospitalization in Elderly Patients with Microscopic Polyangiitis and Granulomatosis with Polyangiitis.

J Rheumatol 2020 04 15;47(4):580-588. Epub 2019 Jul 15.

From the Department of Nephrology and Department of Medical and Health Sciences, Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, Linköping; Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund; Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institute, Stockholm; Department of Nephrology, Lund University, Skåne University Hospital, Lund and Malmö; University College London Centre for Nephrology, Royal Free Hospital; Department of Medicine, Imperial College London, London; Institute of Clinical Sciences, University of Birmingham, Birmingham; Department of Medicine, University of Cambridge, Cambridge, UK; Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; Department of Renal Medicine, Tan Tock Seng Hospital, Singapore.

Objective: Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown.

Methods: Consecutive patients from Sweden, the United Kingdom, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide (CYC), rituximab (RTX), and corticosteroids the first 3 months was registered. Outcomes up to 2 years from diagnosis included Vasculitis Damage Index (VDI), hospitalization, and cause of death.

Results: Treatment data were available for 167 of 202 patients. At 2 years, 4% had no items of damage. There was a positive association between VDI score at 2 years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using CYC or RTX. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. Myeloperoxidase-antineutrophil cytoplasmic antibody positivity and lower creatinine levels decreased the odds of readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose.

Conclusion: Immunosuppressive treatment with CYC or RTX in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first 3 months was associated with treatment-related damage and fatal infections.
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http://dx.doi.org/10.3899/jrheum.190019DOI Listing
April 2020

A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process.

J Thromb Haemost 2019 11 22;17(11):1808-1814. Epub 2019 Jul 22.

Laboratory of Haematology, La Timone Hospital, Marseille, France.

Background: Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process.

Objective: To detect novel genetic loci participating to the regulation of FV plasma levels.

Methods: We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals.

Results: In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions.

Conclusion: Our study identified PLXDC2 as a new molecular player of the coagulation process.
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http://dx.doi.org/10.1111/jth.14562DOI Listing
November 2019

Comparison of quantitative trait loci methods: Total expression and allelic imbalance method in brain RNA-seq.

PLoS One 2019 17;14(6):e0217765. Epub 2019 Jun 17.

Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden.

Background: Of the 108 Schizophrenia (SZ) risk-loci discovered through genome-wide association studies (GWAS), 96 are not altering the sequence of any protein. Evidence linking non-coding risk-SNPs and genes may be established using expression quantitative trait loci (eQTL). However, other approaches such allelic expression quantitative trait loci (aeQTL) also may be of use.

Methods: We applied both the eQTL and aeQTL analysis to a biobank of deeply sequenced RNA from 680 dorso-lateral pre-frontal cortex (DLPFC) samples. For each of 340 genes proximal to the SZ risk-SNPs, we asked how much SNP-genotype affected total expression (eQTL), as well as how much the expression ratio between the two alleles differed from 1:1 as a consequence of the risk-SNP genotype (aeQTL).

Results: We analyzed overlap with comparable eQTL-findings: 16 of the 30 risk-SNPs known to have gene-level eQTL also had gene-level aeQTL effects. 6 of 21 risk-SNPs with known splice-eQTL had exon-aeQTL effects. 12 novel potential risk genes were identified with the aeQTL approach, while 55 tested SNP-pairs were found as eQTL but not aeQTL. Of the tested 108 loci we could find at least one gene to be associated with 21 of the risk-SNPs using gene-level aeQTL, and with an additional 18 risk-SNPs using exon-level aeQTL.

Conclusion: Our results suggest that the aeQTL strategy complements the eQTL approach to susceptibility gene identification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576752PMC
February 2020