Elevated serum TARC levels precede classic Hodgkin lymphoma diagnosis by several years.

Tumor cells in classic Hodgkin lymphoma produce high quantities of the thymus- and activation-related chemokine (TARC). We measured TARC levels in prediagnostic serum samples and found strikingly increased values in the vast majority of patients, as early as 6 years before diagnosis.

Distal-to-proximal etiologically relevant variables associated with the general (p) and specific factors of psychopathology.

BACKGROUND: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors. METHODS: Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle. RESULTS: Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p. CONCLUSIONS: (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.

Pre-donation Assessment of Cystatin C to Improve Prediction of Pre- and Post-Donation GFR in Potential Living Kidney Donors.

BACKGROUND AND HYPOTHESIS: Accurate estimation of glomerular filtration rate (GFR) is crucial in living kidney donation. While most eGFR equations are based on plasma creatinine, its levels are strongly influenced by muscle mass. Application of cystatin C (CysC)-based estimates before donation may improve both estimation of current GFR and prediction of post-donation GFR. METHODS: We assessed the performance of CKD-EPI equations based on creatinine (eGFRcreat-2009, eGFRcreat-2021), cystatin C (eGFRCysC-2012), or both (eGFRcombined-2012, eGFRcombined-2021) for estimating pre- and post-donation measured GFR in 486 living kidney donors. We subsequently focused on a subgroup of individuals with high/low muscle mass (25% highest/lowest 24-hour urinary creatinine excretion, sex-stratified and height-indexed). RESULTS: Pre-donation eGFRcombined 2012 and eGFRcombined 2021 showed the strongest associations with pre- and post-donation mGFR. Pre-donation eGFRcombined 2021 was most accurate for estimating both pre-donation (bias 0.01±11.9 mL/min/1.73m2) and post-donation mGFR (bias 1.3±8.5 mL/min/1.73 m2). In donors with high/low muscle mass, CysC-based equations (with or without creatinine) performed better compared to equations based on only creatinine. CONCLUSIONS: In conclusion, combined eGFR equations yielded a better estimate of pre- and post-donation mGFR, compared to estimates based on creatinine or CysC only. The added value of CysC seems particularly pronounced in donors with high or low muscle mass.

Phase angle and donor type are determinants of coronary artery calcification in stable kidney transplant recipients at twelve months after transplantation.

BACKGROUND AND AIM: Coronary artery calcification (CAC) partially explains the excess cardiovascular morbidity and mortality after kidney transplantation. This study aimed to investigate determinants of CAC in stable kidney transplant recipients at 12 months post-transplantation. METHODS AND RESULTS: CAC-score was quantified by the Agatston method using non-contrast enhanced computed tomography, and age- and sex-standardized CAC-percentiles were calculated. Univariable and multivariable multinomial logistic regression was performed to study potential determinants of CAC. The independent determinants were included in multivariable multinomial logistic regression adjusting for potential confounders. 203 KTRs (age 54.0 ± 14.7 years, 61.1% male) were included. Participants were categorized into four groups according to CAC percentiles (p = 0 [CAC-score = 0], n = 68; p ≥ 1%-p ≤ 50% [CAC score = 29.0 (4.0-166.0)], n = 31; p > 50 ≤ 75% [CAC score = 101.0 (23.8-348.3)], n = 26; and p>75% [CAC score = 581.0 (148.0-1652)], n = 83). Upon multivariable multinomial logistic regression, patients with a narrower phase angle and patients who had received a graft from a deceased donor had a higher risk of being in the >75th CAC-percentile. CONCLUSIONS: This study identifies not only metabolic and transplant-related factors, but also phase angle, a composite marker of cell integrity, as an independent determinant of CAC at 12 months after kidney transplantation. This study offers new perspectives for future research into the value of bioelectrical impedance analysis in relation to vascular calcification in kidney transplant recipients.

Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study.

BACKGROUND: Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. METHODS: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. RESULTS: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. CONCLUSIONS: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Familial co-aggregation and shared genetics of cardiometabolic disorders and traits: data from the multi-generational Lifelines Cohort Study.

BACKGROUND: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study. METHODS: We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λR) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h2), shared environment, and genetic correlation (rg) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age2, and sex. RESULTS: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λFDR of 1.23 (95% CI 1.20-1.25) for hypertension to λFDR of 2.48 (95% CI 2.15-2.86) for T2D. Most of these were higher than in spouses (λSpouses < λFDR), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h2CRP: 0.26 to h2HDL: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λFDR obesity-MetS: 1.28 (95% CI 1.24-1.32) to λFDR MetS-T2D: 1.61 (95% CI 1.52-1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from rg HDL-Triglycerides: - 0.53 to rg LDL-Apolipoprotein B: 0.94). CONCLUSIONS: There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Prediction of measured GFR after living kidney donation from pre-donation parameters.

BACKGROUND: One of the challenges in living kidney donor screening is to estimate remaining kidney function after donation. Here we developed a new model to predict post-donation measured glomerular filtration rate (mGFR) from pre-donation serum creatinine, age and sex. METHODS: In the prospective development cohort (TransplantLines, n = 511), several prediction models were constructed and tested for accuracy, precision and predictive capacity for short- and long-term post-donation 125I-iothalamate mGFR. The model with optimal performance was further tested in specific high-risk subgroups (pre-donation eGFR <90 mL/min/1.73 m2, a declining 5-year post-donation mGFR slope or age >65 years) and validated in internal (n = 509) and external (Mayo Clinic, n = 1087) cohorts. RESULTS: In the development cohort, pre-donation estimated GFR (eGFR) was 86 ± 14 mL/min/1.73 m2 and post-donation mGFR was 64 ± 11 mL/min/1.73 m2. Donors with a pre-donation eGFR ≥90 mL/min/1.73 m2 (present in 43%) had a mean post-donation mGFR of 69 ± 10 mL/min/1.73 m2 and 5% of these donors reached an mGFR <55 mL/min/1.73 m2. A model using pre-donation serum creatinine, age and sex performed optimally, predicting mGFR with good accuracy (mean bias 2.56 mL/min/1.73 m2, R2 = 0.29, root mean square error = 11.61) and precision [bias interquartile range (IQR) 14 mL/min/1.73 m2] in the external validation cohort. This model also performed well in donors with pre-donation eGFR <90 mL/min/1.73 m2 [bias 0.35 mL/min/1.73 m2 (IQR 10)], in donors with a negative post-donation mGFR slope [bias 4.75 mL/min/1.73 m2 (IQR 13)] and in donors >65 years of age [bias 0.003 mL/min/1.73 m2 (IQR 9)]. CONCLUSIONS: We developed a novel post-donation mGFR prediction model based on pre-donation serum creatinine, age and sex.

Genetic confounding in bullying research: Causal claims revisited.

Bullying research has shown repeatedly that victims of bullying have an increased risk for later internalizing problems and bullies have an increased risk for later externalizing problems. Bullying involvement is often, either explicitly or implicitly, presented as part of a causal mechanism for maladjustment. However, genetic vulnerability may confound the reported associations. This study examined to what extent genetic vulnerability can account for the reported associations between bullying involvement (age 11-14) and later internalizing and externalizing problems (age 16), using data from the TRacking Adolescents' Individual Lives Survey (n = 1604). Because polygenic scores capture only a fraction of the total genetic effect, they were extrapolated to the size of single-nucleotide polymorphism and twin heritability estimates to examine genetic confounding while controlling for (hypothetical) polygenic scores that fully capture the genetic effect. Genetic vulnerability for internalizing and externalizing problems confounded, respectively, the association between bullying victimization and later internalizing problems, and the association between bullying perpetration and later externalizing problems. As such, this study showcases a method that can be broadly used to assess the magnitude of genetic confounding. Caution is, however, warranted in interpreting particularly the less straightforward extrapolations of polygenic scores to the size of twin heritability estimates.

Interplay between genetic risk and the parent environment in adolescence and substance use in young adulthood: A TRAILS study.

Many adolescents start using tobacco, alcohol, and cannabis. Genetic vulnerability, parent characteristics in young adolescence, and interaction (GxE) and correlation (rGE) between these factors could contribute to the development of substance use. Using prospective data from the TRacking Adolescent Individuals' Lives Survey (TRAILS; N = 1,645), we model latent parent characteristics in young adolescence to predict young adult substance use. Polygenic scores (PGS) are created based on genome-wide association studies (GWAS) for smoking, alcohol use, and cannabis use. Using structural equation modeling we model the direct, GxE, and rGE effects of parent factors and PGS on young adult smoking, alcohol use, and cannabis initiation. The PGS, parental involvement, parental substance use, and parent-child relationship quality predicted smoking. There was GxE such that the PGS amplified the effect of parental substance use on smoking. There was rGE between all parent factors and the smoking PGS. Alcohol use was not predicted by genetic or parent factors, nor by interplay. Cannabis initiation was predicted by the PGS and parental substance use, but there was no GxE or rGE. Genetic risk and parent factors are important predictors of substance use and show GxE and rGE in smoking. These findings can act as a starting point for identifying people at risk.

Iron Deficiency and Nephrotoxic Heavy Metals: A Dangerous Interplay?

Heavy metals are common in our environment, and all individuals are exposed to them to some extent. These toxic metals have several harmful effects on the body, including the kidney, which is a very sensitive organ. Indeed, heavy metal exposure has been linked to an increased risk of chronic kidney disease (CKD) and its progression, which may be explained by the well-established nephrotoxic effects of these metals. In this hypothesis and narrative literature review, we will shed light on the potential role that another highly common problem in patients with CKD, iron deficiency, may play in the damaging effects of heavy metal exposure in this patient group. Iron deficiency has previously been linked with an increased uptake of heavy metals in the intestine due to the upregulation of iron receptors that also take up other metals. Furthermore, recent research suggests a role of iron deficiency in the retention of heavy metals in the kidney. Therefore, we hypothesize that iron deficiency plays a crucial role in the damaging effects of heavy metal exposure in patients with CKD and that iron supplementation might be a strategy to combat these detrimental processes.

Early increase in single-kidney glomerular filtration rate after living kidney donation predicts long-term kidney function.

Single-kidney glomerular filtration rate (GFR) increases after living kidney donation due to compensatory hyperfiltration and structural changes. The implications of inter-individual variability in this increase in single-kidney GFR are unknown. Here, we aimed to identify determinants of the increase in single-kidney GFR at three-month postdonation, and to investigate its relationship with long-term kidney function. In a cohort study in 1024 donors, we found considerable inter-individual variability of the early increase in remaining single-kidney estimated GFR (eGFR) (median [25th-75th percentile]) 12 [8-18] mL/min/1.73m2. Predonation eGFR, age, and cortical kidney volume measured by CT were the main determinants of the early postdonation increase in single-kidney eGFR. Individuals with a stronger early increase in single-kidney eGFR had a significantly higher five-year postdonation eGFR, independent of predonation eGFR and age. Addition of the postdonation increase in single-kidney eGFR to a model including predonation eGFR and age significantly improved prediction of a five-year postdonation eGFR under 50 mL/min/1.73m2. Results at ten-year follow-up were comparable, while accounting for left-right differences in kidney volume did not materially change the results. Internal validation using 125I-iothalamate-based measured GFR in 529 donors and external validation using eGFR data in 647 donors yielded highly similar results. Thus, individuals with a more pronounced increase in single-kidney GFR had better long-term kidney function, independent of predonation GFR and age. Hence, the early postdonation increase in single-kidney GFR, considered indicative for kidney reserve capacity, may have additional value to eGFR and age to personalize follow-up intensity after living kidney donation.

GWASinspector: comprehensive quality control of genome-wide association study results.

SUMMARY: Quality control (QC) of genome wide association study (GWAS) result files has become increasingly difficult due to advances in genomic technology. The main challenges include continuous increases in the number of polymorphic genetic variants contained in recent GWASs and reference panels, the rising number of cohorts participating in a GWAS consortium, and inclusion of new variant types. Here, we present GWASinspector, a flexible R package for comprehensive QC of GWAS results. This package is compatible with recent imputation reference panels, handles insertion/deletion and multi-allelic variants, provides extensive QC reports and efficiently processes big data files. Reference panels covering three human genome builds (NCBI36, GRCh37 and GRCh38) are available. GWASinspector has a user friendly design and allows easy set-up of the QC pipeline through a configuration file. In addition to checking and reporting on individual files, it can be used in preparation of a meta-analysis by testing for systemic differences between studies and generating cleaned, harmonized GWAS files. Comparison with existing GWAS QC tools shows that the main advantages of GWASinspector are its ability to more effectively deal with insertion/deletion and multi-allelic variants and its relatively low memory use. AVAILABILITY AND IMPLEMENTATION: Our package is available at The Comprehensive R Archive Network (CRAN): https://CRAN.R-project.org/package=GWASinspector. Reference datasets and a detailed tutorial can be found at the package website at http://gwasinspector.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Plasma Lead Concentration and Risk of Late Kidney Allograft Failure: Findings From the TransplantLines Biobank and Cohort Studies.

RATIONALE & OBJECTIVE: Heavy metals are known to induce kidney damage, and recent studies have linked minor exposures to cadmium and arsenic with increased risk of kidney allograft failure, yet the potential association of lead with late graft failure in kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Prospective cohort study in The Netherlands. SETTING & PARTICIPANTS: We studied outpatient KTRs (n = 670) with a functioning graft for ≥1 year recruited at a university setting (2008-2011) and followed for a median of 4.9 (interquartile range, 3.4-5.5) years. Additionally, patients with chronic kidney disease (n = 46) enrolled in the ongoing TransplantLines Cohort and Biobank Study (2016-2017, ClinicalTrials.gov identifier NCT03272841) were studied at admission for transplant and at 3, 6, 12, and 24 months after transplant. EXPOSURE: Plasma lead concentration was log2-transformed to estimate the association with outcomes per doubling of plasma lead concentration and also considered categorically as tertiles of lead distribution. OUTCOME: Kidney graft failure (restart of dialysis or repeat transplant) with the competing event of death with a functioning graft. ANALYTICAL APPROACH: Multivariable-adjusted cause-specific hazards models in which follow-up of KTRs who died with a functioning graft was censored. RESULTS: Median baseline plasma lead concentration was 0.31 (interquartile range, 0.22-0.45) µg/L among all KTRs. During follow-up, 78 (12%) KTRs experienced graft failure. Higher plasma lead concentration was associated with increased risk of graft failure (hazard ratio, 1.59 [95% CI, 1.14-2.21] per doubling; P = 0.006) independent of age, sex, transplant characteristics, estimated glomerular filtration rate, proteinuria, smoking status, alcohol intake, and plasma concentrations of cadmium and arsenic. These findings remained materially unchanged after additional adjustment for dietary intake and were consistent with those of analyses examining lead categorically. In serial measurements, plasma lead concentration was significantly higher at admission for transplant than at 3 months after transplant (P = 0.001), after which it remained stable over 2 years of follow-up (P = 0.2). LIMITATIONS: Observational study design. CONCLUSIONS: Pretransplant plasma lead concentrations, which decrease after transplant, are associated with increased risk of late kidney allograft failure. These findings warrant further studies to evaluate whether preventive or therapeutic interventions to decrease plasma lead concentration may represent novel risk-management strategies to decrease the rate of kidney allograft failure.

Plasma phosphate and all-cause mortality in individuals with and without type 2 diabetes: the Dutch population-based lifelines cohort study.

INTRODUCTION: Individuals with type 2 diabetes have a substantially elevated cardiovascular risk. A higher plasma phosphate level promotes vascular calcification, which may adversely affect outcomes in individuals with type 2 diabetes. We hypothesized that the association between plasma phosphate and all-cause mortality is stronger in individuals with type 2 diabetes, compared to those without diabetes. METHODS: We analysed the association between plasma phosphate and all-cause mortality in the Dutch population-based Lifelines cohort and in subgroups with and without type 2 diabetes, using multivariable Cox regression adjusted for potential confounders. Effect modification was tested using multiplicative interaction terms. RESULTS: We included 57,170 individuals with 9.4 [8.8-10.4] years follow-up. Individuals within the highest phosphate tertile (range 1.00-1.83 mmol/L) were at higher risk of all-cause mortality (fully adjusted HR 1.18 [95% CI 1.02-1.36], p = 0.02), compared with the intermediate tertile (range 0.85-0.99 mmol/L). We found significant effect modification by baseline type 2 diabetes status (p-interaction = 0.003). Within the type 2 diabetes subgroup (N = 1790), individuals within the highest plasma phosphate tertile had an increased mortality risk (HR 1.73 [95% CI 1.10-2.72], p = 0.02 vs intermediate tertile). In individuals without diabetes at baseline (N = 55,380), phosphate was not associated with mortality (HR 1.12 [95% CI 0.96-1.31], p = 0.14). Results were similar after excluding individuals with eGFR < 60 mL/min/1.73 m2. DISCUSSION: High-normal plasma phosphate levels were associated with all-cause mortality in individuals with type 2 diabetes. The association was weaker and non-significant in those without diabetes. Measurement of phosphate levels should be considered in type 2 diabetes; whether lowering phosphate levels can improve health outcomes in diabetes requires further study.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Plasma cadmium is associated with increased risk of long-term kidney graft failure.

The kidney is one of the most sensitive organs to cadmium-induced toxicity, particularly in conditions of long-term oxidative stress. We hypothesized that, in kidney transplant recipients, nephrotoxic exposure to cadmium represents an overlooked hazard for optimal graft function. To test this, we performed a prospective cohort study and included 672 outpatient kidney transplant recipients with a functioning graft of beyond one year. The median plasma cadmium was 58 ng/L. During a median 4.9 years of follow-up, 78 kidney transplant recipients developed graft failure with a significantly different distribution across tertiles of plasma cadmium (13, 26, and 39 events, respectively). Plasma cadmium was associated with an increased risk of graft failure (hazard ratio 1.96, 95% confidence interval 1.56‒2.47 per log2 ng/L). Similarly, a dose-response relationship was observed over increasing tertiles of plasma cadmium, after adjustments for potential confounders (donor, recipient, transplant and lifestyle characteristics), robust in both competing risk and sensitivity analyses. These findings were also consistent for kidney function decline (graft failure or doubling of serum creatinine). Thus, plasma cadmium is independently associated with an increased risk of long-term kidney graft failure and decline in kidney function. Further studies are needed to investigate whether exposure to cadmium represents an otherwise overlooked modifiable risk factor for adverse long-term graft outcomes in different populations.

Metasubtract: an R-package to analytically produce leave-one-out meta-analysis GWAS summary statistics.

SUMMARY: statistics from a meta-analysis of genome-wide association studies (meta-GWAS) can be used for many follow-up analyses. One valuable application is the creation of polygenic scores. However, if polygenic scores are calculated in a validation cohort that was part of the meta-GWAS consortium, this cohort is not independent and analyses will therefore yield inflated results. The R package 'MetaSubtract' was developed to subtract the results of the validation cohort from meta-GWAS summary statistics analytically. The statistical formulas for a meta-analysis were inverted to compute corrected summary statistics of a meta-GWAS leaving one (or more) cohort(s) out. These formulas have been implemented in MetaSubtract for different meta-analyses methods (fixed effects inverse variance or square root sample size weighted z-score) accounting for no, single or double genomic control correction. Results obtained by MetaSubtract correlate very well to those calculated using the traditional way, i.e. by performing a meta-analysis leaving out the validation cohort. In conclusion, MetaSubtract allows researchers to compute meta-GWAS summary statistics that are independent of the GWAS results of the validation cohort without requiring access to the cohort level GWAS results of the corresponding meta-GWAS consortium. AVAILABILITY AND IMPLEMENTATION: https://cran.r-project.org/web/packages/MetaSubtract. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients: a prospective cohort study.

BACKGROUND: It currently remains understudied whether low consumption of fruits and vegetables after kidney transplantation may be a modifiable cardiovascular risk factor. We aimed to investigate the associations between consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients (RTRs). METHODS: Consumption of fruits and vegetables was assessed in an extensively phenotyping cohort of RTRs. Multivariable-adjusted Cox proportional hazards regression analyses were performed to assess the risk of cardiovascular mortality. RESULTS: We included 400 RTRs (age 52 ± 12 years, 54% males). At a median follow-up of 7.2 years, 23% of RTRs died (53% were due to cardiovascular causes). Overall, fruit consumption was not associated with cardiovascular mortality {hazard ratio [HR] 0.82 [95% confidence interval (CI) 0.60-1.14]; P = 0.24}, whereas vegetable consumption was inversely associated with cardiovascular mortality [HR 0.49 (95% CI 0.34-0.71); P < 0.001]. This association remained independent of adjustment for several potential confounders. The association of fruit consumption with cardiovascular mortality was significantly modified by estimated glomerular filtration rate (eGFR; Pinteraction = 0.01) and proteinuria (Pinteraction = 0.01), with significant inverse associations in patients with eGFR > 45 mL/min/1.73 m2 [HR 0.56 (95% CI 0.35-0.92); P = 0.02] or the absence of proteinuria [HR 0.62 (95% CI 0.41-0.92); P = 0.02]. CONCLUSIONS: In RTRs, a relatively higher vegetable consumption is independently and strongly associated with lower cardiovascular mortality. A relatively higher fruit consumption is also associated with lower cardiovascular mortality, although particularly in RTRs with eGFR > 45 mL/min/1.73 m2 or an absence of proteinuria. Further studies seem warranted to investigate whether increasing consumption of fruits and vegetables may open opportunities for potential interventional pathways to decrease the burden of cardiovascular mortality in RTRs.