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Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a cardiovascular autonomic disorder characterized by orthostatic intolerance and high prevalence among young women. The etiology of POTS is uncertain, though autoimmunity and inflammation may play an important role. We aimed to identify novel inflammatory biomarkers associated with POTS. Methods and Results: In the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort, we identified 396 patients (age range, 15-50 years) with either POTS ( n = 113) or normal haemodynamic response during passive head-up-tilt test ( n = 283). Blood samples were analyzed using antibody-based Proximity Extension Assay technique simultaneously measuring 57 inflammatory protein biomarkers. The discovery algorithm was a sequential two-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. POTS patients were younger (26 vs. 31 years; p < 0.001) and there was no significant difference in sex distribution (74% vs. 67% females, p = 0.24). PCA and Bonferroni-adjusted ANOVA identified proconvertase furin as the most robust biomarker signature for POTS. Plasma level of proconvertase furin was lower (6.38 vs. 6.58 of normalized protein expression units (NPX); p < 0.001 in POTS, compared with the reference group. Proconvertase furin met Bonferroni-adjusted significance criteria in both uni- and multivariable regression analyses. Conclusion: Patients with POTS have lower plasma level of proconvertase furin compared with individuals with normal postural hemodynamic response. This finding suggests the presence of a specific autoimmune trait with disruption of immune peripheral tolerance in this hitherto unexplained condition. Further studies are needed for external validation of our results.

Objective: Pacemaker (PM) therapy is effective when syncope is associated with bradycardia, but syncope recurrences and fall injuries after PM implantation may occur. We aimed to survey indications and outcomes of PM implantation, following evaluation of unexplained syncope., Methods: Among 1666 consecutive unpaced patients investigated in a tertiary syncope unit by carotid-sinus massage (CSM), head-up tilt test (HUT) and ECG monitoring, 106 (6.4%; age, 65 ± 17 years) received a PM. We assessed bradycardia detection methods, PM implantation indications, and explored incidence of recurrent syncope, fall-related fractures and mortality., Results: Indications for PM therapy were met in 32/106 patients (30%) by CSM, in 41/106 (39%) by HUT, in 14/106 patients (13%) by implantable loop-recorder (ILR) and in 19/106 (18%) by standard ECG. Sinus arrest with asystole was the predominant PM indication during CSM/HUT and external ECG monitoring, whereas ILR detected proportionally the same numbers o f asystole due to sinus arrest and atrioventricular block. During follow-up (median, 4.3 years), 15 patients (14%) had syncope recurrence, 15 suffered fall-related fractures and 9 died. Neither syncope recurrence nor fall-related fractures were dependent on initial PM indication. The composite endpoint of recurrent syncope/fall-related fracture was associated with treated hypertension (OR 2.45; 95% CI 1.00 to 6.0), reduced glomerular filtration rate (OR 1.63 per 10 mL/min↓; 95% CI 1.22 to 2.19) and atrial fibrillation (OR 3.98; 95% CI 1.11 to 14.3). Recurrent syncope predicted increased mortality (OR 9.20; 95% CI 1.89 to 44.8)., Conclusions: Cardiovascular autonomic testing and ECG monitoring effectively identify pacing indications in patients with unexplained syncope. After PM implantation, treated hypertension, renal failure and atrial fibrillation predict syncope recurrence and fall-related injury. Recurrent syncope predicts increased mortality., Competing Interests: Competing interests: AF reports personal fees from Cardiome Corp. and a patent Thermofisher pending outside the submitted work; RS reports personal fees and other from Medtronic Inc., Abbott Laboratories Inc. outside the submitted work; RS performs consultancy for Medtronic Inc.; RS is a member of the speaker’s Bureau of Abbott Laboratories Inc.; RS is shareholder in Boston Scientific Inc., Edwards Lifesciences Inc., and Astrazeneca PLC; no other relationships oractivities that could appear to have influenced the submitted work.

Purpose: This study investigated whether living in immigrant dense urban districts (IDUDs) and low-income areas in the city of Malmö predicted 5-year mortality among patients admitted to the emergency department (ED) because of acute respiratory distress., Patients and Methods: We randomly selected 184 patients with acute respiratory distress during 2007, visiting the ED at Skåne University Hospital, Malmö. In 2007, Malmö had 36% first- and second-generation immigrants. The main exposure was defined as being resident in any of the five IDUDs of Malmö compared to being resident in the five districts of Malmö with the highest proportion of Sweden-born inhabitants (SDUDs). We recorded vital parameters; medical triage priority according to Adaptive Process Triage (ADAPT), ICD-10 diagnoses, and the mean annual income for the patient's urban district. We examined 5-year mortality risk using Cox proportional hazards model., Results: After adjustment for age and gender, patients from IDUDs (n=100, 54%) had an HR (95% CI) of 1.65 (1.087-2.494; P =0.019) regarding mortality at 5-year follow-up. Patients in the lowest vs highest income quartile had an HR of 2.00 (1.06-3.79; P =0.032) regarding mortality at 5-year follow-up. Age, male gender, presence of cardiopulmonary disease, and ADAPT priority also independently predicted the 5-year mortality. The excess risk of 5-year mortality associated with living in IDUDs remained significant after adjustment for age, gender, ADAPT priority, presence of cardiopulmonary disease, and income with an HR of 1.79 (1.15-2.78; P =0.010)., Conclusion: Living in an IDUD is a strong independent risk factor for 5-year mortality in patients with acute respiratory distress. The cause is unknown. Our study suggests a need for better structured follow-up of cardiopulmonary disease in such patients., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Functional data is data represented by functions (curves or surfaces of a low-dimensional index). Functional data often arise when measurements are collected over time or across locations. In the field of medicine, plasma lipoprotein particles can be quantified according to particle diameter by ion mobility., Goal: We wanted to evaluate the utility of functional analysis for assessing the association of plasma lipoprotein size distribution with cardiovascular disease after adjustment for established risk factors including standard lipids., Methods: We developed a model to predict risk of cardiovascular disease among participants in a case-cohort study of the Malmö Prevention Project. We used a linear model with 311 coefficients, corresponding to measures of lipoprotein mass at each of 311 diameters, and assumed these coefficients varied smoothly along the diameter index. The smooth function was represented as an expansion of natural cubic splines where the smoothness parameter was chosen by assessment of a series of nested splines. Cox proportional hazards models of time to a first cardiovascular disease event were used to estimate the smooth coefficient function among a training set consisting of one half of the participants. The resulting model was used to calculate a functional risk score for the remaining half of the participants (test set) and its association with events was assessed in Cox models that adjusted for traditional cardiovascular risk factors., Results: In the test set, participants with a functional risk score in the highest quartile were found to be at increased risk of cardiovascular events compared with the lowest quartile (Hazard ratio = 1.34; 95% Confidence Interval: 1.05 to 1.70) after adjustment for established risk factors., Conclusion: In an independent test set of Malmö Prevention Project participants, the functional risk score was found to be associated with cardiovascular events after adjustment for traditional risk factors including standard lipids., Competing Interests: Authors CR, DS, MC, and VG are employed by Quest Diagnostics and also own Quest Diagnostics stock. TH receives consulting fees from Quest Diagnostics. There are no patents or products in development associated with this research to declare; results of lipoprotein testing are reported by Quest Diagnostics using traditional subfraction boundaries, not by the functional analysis method reported here. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10 -11 in overall lung cancer and OR=0.41, p value=9.71x10 -11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10 -12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10 -11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes., Competing Interests: CONFLICTS OF INTEREST The authors whose names are listed above certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Objective: To assess the role of four biomarkers of neuroendocrine activation and endothelial dysfunction in the longitudinal prediction of fragility fractures., Methods: We analysed a population-based prospective cohort of 5415 community-dwelling individuals (mean age, 68.9±6.2 years) enrolled in the Malmö Preventive Project followed during 8.1±2.9 years, and investigated the longitudinal association between C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), the mid-regional fragments of pro-adrenomedullin (MR-proADM) and pro-atrial natriuretic peptide (MR-proANP), and incident vertebral, pelvic and extremity fractures., Results: Overall, 1030 (19.0%) individuals suffered vertebral, pelvic or extremity fracture. They were older (70.7±5.8 vs 68.4±6.3 years), more likely women (46.9% vs 26.3%), had lower body mass index and diastolic blood pressure, were more often on antihypertensive treatment (44.1% vs 38.4%) and had more frequently history of fracture (16.3% vs 8.1%). Higher levels of MR-proADM (adjusted HR (aHR) per 1 SD: 1.51, 95% CI 1.01 to 2.28, p<0.001) and MR-proANP (aHR: 1.23, 95% CI 1.05 to 1.45, p<0.001) were independently associated with increased risk of any fracture. The fracture risk increased linearly across MR-proANP quartiles. Individuals who were in the top quartile of all four biomarkers had a significant higher risk of fracture at any site (aHR: 2.32, 95% CI 1.86 to 2.91), vertebral fracture (aHR: 3.16, 95% CI 1.97 to 5.07) and femoral fracture (aHR: 2.35, 95% CI 1.64 to 3.36)., Conclusions: Elevated levels of MR-proADM and MR-proANP independently predict fragility fractures in older adults. In subjects with top quartile levels of all four biomarkers there is a twofold to threefold increase in risk of vertebral and femoral fractures., Competing Interests: Competing interests: AF reports personal fees from Cardiome and a patent Thermo Fisher pending outside the submitted work. RS reports personal fees and other from Medtronic, Abbott Laboratories outside the submitted work; performs consultancy for Medtronic; is a member of the speakers' bureau of Abbott Laboratories; and is a shareholder in Boston Scientific, Edwards Lifesciences and AstraZeneca., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance. We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion). We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Elevated plasma levels of the vasodilating hormone adrenomedullin (ADM) predict cardiovascular disease and have been associated with hypertension and obesity. We aimed to examine the independent relationship between ADM and the progression of major cardiometabolic risk factors during long-term follow-up., Methods: We studied midregional pro-ADM (MR-proADM) in fasting plasma in 3298 participants from the population-based Malmö Diet and Cancer Study - Cardiovascular Cohort, re-examined after 17 years of follow-up and related baseline MR-proADM to cardiometabolic risk factors cross-sectionally and longitudinally., Results: At baseline, after full adjustment, each SD increment of MR-proADM was independently related to (beta ± standard error, P value) higher SBP (0.956 ± 0.319 mmHg, P = 0.003), BMI (0.912 ± 0.061 kg/m, P = 1.42 × 10), waist (2.28 ± 0.158 cm, P = 8.46 × 10) and fasting blood glucose (0.046 ± 0.018 mmol/l, P = 0.01). After full adjustment, including the baseline level of the risk factor whose degree of progression was studied, each SD increment of MR-proADM predicted significantly reduced progression of SBP (-1.170 ± 0.337 mmHg, P = 0.001) and fasting blood glucose (-0.055 ± 0.023 mmol/l, P = 0.015), but greater increase of BMI (0.101 ± 0.051 kg/m, P = 0.047) and waist (0.600 ± 0.144 cm, P = 3.1 × 10)., Conclusion: Despite cross-sectional associations with higher levels of blood pressure and glucose, high levels of MR-proADM predict a slower progression of blood pressure and glycemia during long-term follow-up. Conversely, the cross-sectional associations with higher levels of MR-proADM and obesity were paralleled by a faster progression of obesity markers over time. These results may be important for assessment of long-term effects of therapies modulating levels of ADM.

Background: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need., Methods: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days., Results: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities., Conclusions: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants., Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included., Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10 -11 ) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p interaction  = 7.0 × 10 -4 , β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p Bonferroni  < 2.7 × 10 -6 )., Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.

The aim of this study was to investigate the acute effect of hydration status on glycemic regulation in healthy adults and explore underlying mechanisms. In this randomized crossover trial, 16 healthy adults (8 men, 8 women) underwent an oral glucose tolerance test (OGTT) when hypohydrated and rehydrated after 4 days of pretrial standardization. One day before OGTT, participants were dehydrated for 1 h in a heat tent with subsequent fluid restriction (HYPO) or replacement (RE). The following day, an OGTT was performed with metabolic rate measurements and pre- and post-OGTT muscle biopsies. Peripheral quantitative computer tomography thigh scans were taken before and after intervention to infer changes in cell volume. HYPO (but not RE) induced 1.9% (SD 1.2) body mass loss, 2.9% (SD 2.7) cell volume reduction, and increased urinary hydration markers, serum osmolality, and plasma copeptin concentration (all P ≤ 0.007). Fasted serum glucose [HYPO 5.10 mmol/l (SD 0.42), RE 5.02 mmol/l (SD 0.40); P = 0.327] and insulin [HYPO 27.1 pmol/l (SD 9.7), RE 27.6 pmol/l (SD 9.2); P = 0.809] concentrations were similar between HYPO and RE. Hydration status did not alter the serum glucose ( P = 0.627) or insulin ( P = 0.200) responses during the OGTT. Muscle water content was lower before OGTT after HYPO compared with RE [761 g/kg wet wt (SD 13) vs. 772 g/kg wet wt (SD 18) RE] but similar after OGTT [HYPO 779 g/kg wet wt (SD 15) vs. RE 780 g/kg wet wt (SD 20); time P = 0.011; trial × time P = 0.055]. Resting energy expenditure was similar between hydration states (stable between -1.21 and 5.94 kJ·kg -1 ·day -1 ; trial P = 0.904). Overall, despite acute mild hypohydration increasing plasma copeptin concentrations and decreasing fasted cell volume and muscle water, we found no effect on glycemic regulation. NEW & NOTEWORTHY We demonstrated for the first time that an acute bout of hypohydration does not impact blood sugar control in healthy adults. Physiological responses to mild hypohydration (<2% body mass loss) caused an elevation in copeptin concentrations similar to that seen in those with diabetes as well as reducing cell volume by ~3%; both of these changes had been hypothesized to cause a higher blood sugar response.

Purpose: High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon., Methods: Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water., Results: After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34-45) (p < 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5-25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine ("water-responders"). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected., Conclusions: Both acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low-water drinkers with high copeptin concentration.

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts., Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI., Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 -8 ; and LINC00539/ZDHHC20, p = 5.82 × 10 -9 . Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 -25 ; p [SSBI] = 5.23 × 10 -14 for hypertension), smoking ( p [BI] = 4.4 × 10 -10 ; p [SSBI] = 1.2 × 10 -4 ), diabetes ( p [BI] = 1.7 × 10 -8 ; p [SSBI] = 2.8 × 10 -3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 -18 ; p [SSBI] = 2.3 × 10 -7 ), stroke ( p [BI] = 3.9 × 10 -69 ; p [SSBI] = 3.2 × 10 -24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 -157 ; p [SSBI] = 3.16 × 10 -106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy., Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Multiplex proteomic platforms provide excellent tools for investigating associations between multiple proteins and disease (e.g., diabetes) with possible prognostic, diagnostic, and therapeutic implications. In this study our aim was to explore novel pathophysiological pathways by examining 92 proteins and their association with incident diabetes in a population-based cohort (146 cases of diabetes versus 880 controls) followed over 8 years. After adjusting for traditional risk factors, we identified seven proteins associated with incident diabetes. Four proteins (Scavenger receptor cysteine rich type 1 protein M130, Fatty acid binding protein 4, Plasminogen activator inhibitor 1 and Insulin-like growth factor-binding protein 2) with a previously established association with incident diabetes and 3 proteins (Cathepsin D, Galectin-4, Paraoxonase type 3) with a novel association with incident diabetes. Galectin-4, with an increased risk of diabetes, and Paraoxonase type 3, with a decreased risk of diabetes, remained significantly associated with incident diabetes after adjusting for plasma glucose, implying a glucose independent association with diabetes.

Objective: IgG antibodies against apolipoprotein A-I (ApoA-I) have been found to be elevated in subjects from the general population with clinically manifest cardiovascular disease and in myocardial infarction patients with an adverse prognosis. Here, we investigated whether these antibodies are prospectively associated with carotid artery disease progression and with the risk for first-time cardiovascular events in individuals with no previous history of cardiovascular disease., Approach and Results: We selected 383 subjects from the cardiovascular cohort of Malmö Diet and Cancer study who suffered a coronary event during a median follow-up period of 15.4 (10.3-16.4) years and 395 age- and sex-matched controls. None of the study participants had a previous history of coronary artery disease or stroke. Anti-ApoA-I IgG were measured by ELISA in serum samples collected at baseline. Intima-media thickness (IMT) was measured in the common carotid artery and in the carotid bifurcation at baseline and after 15.9 (±1.5) years. We found no associations between anti-ApoA-I IgG and carotid artery IMT at baseline or with IMT progression during follow-up. In Cox proportional hazards analyses adjusted for traditional cardiovascular risk factors, the hazard ratio (HR 95%CI) for the primary outcome, incident coronary events, was 0.97 (0.75-1.25), P = 0.782, in subjects with anti-ApoA-I IgG within the highest tertile compared with the lowest tertile. Similarly, we did not find any associations with the secondary outcome, incident first-time stroke., Conclusions: Serum autoantibodies against ApoA-I do not correlate with disease progression and adverse events in cardiovascular disease-free individuals from the general population., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Aims/hypothesis: Growth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor-β superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population., Methods: Between 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.4 ± 5.96 years, 38.6% men) who were participants in the Malmö Diet and Cancer-Cardiovascular Cohort. After a follow-up of 19.0 ± 5.16 years (mean ± SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP)., Results: During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p < 0.001) per SD increase of GDF-15. If participants were grouped according to baseline fasting glucose, the association between GDF-15 and diabetes risk was only evident in the group without impaired fasting glucose (n = 3973). The association tended to be less significant with increasing age: multivariate-adjusted HRs for diabetes per SD increase of GDF-15 were 1.24 (95% CI 1.08, 1.42), 1.19 (95% CI 1.00, 1.41) and 1.04 (95% CI 0.89, 1.23) for participants aged ≤55, 56-60 (>55 and ≤60) and >60 years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p = 0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061)., Conclusions/interpretation: GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are ≤60 years old.

Background: Plasma copeptin, a marker of vasopressin, is associated with renal function decline in the general population. Our aim was to study the links between elevated copeptin and future risk of kidney disease., Methods: Copeptin was measured in a sample of the Malmö Preventive Project (MPP) Reinvestigation (n = 5158) and in the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC) (n = 5162). According to national registers, 89 subjects in MPP and 180 in MDC-CC developed chronic kidney disease (CKD) during follow-up (8.7 and 19.6 years, respectively)., Results: After multivariate adjustment (gender, age, body mass index, smoking status, estimated glomerular filtration rate, prevalent diabetes, systolic blood pressure and prevalent antihypertensive treatment), copeptin (beta-coefficient per 1 standard deviation increment of ln copeptin) was independently associated with increased risk of CKD during follow-up in both cohorts (MPP: (HR) 1.46, 95% confidence interval (CI) 1.18-1.80, P < 0.001; MDC-CC: HR 1.25, 95% CI 1.02-1.54, P = 0.03) among subjects free from prevalent kidney disease at baseline. Furthermore, in MPP, elevated copeptin predicted a specified diagnosis of kidney disease other than CKD (HR 1.31, 95% CI 1.08-1.59, P = 0.006) after multivariate adjustment. In a corresponding analysis in MDC-CC, copeptin was associated with a 10% increased risk, which, however, was non-significant (P = 0.25). A meta-analysis of the MPP and MDC-CC data showed significant association between elevated copeptin and a specified diagnosis of kidney disease other than CKD (HR 1.18, 95% CI 1.05-1.34, P = 0.008)., Conclusion: An increased level of copeptin independently predicts development of both CKD and other specified kidney diseases, suggesting that copeptin can be used to identify individuals at risk for kidney disease development.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Introduction: Cardiac syncope heralds significantly higher mortality compared with syncope due to noncardiac causes or unknown etiology, commonly considered a benign event. A few epidemiologic studies have examined the outcome of noncardiac/unexplained syncope comparing individuals with and without syncope, but with controversial results. We performed a systematic review and meta-analysis to clarify whether history of noncardiac/unexplained syncope is associated with increased all-cause mortality in the general population., Methods and Results: Our systematic review of the literature published between January 1, 1966, and March 31, 2018 sought prospective, observational, cohort studies reporting summary-level outcome data about all-cause mortality in subjects with history of noncardiac/unexplained syncope compared with syncope-free participants. Adjusted hazard ratios were pooled through inverse variance random-effect meta-analysis to compute the summary effect size. Meta-regression models were performed to explore the effect of age, cardiovascular risk factors, or other potential confounders on the measured effect size. We identified four studies including 287 382 individuals (51.6% men; age, 64 ± 12 years): 38 843 with history of noncardiac/unexplained syncope and 248 539 without history of syncope. The average follow-up was 4.4 years. History of noncardiac/unexplained syncope was associated with higher all-cause mortality (pooled adjusted hazard ratio = 1.13; 95% confidence interval, 1.05 to 1.23). Meta-regression analysis showed a stronger positive relationship proportional to aging and increasing prevalence of diabetes and hypertension., Conclusions: This study-level meta-analysis showed that among older, diabetic and/or hypertensive individuals, history of noncardiac/unexplained syncope, even in the absence of an obvious cardiac etiology, is associated with higher all-cause mortality., (© 2018 Wiley Periodicals, Inc.)

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Background: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging., Objective: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer., Design, Setting, and Participants: Blood samples from 11 506 men in Sweden were collected during 1991-1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped., Outcome Measurements and Statistical Analysis: A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1×10 -6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis., Results and Limitations: We found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p<5×10 -8 ) and replicated in an independent cohort: rs73055188 (p=5.27×10 -9 , per-allele hazard ratio [HR]=2.27, 95% confidence interval [CI] 1.72-2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p<1×10 -6 ) and replicated in an independent cohort: rs2702185 (p=7.1×10 -7 , per-allele HR=2.55, 95% CI=1.76-3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups., Conclusions: The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer., Patient Summary: We identify two genetic markers that are associated with prostate-cancer-specific survival time., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals., Methods: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651)., Results: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-β., Conclusions: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

Our aim was to identify serum microRNAs (miRNAs) in healthy humans which associate with future onset of both diabetes mellitus and cardiovascular disease. We performed global profiling of 753 mature human miRNAs in serum of 12 pilot subjects followed by measurement of 47 consistently expressed miRNAs in fasting serum of 553 healthy subjects from the baseline exam (1991-1994) of the population based Malmö Diet and Cancer Study Cardiovascular Cohort (MDC-CC), of whom 140 developed diabetes, and 169 cardiovascular diseases during follow-up. We used multivariate logistic regression to test individual miRNAs for association with incident diabetes and cardiovascular disease as compared to control subjects (n = 259). After Bonferroni correction and adjustment for age and sex, each SD increment of log-transformed miR-483-5p was significantly associated with both incident diabetes (OR = 1.48; 95% CI 1.18-1.84, P = 0.001) and cardiovascular disease (OR = 1.40; 95% CI 1.15, 1.72, P = 0.001). In cross sectional analysis, miR-483-5p was correlated with BMI (r = 0.162, P = 0.0001), fasting insulin (r = 0.156, P = 0.0002), HDL (r = -0.099, P = 0.02) and triglycerides (r = 0.11, P = 0.01). Adjustment for these metabolic risk factors, as well as traditional risk factors attenuated the miR-483-5p association with incident diabetes (OR = 1.28 95% CI 1.00-1.64, P = 0.049) whereas its association with incident cardiovascular disease remained virtually unchanged (OR = 1.46 95% CI, 1.18-1.81, P = 0.0005). In conclusion, miR-483-5p associates with both diabetes and cardiovascular disease. The association with diabetes seems partly mediated by obesity and insulin resistance, whereas the association with incident cardiovascular disease is independent of these metabolic factors and traditional cardiovascular disease risk factors., Competing Interests: The authors have declared that no competing interests exist.

Objective: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype., Research Design and Methods: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects ( n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes ( n = 2,454 vs. 968) and type 2 diabetes ( n = 2,779 vs. 10,396)., Results: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3 , encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes., Conclusions: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies., (© 2018 by the American Diabetes Association.)

Background: Certain immunoglobulins (Ig) are proposed to have protective functions in atherosclerosis., Objectives: We tested whether serum levels of IgG and IgM autoantibodies against malondialdehyde low density lipoprotein (MDA-LDL) are associated with clinical coronary heart disease (CHD) and unfavorable plaque characteristics., Methods: NORDIL was a prospective study investigating adverse cardiovascular outcomes in hypertensive patients. IBIS-3 analyzed lesions in a non-culprit coronary artery with <50% stenosis using radiofrequency intravascular ultrasound (RF-IVUS) and near-infrared spectroscopy (NIRS). Imaging was repeated after a median of 386?days on rosuvastatin. Associations of antibodies with incident CHD and imaging parameters were assessed in the two sub-studies respectively., Findings: From 10,881 NORDIL patients, 87 had serum sampled at baseline and developed CHD over 4.5 years, matched to 227 controls. Higher titers of IgM anti-MDA-LDL had a protective effect on adverse outcomes, with odds ratio 0.29 (0.11, 0.76; p=0.012; p=0.016 for trend). Therefore, the effect was explored at the lesional level in IBIS-3. 143 patients had blood samples and RF-IVUS measurements available, and NIRS was performed in 90 of these. At baseline, IgM anti-MDA-LDL levels had a strong independent inverse relationship with lesional necrotic core volume (p=0.027) and percentage of plaque occupied by necrotic core (p=0.011), as well as lipid core burden index (p=0.024) in the worst 4 mm segment., Interpretation: Our study supports the hypothesis that lower circulating levels of IgM anti-MDA-LDL are associated with clinical CHD development, and for the first time relates these findings to atherosclerotic plaque characteristics that are linked to vulnerability., (© 2018 The Authors. Published by Elsevier B.V.)

Purpose: Leptin is an adipokine which regulates appetite and energy balance through a mechanism partially mediated by neurotensin (NT) in central nervous system. Besides acting as a neurotransmitter, NT is expressed in human intestine where it promotes fat absorption and its circulating levels associate with obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Whether a relation exists between circulating leptin and NT levels has not been investigated yet. The aim of this study was to test the hypothesis of an association between plasma leptin and NT concentration in adults with or without T2DM., Methods: We recruited a population of 72 subjects (M/F: 39/33; age: 49.5 ± 10.6 years; BMI: 26.5 ± 4.7 kg/m 2 ) including individuals with T2DM (n = 32) referring to our Diabetes Outpatient Clinics, Sapienza University of Rome, and healthy controls. Study participants underwent metabolic characterization; plasma leptin was measured by MILLIPLEX, Luminex, and proneurotensin (proNT), a stable precursor of NT, by chemiluminometric sandwich immunoassay., Results: Circulating median (25°-75°) leptin levels were 2.75 (1.27-4.93) ng/mL and did not differ between T2DM and non-diabetic subjects. Leptin concentration directly correlated with proNT (r = 0.41; p = 0.015); higher leptin levels were also associated with age, male gender, obesity, higher HOMA-IR, systolic blood pressure and C-reactive protein. Belonging to the highest pro-NT quartile correlated with greater leptin levels independent of age, gender and other confounders (r 2  = 0.82, p = 0.02)., Conclusions: Circulating leptin is associated with higher proNT levels independent of diabetes, obesity and metabolic syndrome components; besides its effects on central leptin signaling, NT may influence energy balance by modulating circulating leptin concentration likely through a mechanism involving gut fat absorption.

Background: Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality., Objectives: To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality., Methods: Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population-based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3-21.7 years follow-up., Results: An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ β ≤ |0.31|, P < 0.001). Plasma furin (hazard ratio [HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14-1.36, P < 0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all-cause mortality (1229 events; HR = 1.12, CI = 1.05-1.19, P = 0.001) after full multivariable adjustment., Conclusion: Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality., (© 2018 The Authors Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity., Summary: Background Factor VII-activating protease (FSAP) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low-frequency missense variant Marburg-I (rs7080536) in the FSAP-encoding gene HABP2, determinants of this variation are unclear. Objectives To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity. Patients/Methods We performed an exploratory genome-wide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. HABP2 was also significant in the gene-based analysis, and remained significant after exclusion of Marburg-I carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP. Results and Conclusions This study verified the Marburg-I variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Hip fractures in elderly carry a high mortality. Our objective was to test the hypothesis that plasma lactate concentration at hospital admission can be used to identify patients with a high risk for poor outcome. Hip fracture patients admitted to a university hospital in Sweden from January 2011 to August 2014 in whom a venous lactate was obtained at admission were included in this prospective observational study. Primary outcome measure was 30-d mortality and secondary outcome measure was a composite outcome of 30-d mortality and postoperative complications. Lactate concentration was evaluated as a continuous predictor using logistic regression, crude and adjusted for age, gender and American Society of Anesthesiology Physical Status (ASA PS) score. Discrimination was evaluated using receiver operating characteristics (ROC) analysis. Totally, 690 patients were included. Median age was 84 years (interquartile range [IQR] 77-90). At 30-d follow-up, mortality was 7.2%, and 45% of the patients had suffered the composite outcome. Median lactate level was 1.3 mmol/L (IQR 1.0-1.8 mmol/L). The odds ratio (OR) by each 1.0 mmol/L increase in the lactate concentration for 30-d mortality was 1.13 (95% CI 0.77-1.68) while for the composite outcome it was 1.06 (95% CI 0.85-1.3). Similar results were obtained after adjustment for age, sex and ASA PS classification for both outcomes. Area under the ROC curve for lactate as a predictor of 30-d mortality was 0.51 (95% CI 0.45-0.57). In our cohort, plasma lactate at admission does not appear to be a useful biomarker to identify high-risk patients after hip fracture.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

Background: Low-energy fractures are a growing health challenge as their incidence increases with advancing age. As cardiovascular instability may be associated with higher likelihood of traumatic falls, we aimed to investigate the associations between four cardiovascular biomarkers and the risk of low-energy fractures in a middle-aged population., Methods: A total of 5291 individuals from the prospective Malmö Diet and Cancer (MDC) study (mean age, 57 years; 59% women) with data on baseline levels of four cardiovascular biomarkers: mid-regional-fragment of pro-adrenomedullin-peptide (MR-pro-ADM), mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and C-terminal-pro-arginine-vasopressin (CT-pro-AVP/Copeptin) were included. The associations between biomarker levels and first incident low-energy fracture were tested in Cox proportional-hazard models, taking potential interactions and traditional risk factors into account., Results: Participants were followed for a median time of 21.0 years, during which 1002 subjects (19%) experienced at least one low-energy fracture. Subjects with incident fracture were older, more likely to be women, had lower BMI and higher prevalence of previous fractures. Among biomarkers, there was a significant interaction between gender and MR-pro-ADM on the risk of fracture (p = 0.002). MR-pro-ADM predicted fractures in men only (hazard ratio, 1.23; 95% CI 1.09-1.40; p = 0.001), whereas there was no association among women. Levels of MR-pro-ANP, NT-pro-BNP and CT-pro-AVP did not predict fractures., Conclusions: Higher circulating levels of MR-pro-ADM predict low-energy fractures among middle-aged-men, whereas levels of MR-pro-ANP, NT-pro-BNP and CT-pro-AVP are not associated with increased fracture risk. Further controlled studies should test the hypothesis whether MR-pro-ADM may improve prediction of bone fractures., Competing Interests: The authors have declared that no competing interests exist.

Aims: We applied near-infrared-spectroscopy (NIRS) to measure absolute frontal cerebral tissue oxygen saturation (SctO2) during head-up tilt test (HUT) in patients investigated for unexplained syncope., Methods and Results: Synchronized non-invasive beat-to-beat haemodynamic monitoring, ECG, SctO2 (NIRS; normal range: 60-80%), and peripheral oxygen saturation (left hand, SpO2) were applied during HUT in a random sample of patients with unexplained syncope. Tracings of 54 patients (mean-age: 55 ± 19 years, 39% male) with negative HUT, vasovagal syncope (VVS), or orthostatic hypotension (OH) were analysed. In 44 patients HUT was diagnostic, in 10 HUT was negative. Thirty-one experienced VVS. Of these, 6 had spontaneous and 25 nitroglycerin-induced syncope. Thirteen patients had orthostatic hypotension (OH). Although there was no significant change in mean-arterial pressure from baseline to 1 min before syncope or end of passive HUT phase (-1.4 ± 13.9 mmHg; P = 0.45), there was a significant fall in SctO2 during the same period (-3.2 ± 3.2%; P ≤ 0.001). Among patients who experienced syncope, a decrease in SctO2 from 71 ± 5% at baseline to 53 ± 9% (P < 0.001) at syncope was observed. During HUT, there was a significant difference in delta SctO2 between spontaneous VVS (-4.5 ± 3.0%) and negative HUT (-1.3 ± 1.9%; P  = 0.021), but not between spontaneous VVS and OH (-5.4 ± 4.2%; P = 0.65). In spontaneous VVS, progressive decrease of SctO2 was independent of mean arterial pressure decrease (P  = 0.22)., Conclusions: Progressive decrease in cerebral tissue oxygenation independent of mean-arterial pressure may precede spontaneous vasovagal reflex during tilt. Patients experience syncope when SctO2 falls below 60%. These data confirm clinical utility of absolute cerebral oximetry monitoring for syncope investigation. We applied NIRS to measure frontal cerebral tissue oxygen saturation (SctO2) during head-up tilt test (HUT) in patients with unexplained syncope. In 44 of 54 patients, HUT was diagnostic. In patients with syncope, a significant SctO2-decrease was observed. Different patterns of SctO2 can be detected.

Background: Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association of low levels of lead exposure with kidney function and kidney disease., Study Design: Prospective population-based cohort., Setting & Participants: 4,341 individuals aged 46 to 67 years enrolled into the Malmö Diet and Cancer Study-Cardiovascular Cohort (1991-1994) and 2,567 individuals subsequently followed up (2007-2012)., Predictor: Blood lead concentrations in quartiles (Q1-Q4) at baseline., Outcomes: Change in estimated glomerular filtration rate (eGFR) between the baseline and follow-up visit based on serum creatinine level alone or in combination with cystatin C level. Chronic kidney disease (CKD) incidence (185 cases) through 2013 detected using a national registry., Measurements: Multivariable-adjusted linear regression models to assess associations between lead levels and eGFRs at baseline and follow-up and change in eGFRs over time. Cox regression was used to examine associations between lead levels and CKD incidence. Validation of 100 randomly selected CKD cases showed very good agreement between registry data and medical records and laboratory data., Results: At baseline, 60% of study participants were women, mean age was 57 years, and median lead level was 25 (range, 1.5-258) μg/L. After a mean of 16 years of follow-up, eGFR decreased on average by 6mL/min/1.73m 2 (based on creatinine) and 24mL/min/1.73m 2 (based on a combined creatinine and cystatin C equation). eGFR change was higher in Q3 and Q4 of blood lead levels compared with Q1 (P for trend = 0.001). The HR for incident CKD in Q4 was 1.49 (95% CI, 1.07-2.08) compared with Q1 to Q3 combined., Limitations: Lead level measured only at baseline, moderate number of CKD cases, potential unmeasured confounding., Conclusions: Low-level lead exposure was associated with decreased kidney function and incident CKD. Our findings suggest lead nephrotoxicity even at low levels of exposure., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Arterial stiffness is recognized as an intermediate phenotype and predictor of cardiovascular disease. Arterial stiffness is complex in origin with contributions from lifestyle and genetic factors. However, the association between single nucleotide polymorphisms (SNPs) and arterial stiffness remains unclear., Objective: The aim is to assess whether a multilocus genetic risk score (GRS), composed of selected SNPs linked to cardiovascular traits and outcomes, is associated with arterial stiffness in patients with hypertension., Design and Methods: This study included 730 participants derived from the CARE NORTH study. The arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cfPWV). An adjusted linear regression was used to evaluate the association between cfPWV and each individual SNP using multiple genetic models. The association between a constructed GRS and cfPWV was tested in an unadjusted and adjusted model., Results: We selected 13 SNPs found to be associated with cfPWV (P < .05): 6 SNPs in additive, 4 SNPs in recessive and 3 SNPs in dominant mode of inheritance. The GRS based on these SNPs was positively associated with cfPWV both in unadjusted and adjusted models (β = 0.2 m/s, 95% CI 0.11 - 0.29, P = 7.6 × 10 and β = 0.22 m/s, 95% CI 0.15 - 0.28, P = 1.4 × 10, respectively). The GRS explained an additional 3.6% cfPWV variance above clinical covariates., Conclusion: We demonstrate that the GRS composed of 13 SNPs related to cardiovascular phenotypes is associated with an increased arterial stiffness in hypertensive patients. Our findings may help to clarify genetic basis of arterial stiffening and provide insight into mechanisms underlying this phenotype.

Background and Purpose- Apoptosis has been implicated in atherosclerosis and plaque rupture. This population-based study examined the relationship between 3 markers of apoptosis, that is, FADD (Fas-associated protein with death domain), caspase-3, and caspase-8, and incidence of ischemic stroke. Methods- The study population included 4356 participants from the MDCS (Malmö Diet and Cancer Study) cardiovascular cohort, without a history of stroke. Incidence of ischemic stroke was followed by linkages to local and national registers. Cox proportional hazards regression was used to assess the incidence of ischemic stroke in relation to quartiles of FADD, caspase-3, and caspase-8, adjusted for potential confounders. Results- During a mean follow-up period of 19.5±4.9 years, a total of 321 (7.4%) participants were diagnosed with incident ischemic stroke. Individuals with high levels of FADD and caspase-8 had a significantly increased risk of ischemic stroke, after adjustment for potential confounders. The multivariable-adjusted hazard ratios for Q4 versus Q1-Q3 of FADD and caspase-8 were 1.49 (95% CI, 1.18-1.87; P<0.01) and 1.77 (95% CI, 1.41-2.22; P<0.001), respectively. The hazard ratios per 1-SD increment of FADD and caspase-8 were 1.27 (95% CI, 1.14-1.41) and 1.31 (95% CI, 1.18-1.45), respectively. No association was observed for caspase-3 with ischemic stroke. Conclusions- Elevated levels of FADD and caspase-8, but not caspase-3, are associated with increased incidence of ischemic stroke.

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

Context: Type 2 diabetes mellitus (T2DM) is accompanied by an increased risk for coronary artery disease (CAD), but the overlapping metabolic disturbances preceding both diseases are insufficiently described., Objective: We hypothesized that alterations in metabolism occur years before clinical manifestation of T2DM and CAD and that these alterations are reflected in the plasma metabolome. We thus aimed to identify plasma metabolites that predict future T2DM and CAD., Design: Through use of targeted liquid chromatography-mass spectrometry, 35 plasma metabolites (amino acid metabolites and acylcarnitines) were quantified in 1049 individuals without CAD and diabetes, drawn from a population sample of 5386 in the Malmö Preventive Project (mean age, 69.5 years; 31% women). The sample included 204 individuals who developed T2DM, 384 who developed CAD, and 496 who remained T2DM and CAD free during a mean follow-up of 6.1 years., Results: In total, 16 metabolites were significantly associated with risk for developing T2DM according to logistic regression models. Glutamate (OR, 1.96; P = 5.4e-12) was the most strongly associated metabolite, followed by increased levels of branched-chain amino acids. Incident CAD was predicted by three metabolites: glutamate (OR, 1.28; P = 6.6e-4), histidine (OR, 0.76; P = 5.1e-4), and asparagine (OR, 0.80; P = 2.2e-3). Glutamate (OR, 1.48; P = 1.6e-8) and asparagine (OR, 0.75; P = 1.8e-5) were both associated with a composite endpoint of developing T2DM or CAD., Conclusion: Several plasma metabolites were associated with incidence of T2DM and CAD; elevated glutamate and reduced asparagine levels were associated with both diseases. We thus discovered associations that might help shed additional light on why T2DM and CAD commonly co-occur.

Purpose: Inter-individual variation in median plasma copeptin is associated with incident type 2 diabetes mellitus, progression of chronic kidney disease, and cardiovascular events. In this study, we examined whether 24-h urine osmolality was associated with plasma copeptin and whether increasing daily water intake could impact circulating plasma copeptin., Methods: This trial was a prospective study conducted at a single investigating center. Eighty-two healthy adults (age 23.6 ± 2.9 years, BMI 22.2 ± 1.5 kg/m 2 , 50% female) were stratified based upon habitual daily fluid intake volumes: arm A (50-80% of EFSA dietary reference values), arm B (81-120%), and arm C (121-200%). Following a baseline visit, arms A and B increased their water intake to match arm C for a period of 6 consecutive weeks., Results: At baseline, plasma copeptin was positively and significantly associated with 24-h urine osmolality (p = 0.002) and 24-h urine specific gravity (p = 0.003) but not with plasma osmolality (p = 0.18), 24-h urine creatinine (p = 0.09), and total fluid intake (p = 0.52). Over the 6-week follow-up, copeptin decreased significantly from 5.18 (3.3;7.4) to 3.90 (2.7;5.7) pmol/L (p = 0.012), while urine osmolality and urine specific gravity decreased from 591 ± 206 to 364 ± 117 mOsm/kg (p < 0.001) and from 1.016 ± 0.005 to 1.010 ± 0.004 (p < 0.001), respectively., Conclusions: At baseline, circulating levels of copeptin were positively associated with 24-h urine concentration in healthy young subjects with various fluid intakes. Moreover, this study shows, for the first time, that increased water intake over 6 weeks results in an attenuation of circulating copeptin., Clinical Trial Registration Number: NCT02044679.

Background: Non-communicable diseases (NCDs, e.g. cardiovascular disease) are responsible for high rates of morbidity and the majority of premature deaths worldwide. It is necessary to develop preventative interventions that can reduce the associated risk factors of NCDs. Researchers have found that the biomarker adrenomedullin (ADM) becomes elevated years before the onset of NCDs and might play an important role in their development. ADM has also been linked to psychological problems such as stress, anxiety, and depression, which are known risk factors of NCDs. In this randomized controlled trial, we examined whether participating in a five-week yoga intervention reduces ADM and increases psychological health in middle-aged adults who self-report as moderately to highly stressed, but who otherwise exhibit no physical complaints., Methods: One hundred and five adults (78% women; mean age = 53.5, SD = 6.7) were randomly assigned to (1) a five-week Yin yoga intervention, (2) a five-week intervention combining Yin yoga with psychoeducation and mindfulness practice (called the YOMI program), or (3) a control group who did not practice yoga or mindfulness for five weeks., Results: Compared to the control group, we observed significantly greater pre-post reductions in plasma ADM levels (p < .001), anxiety (p ≤ .002), and sleep problems (p ≤ .003) in both intervention groups. Furthermore, the YOMI group exclusively showed significantly greater pre-post reductions in stress (p = .012) and depression (p = .021) compared to the control group. Significant correlations (p < .05) were found between pre-post reductions in ADM and anxiety symptoms (p = .02) and depression (p = .04) in the entire sample., Conclusion: The five-week Yin yoga-based interventions appeared to reduce both the physiological and psychological risk factors known to be associated with NCDs. The study suggests that incorporating Yin yoga could be an easy and low-cost method of limiting the negative health effects associated with high stress., Trial Registration: ClinicalTrials.gov NCT03428542., Competing Interests: The authors have declared that no competing interests exist.

Background: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population., Methods: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria., Results: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008)., Conclusions: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action., Funding: INSERM and Danone Research Centre for Specialized Nutrition.

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10 -8 ) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2 , both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD., (© 2018 by the American Diabetes Association.)

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 -10 ), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Context: Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated., Objective: To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels., Design/setting/participants: For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery., Main Outcome Measures: Plasma pro-NT levels in relation to NAFLD/NASH., Results: Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P < 0.001). Greater pro-NT correlated with NAFLD presence (P < 0.001) and severity (P < 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P < 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders., Conclusions: Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance.

Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined β = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 × 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 × 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.