Publications by authors named "Florian Kronenberg"

354 Publications

Association of the metabolic syndrome with mortality and major adverse cardiac events: A large chronic kidney disease cohort.

J Intern Med 2021 Aug 3. Epub 2021 Aug 3.

Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Metabolic syndrome with its key components insulin resistance, central obesity, dyslipidaemia, and hypertension is associated with a high risk for cardiovascular events and all-cause mortality in the general population. However, evidence that these findings apply to patients with chronic kidney disease (CKD) with moderately reduced estimated glomerular filtration rate and/or albuminuria is limited.

Objectives: We aimed to investigate the association between metabolic syndrome and its components with all-cause mortality and cardiovascular outcomes in CKD patients.

Methods: Prospective observation of a cohort of 5110 CKD patients from the German Chronic Kidney Disease study with 3284 (64.3%) of them having a metabolic syndrome at baseline.

Results: During the follow-up of 6.5 years, 605 patients died and 650 patients experienced major cardiovascular events. After extended data adjustment, patients with a metabolic syndrome had a higher risk for all-cause mortality (hazard ratio [HR] = 1.26, 95% confidence interval [CI]: 1.04-1.54) and cardiovascular events (HR = 1.48, 95% CI: 1.22-1.79). The risk increased steadily with a growing number of metabolic syndrome components (increased waist circumference, glucose, triglycerides, hypertension and decreased HDL cholesterol): HR per component = 1.09 (95% CI: 1.02-1.17) for all-cause mortality, and 1.23 (95% CI: 1.15-1.32) for cardiovascular events. This resulted in hazard ratios between 1.50 and 2.50 in the case of four or five components present. Analysis of individual components of metabolic syndrome showed that the glucose component led to the highest increase in risk for all-cause mortality (HR = 1.68, 95% CI: 1.38-2.03) and cardiovascular events (HR = 1.81, 95% CI: 1.51-2.18), followed by the HDL cholesterol and triglyceride components.

Conclusions: We observed a high prevalence of metabolic syndrome among patients with moderate CKD. Metabolic syndrome increases the risk for all-cause mortality and cardiovascular events. The glucose and lipid components seem to be the main drivers for the association with outcomes.
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http://dx.doi.org/10.1111/joim.13355DOI Listing
August 2021

Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease.

J Am Coll Cardiol 2021 Aug;78(5):437-449

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background: Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants.

Objectives: This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD.

Methods: We genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project.

Results: The 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably.

Conclusions: Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction.
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http://dx.doi.org/10.1016/j.jacc.2021.05.037DOI Listing
August 2021

Use of lipoprotein(a) for refining cardiovascular risk prediction in a low-risk population: The CoLaus/PsyCoLaus study.

Eur J Prev Cardiol 2021 Jul;28(8):e18-e20

Department of Medicine, Lausanne University Hospital and University of Lausanne, Switzerland.

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http://dx.doi.org/10.1177/2047487320938271DOI Listing
July 2021

A Predictive Model for Progression of CKD to Kidney Failure Based on Routine Laboratory Tests.

Am J Kidney Dis 2021 Jul 11. Epub 2021 Jul 11.

Chair and Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. Electronic address:

Rationale & Objective: Stratification of chronic kidney disease (CKD) patients at risk for progressing to end-stage kidney disease (ESKD) requiring kidney replacement therapy (KRT) is important for clinical decision-making and trial enrollment.

Study Design: Four independent prospective observational cohort studies.

Setting & Participants: The development cohort was comprised of 4,915 CKD patients and three independent validation cohorts were comprised of a total of 3,063. Patients were followed-up for approximately five years.

New Predictors & Established Predictors: 22 demographic, anthropometric and laboratory variables commonly assessed in CKD patients.

Outcomes: Progression to ESKD requiring KRT.

Analytical Approach: A Least Absolute Shrinkage and Selection Operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for ESKD. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation. Both used a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs.

Results: The newly derived 6-variable (Z6) risk score included serum creatinine, albumin, cystatin C and urea, as well as hemoglobin and the urine albumin-to-creatinine ratio. Based on the resampling approach, Z6 achieved a median C value of 0.909 (95% CI, 0.868-0.937) at two years after the baseline visit, whereas the T4 achieved a median C value of 0.855 (95% CI, 0.799-0.915). In the three independent validation cohorts, Z6 C values were 0.894, 0.921, and 0.891, whereas the T4 C values were 0.882, 0.913, and 0.862.

Limitations: The Z6 was both derived and tested only in White European cohorts.

Conclusions: A new risk equation, based on six routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to ESKD.
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http://dx.doi.org/10.1053/j.ajkd.2021.05.018DOI Listing
July 2021

Lipoprotein(a) levels and atherosclerotic plaque characteristics in the carotid artery: The Plaque at RISK (PARISK) study.

Atherosclerosis 2021 07 11;329:22-29. Epub 2021 Jun 11.

Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Background And Aims: Lipoprotein(a) is an independent risk factor for cardiovascular disease and recurrent ischemic stroke. Lipoprotein(a) levels are known to be associated with carotid artery stenosis, but the relation of lipoprotein(a) levels to carotid atherosclerotic plaque composition and morphology is less known. We hypothesize that higher lipoprotein(a) levels and lipoprotein(a)-related SNPs are associated with a more vulnerable carotid plaque and that this effect is sex-specific.

Methods: In 182 patients of the Plaque At RISK study we determined lipoprotein(a) concentrations, apo(a) KIV-2 repeats and LPA SNPs. Imaging characteristics of carotid atherosclerosis were determined by MDCTA (n = 161) and/or MRI (n = 171). Regressions analyses were used to investigate sex-stratified associations between lipoprotein(a) levels, apo(a) KIV-2 repeats, and LPA SNPs and imaging characteristics.

Results: Lipoprotein(a) was associated with presence of lipid-rich necrotic core (LRNC) (aOR = 1.07, 95% CI: 1.00; 1.15), thin-or-ruptured fibrous cap (TRFC) (aOR = 1.07, 95% CI: 1.01; 1.14), and degree of stenosis (β = 0.44, 95% CI: 0.00; 0.88). In women, lipoprotein(a) was associated with presence of intraplaque hemorrhage (IPH) (aOR = 1.25, 95% CI: 1.06; 1.61). In men, lipoprotein(a) was associated with degree of stenosis (β = 0.58, 95% CI: 0.04; 1.12). Rs10455872 was significantly associated with increased calcification volume (β = 1.07, 95% CI: 0.25; 1.89) and absence of plaque ulceration (aOR = 0.25, 95% CI: 0.04; 0.93). T3888P was associated with absence of LRNC (aOR = 0.36, 95% CI: 0.16; 0.78) and smaller maximum vessel wall area (β = -10.24, 95%CI: -19.03; -1.44).

Conclusions: In patients with symptomatic carotid artery stenosis, increased lipoprotein(a) levels were associated with degree of stenosis, and IPH, LRNC, and TRFC, known as vulnerable plaque characteristics, in the carotid artery. T3888P was associated with lower LRNC prevalence and smaller maximum vessel wall area. Further research in larger study populations is needed to confirm these results.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.06.004DOI Listing
July 2021

Lipoprotein(a).

Handb Exp Pharmacol 2021 Jul 2. Epub 2021 Jul 2.

Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein with a strong genetic regulation. Up to 90% of the concentrations are explained by a single gene, the LPA gene. The concentrations show a several-hundred-fold interindividual variability ranging from less than 0.1 mg/dL to more than 300 mg/dL. Lp(a) plasma concentrations above 30 mg/dL and even more above 50 mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Since concentrations above 50 mg/dL are observed in roughly 20% of the Caucasian population and in an even higher frequency in African-American and Asian-Indian ethnicities, it can be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.Carriers of genetic variants that are associated with high Lp(a) concentrations have a markedly increased risk for cardiovascular events. Studies that used these genetic variants as a genetic instrument to support a causal role for Lp(a) as a cardiovascular risk factor are called Mendelian randomization studies. The principle of this type of studies has been introduced and tested for the first time ever with Lp(a) and its genetic determinants.There are currently no approved pharmacologic therapies that specifically target Lp(a) concentrations. However, some therapies that target primarily LDL cholesterol have also an influence on Lp(a) concentrations. These are mainly PCSK9 inhibitors that lower LDL cholesterol by 60% and Lp(a) by 25-30%. Furthermore, lipoprotein apheresis lowers both, Lp(a) and LDL cholesterol, by about 60-70%. Some sophisticated study designs and statistical analyses provided support that lowering Lp(a) by these therapies also lowers cardiovascular events on top of the effect caused by lowering LDL cholesterol, although this was not the main target of the therapy. Currently, new therapies targeting RNA such as antisense oligonucleotides (ASO) or small interfering RNA (siRNA) against apolipoprotein(a), the main protein of the Lp(a) particle, are under examination and lower Lp(a) concentrations up to 90%. Since these therapies specifically lower Lp(a) concentrations without influencing other lipoproteins, they will serve the last piece of the puzzle whether a decrease of Lp(a) results also in a decrease of cardiovascular events.
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http://dx.doi.org/10.1007/164_2021_504DOI Listing
July 2021

Lipoprotein(a) and SARS-CoV-2 infections: susceptibility to infections, ischemic heart disease and thromboembolic events.

J Intern Med 2021 Jun 7. Epub 2021 Jun 7.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Comorbidities including ischemic heart disease (IHD) worsen outcomes after SARS-CoV-2 infections. High lipoprotein(a) [Lp(a)] concentrations are a strong risk factor for IHD and possibly for thromboembolic events. We therefore evaluated whether SARS-CoV-2 infections modify the risk of high Lp(a) concentrations for IHD or thromboembolic events during the first 8.5 months follow-up of the pandemic.

Method: Cohort study using data from the UK Biobank during the SARS-CoV-2 pandemic. Baseline Lp(a) was compared between SARS-CoV-2 positive patients and the population controls. UK Biobank received ethical approval from the North West Multi-Centre Research Ethics Committee (REC reference: 11/NW/0382). All participants gave written informed consent before enrolment in the study, which was conducted in accordance with the principles of the Declaration of Helsinki.

Results: SARS-CoV-2 positive patients had Lp(a) concentrations similar to the population controls. The risk for IHD increased with higher Lp(a) concentrations in both, the population controls (n = 435,104) and SARS-CoV-2 positive patients (n = 6,937). The causality of the findings was supported by a genetic risk score for Lp(a). A SARS-CoV-2 infection modified the association with a steeper increase in risk for infected patients (interaction P-value = 0.03). Although SARS-CoV-2 positive patients had a 5-times higher frequency of thromboembolic events compared to the population controls (1.53% vs. 0.31%), the risk was not influenced by Lp(a).

Conclusions: SARS-CoV-2 infections enforce the association between high Lp(a) and IHD but the risk for thromboembolic events is not influenced by Lp(a). This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/joim.13338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242884PMC
June 2021

Causal Effects of Body Mass Index on Airflow Obstruction and Forced Mid-Expiratory Flow: A Mendelian Randomization Study Taking Interactions and Age-Specific Instruments Into Consideration Toward a Life Course Perspective.

Front Public Health 2021 11;9:584955. Epub 2021 May 11.

Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.

Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18-60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25-75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25-75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25-75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.
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http://dx.doi.org/10.3389/fpubh.2021.584955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144328PMC
June 2021

An in-depth analysis of the mitochondrial phylogenetic landscape of Cambodia.

Sci Rep 2021 May 24;11(1):10816. Epub 2021 May 24.

Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.

Cambodia harbours a variety of human aboriginal populations that have scarcely been studied in terms of genetic diversity of entire mitochondrial genomes. Here we present the matrilineal gene pool of 299 Cambodian refugees from three different ethnic groups (Cham, Khmer, and Khmer Loeu) deriving from 16 Cambodian districts. After establishing a DNA-saving high-throughput strategy for mitochondrial whole-genome Sanger sequencing, a HaploGrep based workflow was used for quality control, haplogroup classification and phylogenetic reconstruction. The application of diverse phylogenetic algorithms revealed an exciting picture of the genetic diversity of Cambodia, especially in relation to populations from Southeast Asia and from the whole world. A total of 224 unique haplotypes were identified, which were mostly classified under haplogroups B5a1, F1a1, or categorized as newly defined basal haplogroups or basal sub-branches of R, N and M clades. The presence of autochthonous maternal lineages could be confirmed as reported in previous studies. The exceptional homogeneity observed between and within the three investigated Cambodian ethnic groups indicates genetic isolation of the whole population. Between ethnicities, genetic barriers were not detected. The mtDNA data presented here increases the phylogenetic resolution in Cambodia significantly, thereby highlighting the need for an update of the current human mtDNA phylogeny.
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http://dx.doi.org/10.1038/s41598-021-90145-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144189PMC
May 2021

The year 2020 in Atherosclerosis.

Atherosclerosis 2021 06 28;326:35-44. Epub 2021 Apr 28.

Institute of Clinical Chemistry, University of Zurich and University Hospital of Zurich, Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.013DOI Listing
June 2021

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Cardiovasc Res 2021 Apr 20. Epub 2021 Apr 20.

Estonian Genome Center, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.

Aims: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

Methods And Results: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

Conclusions: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

Translational Perspective: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.
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http://dx.doi.org/10.1093/cvr/cvab136DOI Listing
April 2021

Survival on four compared with three times per week haemodialysis in high ultrafiltration patients: an observational study.

Clin Kidney J 2021 Feb 28;14(2):665-672. Epub 2020 Dec 28.

Department of Renal Medicine, University College London, UK.

Background: The harm caused by the long interdialytic interval in three-times-per-week haemodialysis regimens (3×WHD) may relate to fluid accumulation and associated high ultrafiltration rate (UFR). Four-times-per-week haemodialysis (4×WHD) may offer a solution, but its impact on mortality, hospitalization and vascular access complications is unknown.

Methods: From the AROii cohort of incident in-centre haemodialysis patients, 3×WHD patients with a UFR >10 mL/kg/h were identified. The hazard for the outcomes of mortality, hospitalization and vascular access complications in those who switched to 4×WHD compared with staying on 3×WHD was estimated using a marginal structural Cox proportional hazards model. Adjustment included baseline patient and treatment characteristics with inverse probability weighting used to adjust for time-varying UFR and cardiovascular comorbidities.

Results: From 10 637 European 3×WHD patients, 3842 (36%) exceeded a UFR >10 mL/kg/h. Of these, 288 (7.5%) started 4×WHD and at baseline were more comorbid. Event rates while receiving 4×WHD compared with 3×WHD were 12.6 compared with 10.8 per 100 patient years for mortality, 0.96 compared with 0.65 per year for hospitalization and 14.7 compared with 8.0 per 100 patient years for vascular access complications. Compared with 3×WHD, the unadjusted hazard ratio (HR) for mortality on 4×WHD was 1.05 [95% confidence interval (CI) 0.78-1.42]. Following adjustment for baseline demographics, time-varying treatment probability and censoring risks, this HR was 0.73 (95% CI 0.50-1.05; P = 0.095). Despite these adjustments on 4×WHD, the HR for hospitalization remained elevated and vascular access complications were similar to 3×WHD.

Conclusions: This observational study was not able to demonstrate a mortality benefit in patients switched to 4×WHD. To demonstrate the true benefits of 4×WHD requires a large, well-designed clinical trial. Our data may help in the design of such a study.
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http://dx.doi.org/10.1093/ckj/sfaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886573PMC
February 2021

Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism.

Nat Commun 2021 02 11;12(1):964. Epub 2021 Feb 11.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e-7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
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http://dx.doi.org/10.1038/s41467-020-20877-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878905PMC
February 2021

The causal association of bilirubin with cardiovascular disease: Are there still any questions?

Atherosclerosis 2021 03 28;320:92-94. Epub 2021 Jan 28.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.020DOI Listing
March 2021

Aortic valve stenosis: the long and winding road.

Eur Heart J 2021 06;42(22):2212-2214

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1093/eurheartj/ehaa1069DOI Listing
June 2021

Analyzing Low-Level mtDNA Heteroplasmy-Pitfalls and Challenges from Bench to Benchmarking.

Int J Mol Sci 2021 Jan 19;22(2). Epub 2021 Jan 19.

Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.

Massive parallel sequencing technologies are promising a highly sensitive detection of low-level mutations, especially in mitochondrial DNA (mtDNA) studies. However, processes from DNA extraction and library construction to bioinformatic analysis include several varying tasks. Further, there is no validated recommendation for the comprehensive procedure. In this study, we examined potential pitfalls on the sequencing results based on two-person mtDNA mixtures. Therefore, we compared three DNA polymerases, six different variant callers in five mixtures between 50% and 0.5% variant allele frequencies generated with two different amplification protocols. In total, 48 samples were sequenced on Illumina MiSeq. Low-level variant calling at the 1% variant level and below was performed by comparing trimming and PCR duplicate removal as well as six different variant callers. The results indicate that sensitivity, specificity, and precision highly depend on the investigated polymerase but also vary based on the analysis tools. Our data highlight the advantage of prior standardization and validation of the individual laboratory setup with a DNA mixture model. Finally, we provide an artificial heteroplasmy benchmark dataset that can help improve somatic variant callers or pipelines, which may be of great interest for research related to cancer and aging.
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http://dx.doi.org/10.3390/ijms22020935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832847PMC
January 2021

Contamination detection in sequencing studies using the mitochondrial phylogeny.

Genome Res 2021 Jan 15. Epub 2021 Jan 15.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Within-species contamination is a major issue in sequencing studies, especially for mitochondrial studies. Contamination can be detected by analyzing the nuclear genome or by inspecting polymorphic sites in the mitochondrial genome (mtDNA). Existing methods using the nuclear genome are computationally expensive, and no appropriate tool for detecting sample contamination in large-scale mtDNA data sets is available. Here we present haplocheck, a tool that requires only the mtDNA to detect contamination in both targeted mitochondrial and whole-genome sequencing studies. Our in silico simulations and amplicon mixture experiments indicate that haplocheck detects mtDNA contamination accurately and is independent of the phylogenetic distance within a sample mixture. By applying haplocheck to The 1000 Genomes Project Consortium data, we further evaluate the application of haplocheck as a fast proxy tool for nDNA-based contamination detection using the mtDNA and identify the mitochondrial copy number within a mixture as a critical component for the overall accuracy. The haplocheck tool is available both as a command-line tool and as a cloud web service producing interactive reports that facilitates the navigation through the phylogeny of contaminated samples.
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http://dx.doi.org/10.1101/gr.256545.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849411PMC
January 2021

How significant is the antifibrinolytic effect of lipoprotein(a) for blood clot lysis?

Thromb Res 2021 02 26;198:210-212. Epub 2020 Dec 26.

Department of Internal Medicine, Division Vascular Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.thromres.2020.12.014DOI Listing
February 2021

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

Arterioscler Thromb Vasc Biol 2021 02 24;41(2):962-975. Epub 2020 Dec 24.

Department of Molecular and Clinical Medicine (E.B., L.A., M. Adiels, J.B.), University of Gothenburg, Sweden.

Objective: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL (very low-density lipoprotein) and VLDL; and apoB100 in VLDL, VLDL, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL. In contrast, the fractional catabolic rates of VLDL-apoB100 and VLDL-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL- and IDL-apoB100 concentrations.

Conclusions: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.
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http://dx.doi.org/10.1161/ATVBAHA.120.315446DOI Listing
February 2021

Towards an SI-Traceable Reference Measurement System for Seven Serum Apolipoproteins Using Bottom-Up Quantitative Proteomics: Conceptual Approach Enabled by Cross-Disciplinary/Cross-Sector Collaboration.

Clin Chem 2021 03;67(3):478-489

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Current dyslipidemia management in patients with atherosclerotic cardiovascular disease (ASCVD) is based on traditional serum lipids. Yet, there is some indication from basic research that serum apolipoproteins A-I, (a), B, C-I, C-II, C-III, and E may give better pathophysiological insight into the root causes of dyslipidemia. To facilitate the future adoption of clinical serum apolipoprotein (apo) profiling for precision medicine, strategies for accurate testing should be developed in advance. Recent discoveries in basic science and translational medicine set the stage for the IFCC Working Group on Apolipoproteins by Mass Spectrometry. Main drivers were the convergence of unmet clinical needs in cardiovascular disease (CVD) patients with enabling technology and metrology. First, the residual cardiovascular risk after accounting for established risk factors demonstrates that the current lipid panel is too limited to capture the full complexity of lipid metabolism in patients. Second, there is a need for accurate test results in highly polymorphic and atherogenic apolipoproteins such as apo(a). Third, sufficient robustness of mass spectrometry technology allows reproducible protein quantification at the molecular level. Fourth, several calibration hierarchies in the revised ISO 17511:2020 guideline facilitate metrological traceability of test results, the highest achievable standard being traceability to SI. This article outlines the conceptual approach aimed at achieving a novel, multiplexed Reference Measurement System (RMS) for seven apolipoproteins based on isotope dilution mass spectrometry and peptide-based calibration. This RMS should enable standardization of existing and emerging apolipoprotein assays to SI, within allowable limits of measurement uncertainty, through a sustainable network of Reference Laboratories.
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http://dx.doi.org/10.1093/clinchem/hvaa239DOI Listing
March 2021

Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial.

Eur Respir J 2021 04 29;57(4). Epub 2021 Apr 29.

Dept of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria.

Background: After the 2002/2003 severe acute respiratory syndrome outbreak, 30% of survivors exhibited persisting structural pulmonary abnormalities. The long-term pulmonary sequelae of coronavirus disease 2019 (COVID-19) are yet unknown, and comprehensive clinical follow-up data are lacking.

Methods: In this prospective, multicentre, observational study, we systematically evaluated the cardiopulmonary damage in subjects recovering from COVID-19 at 60 and 100 days after confirmed diagnosis. We conducted a detailed questionnaire, clinical examination, laboratory testing, lung function analysis, echocardiography and thoracic low-dose computed tomography (CT).

Results: Data from 145 COVID-19 patients were evaluated, and 41% of all subjects exhibited persistent symptoms 100 days after COVID-19 onset, with dyspnoea being most frequent (36%). Accordingly, patients still displayed an impaired lung function, with a reduced diffusing capacity in 21% of the cohort being the most prominent finding. Cardiac impairment, including a reduced left ventricular function or signs of pulmonary hypertension, was only present in a minority of subjects. CT scans unveiled persisting lung pathologies in 63% of patients, mainly consisting of bilateral ground-glass opacities and/or reticulation in the lower lung lobes, without radiological signs of pulmonary fibrosis. Sequential follow-up evaluations at 60 and 100 days after COVID-19 onset demonstrated a vast improvement of symptoms and CT abnormalities over time.

Conclusion: A relevant percentage of post-COVID-19 patients presented with persisting symptoms and lung function impairment along with radiological pulmonary abnormalities >100 days after the diagnosis of COVID-19. However, our results indicate a significant improvement in symptoms and cardiopulmonary status over time.
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http://dx.doi.org/10.1183/13993003.03481-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736754PMC
April 2021

Elevated levels of serum PCSK9 in male patients with symptomatic peripheral artery disease: The CAVASIC study.

Atherosclerosis 2021 01 28;316:41-47. Epub 2020 Nov 28.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Peripheral artery disease (PAD) affects more than 200 million people worldwide. Increased low-density lipoprotein cholesterol (LDL-C)levels are a risk factor for PAD and the concentrations are influenced by proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 regulates the recycling of the LDL receptors to the cell membrane surface. Only a limited number of mostly small studies investigated the association between serum PCSK9 concentrations and PAD of different definition, which revealed contrasting results.

Methods: Serum PCSK9, lipoprotein(a) [Lp(a)] and other lipoprotein concentrations were measured in male participants of the CAVASIC study, a case-control study of 248 patients with intermittent claudication and 251 age and diabetes-matched controls.

Results: PAD patients had significantly higher PCSK9 concentrations when compared to controls (250 ± 77 vs. 222 ± 68 ng/mL, p < 0.001). Logistic regression analysis with adjustment for age revealed that an increase in PCSK9 concentrations of 100 ng/mL was associated with a 1.78-fold higher risk for PAD (95%CI 1.38-2.33, p = 1.43 × 10). The association attenuated, but was still significant when adjusting additionally for age, Lp(a)-corrected LDL cholesterol, HDL cholesterol, high-sensitivity-CRP, statin treatment, hypertension, diabetes mellitus and smoking (OR = 1.49, 95%CI 1.03-2.18, p = 0.035). The strongest association was observed when both PCSK9 concentrations were above the median and Lp(a) concentrations were above 30 mg/dL (OR = 3.35, 95%CI 1.49-7.71, p = 0.0038).

Conclusions: Our findings suggest an association of higher PCSK9 concentrations with PAD, which was independent of other lipid parameters and classical cardiovascular risk factors.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.11.025DOI Listing
January 2021

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Kidney Int 2021 04 31;99(4):926-939. Epub 2020 Oct 31.

Division of Nephrology, University of Washington, Seattle, Washington, USA; Kidney Research Institute, University of Washington, Seattle, Washington, USA.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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http://dx.doi.org/10.1016/j.kint.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010357PMC
April 2021

Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals.

Genome Med 2020 08 21;12(1):74. Epub 2020 Aug 21.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Schöpfstrasse 41, A-6020, Innsbruck, Austria.

Background: The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts.

Methods: We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline.

Results: R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping.

Conclusions: We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.
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http://dx.doi.org/10.1186/s13073-020-00771-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442989PMC
August 2020

Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study.

Cancers (Basel) 2020 Jul 17;12(7). Epub 2020 Jul 17.

University Hospital for Craniomaxillofacial and Oral Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria.

While a shift in energy metabolism is essential to cancers, the knowledge about the involvement of the mitochondrial genome in tumorigenesis and progression in oral squamous cell carcinoma (OSCC) is still very limited. In this study, we evaluated 37 OSCC tumors and the corresponding benign mucosa tissue pairs by deep sequencing of the complete mitochondrial DNA (mtDNA). After extensive quality control, we identified 287 variants, 137 in tumor and 150 in benign samples exceeding the 1% threshold. Variant heteroplasmy levels were significantly increased in cancer compared to benign tissues ( = 0.0002). Furthermore, pairwise high heteroplasmy frequency difference variants (∆HF% > 20) with potential functional impact were increased in the cancer tissues ( = 0.024). Fourteen mutations were identified in the protein-coding region, out of which thirteen were detected in cancer and only one in benign tissue. After eight years of follow-up, the risk of mortality was higher for patients who harbored at least one ∆HF% > 20 variant in mtDNA protein-coding regions relative to those with no mutations (HR = 4.6, (95%CI = 1.3-17); = 0.019 in primary tumor carriers). Haplogroup affiliation showed an impact on survival time, which however needs confirmation in a larger study. In conclusion, we observed a significantly higher accumulation of somatic mutations in the cancer tissues associated with a worse prognosis.
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http://dx.doi.org/10.3390/cancers12071933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409097PMC
July 2020

Results from the German Chronic Kidney Disease (GCKD) study support association of relative telomere length with mortality in a large cohort of patients with moderate chronic kidney disease.

Kidney Int 2020 08 7;98(2):488-497. Epub 2020 Apr 7.

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. Relative telomere length was quantified in peripheral blood by a quantitative PCR method in 4,955 patients from the GCKD study, an ongoing prospective observational cohort. Complete four-year follow-up was available from 4,926 patients in whom we recorded 354 deaths. Relative telomere length was a strong and independent predictor of all-cause mortality. Each decrease of 0.1 relative telomere length unit was highly associated with a 14% increased risk of death (hazard ratio1.14 [95% confidence interval 1.06-1.22]) in a model adjusted for age, sex, baseline eGFR, urine albumin/creatinine ratio, diabetes mellitus, prevalent cardiovascular disease, LDL-cholesterol, HDL-cholesterol, smoking, body mass index, systolic and diastolic blood pressure, C-reactive protein and serum albumin. This translated to a 75% higher risk for those in the lowest compared to the highest quartile of relative telomere length. The association was mainly driven by 117 cardiovascular deaths (1.20 [1.05-1.35]) as well as 67 deaths due to infections (1.27 [1.07-1.50]). Thus, our findings support an association of shorter telomere length with all-cause mortality, cardiovascular mortality and death due to infections in patients with moderate chronic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2020.02.034DOI Listing
August 2020

Use of lipoprotein(a) for refining cardiovascular risk prediction in a low-risk population: The CoLaus/PsyCoLaus study.

Eur J Prev Cardiol 2020 Jul 5:2047487320938271. Epub 2020 Jul 5.

Department of Medicine, Lausanne University Hospital and University of Lausanne, Switzerland.

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http://dx.doi.org/10.1177/2047487320938271DOI Listing
July 2020

Hospitalization and mortality following non-attendance for hemodialysis according to dialysis day of the week: a European cohort study.

BMC Nephrol 2020 06 9;21(1):218. Epub 2020 Jun 9.

Department of Renal Medicine, University College London, London, UK.

Background: The extension of the interdialytic interval due to due to dialysis session non-attendance varies according to which session of the week the patient misses. The impact of this on subsequent hospitalization and mortality is unknown.

Methods: The ARO cohort study prospectively collected data from hemodialysis patients across 15 European countries on demography, comorbidity, laboratory, hospitalisation, mortality and individual hemodialysis sessions from 2007 to 2014. Event rates for death and hospitalisation according to dialysis day of the week were calculated for patients who attended the three previous scheduled hemodialysis sessions, who then on the next scheduled dialysis day either attended or did not attend. The hazard ratio for these events following non-attendance for the first compared to the second dialysis session of the week was estimated using Cox proportional hazards model adjusted for patient demographics.

Results: 3.8 million hemodialysis sessions in 9397 patients were analysed. The non-attendance rates for Monday/Wednesday/Friday sessions were 0.8, 0.9% & 1.4% respectively, and for Tuesday/Thursday/Saturday sessions were 0.6, 1.0% & 1.2% respectively. Compared to those who attended, for the 48-72 h between non-attendance and the next scheduled haemodialysis session, mortality significantly increased from 4.86 to 51.9/100 pt-yrs and hospitalisation increased from 0.58 to 2.1/yr. As time from the two-day break increased, the risk associated with non-attendance lessened: compared to missing the second hemodialysis session, missing the first session had a hazard ratio for mortality of 2.04 (95% CI 1.27-3.29), and for hospitalisation 1.78 (95% CI 1.29-2.47). In patients who attended their scheduled dialysis session and the three preceding, after the two-day break there were absolute increases in mortality (8.3 vs. 4.9/100 pt-yrs) and hospitalisation (1.0 vs. 0.6/yr for the rest of the week) comparable to previous studies.

Conclusions: In addition to hospitalisation and mortality increases seen after the two-day break, additional harm may be manifested in the greater increases in mortality and hospitalisation observed after non-attendance for the first hemodialysis session after the two-day break compared to missing other sessions.
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http://dx.doi.org/10.1186/s12882-020-01874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285433PMC
June 2020

Genome-Wide DNA Methylation in Peripheral Blood and Long-Term Exposure to Source-Specific Transportation Noise and Air Pollution: The SAPALDIA Study.

Environ Health Perspect 2020 06 1;128(6):67003. Epub 2020 Jun 1.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease.

Objective: We performed mutually independent EWAS on transportation noise and air pollution exposures.

Methods: We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (); and particulate matter (PM) with aerodynamic diameter (). We performed candidate (CpG-based; cross-systemic phenotypes, combined into "allostatic load") and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals.

Results: We found no statistically significant CpGs at false discovery rate . However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; ; and , respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and ), renal function and "allostatic load" (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 () and decreased methylation in cg17629796 ().

Conclusions: Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. https://doi.org/10.1289/EHP6174.
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http://dx.doi.org/10.1289/EHP6174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263738PMC
June 2020

Mechanistic insights into lipoprotein(a): from infamous to 'inflammous'.

Eur Heart J 2020 06;41(24):2272-2274

Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1093/eurheartj/ehaa420DOI Listing
June 2020
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