Abstract
Predicting all-cause mortality risk is challenging and requires extensive medical data. Recently, large-scale proteomics datasets have proven useful for predicting health-related outcomes. ...Here, we use measurements of levels of 4,684 plasma proteins in 22,913 Icelanders to develop all-cause mortality predictors both for short- and long-term risk. The participants were 18-101 years old with a mean follow up of 13.7 (sd. 4.7) years. During the study period, 7,061 participants died. Our proposed predictor outperformed, in survival prediction, a predictor based on conventional mortality risk factors. We could identify the 5% at highest risk in a group of 60-80 years old, where 88% died within ten years and 5% at the lowest risk where only 1% died. Furthermore, the predicted risk of death correlates with measures of frailty in an independent dataset. Our results show that the plasma proteome can be used to assess general health and estimate the risk of death.
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
). 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.
Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP ...using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P < 5 × 10
); seven common (minor allele frequency >5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP.
Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We ...performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in
, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in
results in exon skipping. We also observe an association with a missense variant in
(OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary ...atherosclerosis.
To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis.
This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait.
Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides.
The extent of angiographic CAD and coronary artery calcium quantity.
A total of 12 460 adults (mean SD age, 65.1 10.7 years; 8383 men 67.3%) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL to convert to millimoles per liter, multiply by 0.0259) was associated with greater odds of obstructive CAD (odds ratio OR, 1.83 95% CI, 1.63-2.07; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 95% CI, 1.11-1.44; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 95% CI, 1.26-1.72; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 95% CI, 1.70-2.44; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 95% CI, 0.53-0.87; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol.
In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.
The leucine-rich repeat containing 8A (LRRC8A) protein is an essential component of the volume-sensitive organic anion channel (VSOAC), and using pharmacological anion channel inhibitors (NS3728, ...DIDS) and LRRC8A siRNA we have investigated its role in development of Cisplatin resistance in human ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21(Waf1/Cip1), Bax, Noxa, MDM2, and activation of Caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter apoptosis, i.e., their p53 and downstream signaling are reduced and caspase activity unaltered following Cisplatin exposure. Reduced LRRC8A expression and VSOAC activity are previously shown to correlate with Cisplatin resistance, and here we demonstrate that pharmacological inhibition and transient knockdown of LRRC8A reduce the protein level of p53, MDM2, and p21(Waf1/Cip1) as well as Caspase-9/-3 activation in Cisplatin-sensitive cells. Cisplatin resistance is accompanied by reduction in total LRRC8A expression (A2780) or LRRC8A expression in the plasma membrane (A549). Activation of Caspase-3 dependent apoptosis by TNFα-exposure or hyperosmotic cell shrinkage is almost unaffected by pharmacological anion channel inhibition. Our data indicate 1) that expression/activity of LRRC8A is essential for Cisplatin-induced increase in p53 protein level and its downstream signaling, i.e., Caspase-9/-3 activation, expression of p21(Waf1/Cip1) and MDM2; and 2) that downregulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A-containing channels is upstream to apoptotic volume decrease as hypertonic cell shrinkage induces apoptosis independent of the presence of LRRC8A.
•Relation between geological structures and geothermal resources.•Location of geothermal resources is controlled by fault interaction.•Integration between fieldwork and geophysical data.•Intersection ...of faults increases rock permeability.
The Krafla volcano-geothermal area is located in Northeast Iceland, within the active Northern Volcanic Zone sector of the axial rift and has experienced two eruptions in historical times. The Krafla system displays NNE-SSW oriented fissure swarm, a central volcano and associated geothermal manifestations (i.e. steam and gas emissions, hydrothermal alterations). However, during its exploration and exploitation, several geophysical indications have suggested the occurrence of WNW-ESE trending structures, i.e. near orthogonal with respect to the faults delimiting the axial rift. This paper describes the results of a structural survey carried out in a wide area in the NE-sector of Iceland along the Húsavík-Flatey shear zone and in the Krafla area, measuring fractures and alignments of geothermal manifestations and fissure swarms. The dataset highlights the occurrence of structures oriented in two main trends, i.e. NNW-SSE to NNE-SSW and WNW-ESE. At their intersection, geothermal manifestations and silica sinter deposits commonly occur. Both of these trends have been documented in the Krafla geothermal area and compared with borehole and geophysical data. Our conclusions support that the location of the high-temperature Krafla geothermal area is mainly controlled by the enhanced permeability at the intersection between structures of the axial rift zone and incipient transform faults crossing the Krafla area.
Abstract Background and Aims Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder of purine metabolism, characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine ...(DHA), leading to nephrolithiasis and chronic kidney disease (CKD). Treatment with xanthine oxidoreductase (XOR) inhibitor, allopurinol or febuxostat, reduces DHA excretion and slows or halts CKD progression. The aim of the study was to optimize and validate an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based assay for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma, for monitoring of pharmacotherapy in patients with APRT deficiency. Method The UPLC-MS/MS-based assay was optimized employing the chemometric approach design of experiments, using the software Modde Pro 13 (Sartorius, Umeå, Sweden). The assay was validated and used for absolute quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in plasma samples from both untreated and treated APRTd patients and healthy controls. Results Accuracy and precision were within ±15% for all analytes, and the analytes were stable in plasma for 12 months at −80°C. The median (range) concentration of DHA in plasma samples from six APRT deficiency patients was 204.0 (187.2–315.8) ng/mL when they were untreated and 69.2 (below the limit of quantification BLQ–131.6) ng/mL when treated with allopurinol (400 mg/day), and BLQ when febuxostat (80 mg/day) was the therapeutic agent. The median (range) plasma adenine concentration was 238.1 (218–502) ng/mL in the untreated patients, and 561.1 (418–2104) and 856.0 (726–1711) ng/mL in those on treatment with allopurinol and febuxostat, respectively. DHA was not detected in plasma samples from healthy controls. The median (range) plasma concentration of allopurinol, oxypurinol and febuxostat in patients receiving XOR inhibitor therapy was 1657 (BLQ-3266) ng/mL, 8102 (4778–34906) ng/mL and 109 (BLQ-1657) ng/mL, respectively. Conclusion The UPLC-MS/MS-based assay provides accurate and precise quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma. Measurement of plasma DHA is being implemented as a diagnostic test for APRT deficiency and the full assay for monitoring of XOR inhibitor treatment in patients with the disorder.
Design of experiment (DoE) is a chemometric approach to study the influence of each experimental factor simultaneously at various levels with a predefined number of experiments, considering all ...possible interactions between the factors. In this tutorial special feature article, Margrét Thorsteinsdóttir and colleague provide an overview of the basic concepts of DoE and a strategy for implementation of DoE for the optimization of a quantitative LC‐MS/MS methods. Indeed, DoE is an excellent tool for the development and optimization of hyphenated techniques such as LC‐MS/MS, where several experimental factors need to be simultaneously optimized to obtain maximum sensitivity with adequate resolution between closely eluting peaks. The results are expressed as a mathematical function of the experimental conditions providing a mean to predict and estimate results at levels that were not directly studied. The data can be explored by use of counter plots and response surface plots to visualize how the response is affected by the factors studied and for finding a combination of factor settings that will result in optimum analytical conditions. With better designed experiments, flow of measurements to knowledge can proceed in the most cost‐effective way. Margrét Thorsteinsdóttir (PhD) is Professor at the Faculty of Pharmaceutical Science at the University of Iceland (Reykjavik, Iceland). Her main research interest is focused on the development of high‐performance separation science with applications in clinical MS.
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