Familial Aggregation of CKD and Heritability of Kidney Biomarkers in the General Population:The Lifelines Cohort Study

Rationale & Objective: Chronic kidney disease (CKD) has a heritable component. We aimed to quantify familial aggregation of CKD in the general population and assess the extent to which kidney traits could be explained by genetic and environmental factors. Study Design: Cross-sectional 3-generation family study. Setting & Participants: Data were collected at entry into the Lifelines Cohort Study from a sample of the general population of the northern Netherlands, composed predominantly of individuals of European ancestry. Exposure: Family history of CKD. Outcomes: The primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR) Analytical Approach: Familial aggregation of CKD was assessed by calculating the recurrence risk ratio (RRR), using adapted Cox proportional hazards models. Heritability of continuous kidney-related traits was estimated using linear mixed models and defined as the ratio of the additive genetic variance to total phenotypic variance. All models were adjusted for age, sex, and known risk factors for kidney disease. Results: Among 155,911 participants with available eGFR data, the prevalence of CKD was 1.19% (1,862 cases per 155,911). The risk of CKD in those with an affected first-degree relative was 3 times higher than the risk in the total sample ( RRR, 3.04 [95% CI, 2.26-4.09). In those with an affected spouse, risk of CKD was also higher (RRR, 1.56 [95% CI, 1.20-1.96]), indicative of shared environmental factors and/or assortative mating. Heritability estimates of eGFR, UAE, and UACR were 44%, 20%, and 18%, respectively. For serum urea, creatinine, and uric acid, estimates were 31%, 37%, and 48%, respectively, whereas estimates for serum electrolytes ranged from 22% to 28%. Limitations: Use of estimated rather than measured GFR. UAE data only available in a subsample. Conclusions: In this large population-based family study, a positive family history was strongly associated with increased risk of CKD. We observed moderate to high heritability of kidney traits and related biomarkers. These results indicate an important role of genetic factors in CKD risk

DNA methylation:a potential mediator between air pollution and metabolic syndrome

Given the global increase in air pollution and its crucial role in human health, as well as the steep rise in prevalence of metabolic syndrome (MetS), a better understanding of the underlying mechanisms by which environmental pollution may influence MetS is imperative. Exposure to air pollution is known to impact DNA methylation, which in turn may affect human health. This paper comprehensively reviews the evidence for the hypothesis that the effect of air pollution on the MetS is mediated by DNA methylation in blood. First, we present a summary of the impact of air pollution on metabolic dysregulation, including the components of MetS, i.e., disorders in blood glucose, lipid profile, blood pressure, and obesity. Then, we provide evidence on the relation between air pollution and endothelial dysfunction as one possible mechanism underlying the relation between air pollution and MetS. Subsequently, we review the evidence that air pollution (PM, ozone, NO2 and PAHs) influences DNA methylation. Finally, we summarize association studies between DNA methylation and MetS. Integration of current evidence supports our hypothesis that methylation may partly mediate the effect of air pollution on MetS

Observational and Genetic Evidence for Bidirectional Effects Between Red Blood Cell Traits and Diastolic Blood Pressure

Background: Previous studies have found associations of red blood cell traits (hemoglobin and red blood cell count, RBC) with blood pressure; whether these associations are causal is unknown.Methods: We performed cross-sectional analyses in the Lifelines Cohort Study (n=167,785). Additionally, we performed bidirectional two sample Mendelian randomization (MR) analyses to explore the causal effect of the two traits on systolic (SBP) and diastolic blood pressure (DBP), using genetic instrumental variables regarding hemoglobin and RBC identified in UK Biobank (n=350,475) and International Consortium of Blood Pressure studies for SBP and DBP (n= 757,601).Results: In cross-sectional analyses we observed positive associations with hypertension and blood pressure for both hemoglobin (OR=1.18, 95% CI: 1.16 to 1.20 for hypertension; B=0.11, 95% CI: 0.11 to 0.12 for SBP; B=0.11, 95% CI: 0.10 to 0.11 for DBP, all per SD) and RBC (OR=1.14, 95% CI: 1.12 to 1.16 for hypertension; B=0.11, 95% CI: 0.10 to 0.12 for SBP; B=0.08, 95% CI: 0.08 to 0.09 for DBP, all per SD). MR analyses suggested that higher hemoglobin and RBC cause higher DBP (inverse variance weighted [IVW] B=0.11, 95% CI: 0.07 to 0.16 for hemoglobin; B=0.07, 95% CI: 0.04 to 0.10 for RBC, all per SD). Reverse MR analyses (all per SD) suggested causal effects of DBP on both hemoglobin (B=0.06, 95% CI: 0.03 to 0.09) and RBC (B=0.08, 95% CI: 0.04 to 0.11). No significant effects on SBP were found.Conclusions: Our results suggest bidirectional causal relationships of hemoglobin and RBC with DBP, but not with SBP

Educational level and risk of chronic kidney disease:longitudinal data from the PREVEND study

BACKGROUND: The longitudinal association between low education and chronic kidney disease (CKD) and its underlying mechanisms is poorly characterized. We therefore examined the association of low education with incident CKD and change in kidney function, and explored potential mediators of this association. METHODS: We analysed data on 6078 participants from the community-based Prevention of Renal and Vascular End-stage Disease study. Educational level was categorized into low, medium and high ( secondary schooling, respectively). Kidney function was assessed by estimating glomerular filtration rate (eGFR) by serum creatinine and cystatin C at five examinations during ∼11 years of follow-up. Incident CKD was defined as new-onset eGFR <60 mL/min/1.73 m2 and/or urinary albumin ≥30 mg/24 h in those free of CKD at baseline. We estimated main effects with Cox regression and linear mixed models. In exploratory causal mediation analyses, we examined mediation by several potential risk factors. RESULTS: Incident CKD was observed in 861 (17%) participants. Lower education was associated with higher rates of incident CKD [low versus high education; hazard ratio (HR) (95% CI) 1.25 (1.05-1.48), Ptrend = 0.009] and accelerated eGFR decline [B (95% CI) -0.15 (-0.21 to -0.09) mL/min/1.73 m2/year, Ptrend < 0.001]. The association between education and incident CKD was mediated by smoking, potassium excretion, body mass index (BMI), waist-to-hip ratio (WHR) and hypertension. Analysis on annual eGFR change in addition suggested mediation by magnesium excretion, protein intake and diabetes. CONCLUSIONS: In the general population, we observed an inverse association of educational level with CKD. Diabetes and the modifiable risk factors smoking, poor diet, BMI, WHR and hypertension are suggested to underlie this association. These findings provide support for targeted preventive policies to reduce socioeconomic disparities in kidney disease

Associations of Genetic Factors, Educational Attainment, and Their Interaction With Kidney Function Outcomes

Both genetic predisposition and low educational attainment (EA) are associated with higher risk of chronic kidney disease. We examined the interaction of EA and genetic risk in kidney function outcomes. We included 3,597 participants from the Prevention of Renal and Vascular End-Stage Disease Cohort Study, a longitudinal study in a community-based sample from Groningen, the Netherlands (median follow-up, 11 years; 1997-2012). Kidney function was approximated by obtaining estimated glomerular filtration rate (eGFR) from serum creatinine and cystatin C. Individual longitudinal linear eGFR trajectories were derived from linear mixed models. Genotype data on 63 single-nucleotide polymorphisms, with known associations with eGFR, were used to calculate an allele-weighted genetic score (WGS). EA was categorized into high, medium, and low. In ordinary least squares analysis, higher WGS and lower EA showed additive effects on reduced baseline eGFR; the interaction term was nonsignificant. In analysis of eGFR decline, the significant interaction term suggested amplification of genetic risk by low EA. Adjustment for known renal risk factors did not affect our results. This study presents the first evidence of gene-environment interaction between EA and a WGS for eGFR decline and provides population-level insights into the mechanisms underlying socioeconomic disparities in chronic kidney disease

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 (λ R) 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 (h 2), shared environment, and genetic correlation (r g) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age 2, and sex. RESULTS: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λ FDR of 1.23 (95% CI 1.20-1.25) for hypertension to λ FDR of 2.48 (95% CI 2.15-2.86) for T2D. Most of these were higher than in spouses (λ Spouses  &lt; λ FDR), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h 2 CRP: 0.26 to h 2 HDL: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λ FDR obesity-MetS: 1.28 (95% CI 1.24-1.32) to λ FDR MetS-T2D: 1.61 (95% CI 1.52-1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from r g HDL-Triglycerides: - 0.53 to r g 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.</p

The association of depression and anxiety with cardiac autonomic activity:The role of confounding effects of antidepressants

Background: Depression and anxiety may unfavorably impact on cardiac autonomic dysregulation. However, it is unclear whether this relationship results from a causal effect or may be attributable to confounding factors. We tested the relationship between depression and anxiety with heart rate (HR) and heart rate variability (HRV) across a 9-year follow-up (FU) period and investigated possible confounding by antidepressant use and genetic pleiotropy. Methods: Data (no. of observations = 6,994, 65% female) were obtained from the longitudinal Netherlands Study of Depression and Anxiety, with repeated waves of data collection of HR, HRV, depression, anxiety, and antidepressant use. Summary statistics from meta-analyses of genome-wide association studies were used to derive polygenic risk scores of depression, HR, and HRV. Results: Across the 9-year FU, generalized estimating equations analyses showed that the relationship between cardiac autonomic dysregulation and depression/anxiety rendered nonsignificant after adjusting for antidepressant use. A robust association was found between antidepressant use (especially tricyclic antidepressants, selective serotonin, and noradrenalin reuptake inhibitors) and unfavorable cardiac autonomic activity across all waves. However, no evidence was found for a genetic correlation of depression with HR and HRV, indicating that confounding by genetic pleiotropy is minimal. Conclusions: Our results indicate that the association between depression/anxiety and cardiac autonomic dysregulation does not result from a causal pathway or genetic pleiotropy, and these traits might therefore not be inevitably linked. Previously reported associations were likely confounded by the use of certain classes of antidepressants

Influence of Dietary Approaches to Stop Hypertension-Type Diet, Known Genetic Variants and Their Interplay on Blood Pressure in Early Childhood ABCD Study

There is limited evidence on association between adherence to the Dietary Approaches to Stop Hypertension (DASH diet) and a lower blood pressure (BP) in children. In a population-based cohort study, among 1068 Dutch children aged 5 to 7, we evaluated the association between a DASH-type diet, 29 known genetic variants incorporated in a genetic risk score, and their interaction on BP. We calculated DASH score based on the food intake data measured through a validated 71-item food frequency questionnaire. In our sample, DASH score ranged from 9 (low adherence to the DASH diet) to 33 (median=21), and genetic score ranged from 18 (low genetic risk on high BP) to 41 (median=29). After adjustment for covariates, each 10 unit increase in DASH score was associated with a lower systolic BP of 0.7 mm Hg (P=0.033). DASH score was negatively associated with hypertension (odds ratio=0.96 [0.92-0.99], P=0.044). Similarly, each SD increment in genetic score was associated with 0.5 mm Hg higher diastolic BP (P=0.002). We found a positive interaction between low DASH score and high genetic score on diastolic BP adjusted for BP risk factors (β=1.52, Pinteraction=0.019 in additive scale and β=0.03, Pinteraction=0.021 in multiplicative scale). Our findings show that adherence to the DASH-type diet, as well as a low (adult-derived) genetic risk profile for BP, is associated with lower BP in children and that the genetic basis of BP phenotypes at least partly overlaps between adults and children. In addition, we found evidence of a gene-diet interaction on BP in children

DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA(1c) levels:a systematic review and replication in a case-control sample of the Lifelines study

AIMS/HYPOTHESIS: Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels. Here we present a systematic review of these studies and attempt to replicate the CpG sites (CpGs) with the most significant associations from these EWASs in a case-control sample of the Lifelines study.METHODS: We performed a systematic literature search in PubMed and EMBASE for EWASs to test the association between DNA methylation and type 2 diabetes and/or glycaemic traits and reviewed the search results. For replication purposes we selected 100 unique CpGs identified in peripheral blood, pancreas, adipose tissue and liver from 15 EWASs, using study-specific Bonferroni-corrected significance thresholds. Methylation data (Illumina 450K array) in whole blood from 100 type 2 diabetic individuals and 100 control individuals from the Lifelines study were available. Multivariate linear models were used to examine the associations of the specific CpGs with type 2 diabetes and glycaemic traits.RESULTS: From the 52 CpGs identified in blood and selected for replication, 15 CpGs showed nominally significant associations with type 2 diabetes in the Lifelines sample (p &lt; 0.05). The results for five CpGs (in ABCG1, LOXL2, TXNIP, SLC1A5 and SREBF1) remained significant after a stringent multiple-testing correction (changes in methylation from -3% up to 3.6%, p &lt; 0.0009). All associations were directionally consistent with the original EWAS results. None of the selected CpGs from the tissue-specific EWASs were replicated in our methylation data from whole blood. We were also unable to replicate any of the CpGs associated with HbA1c levels in the healthy control individuals of our sample, while two CpGs (in ABCG1 and CCDC57) for fasting glucose were replicated at a nominal significance level (p &lt; 0.05).CONCLUSIONS/INTERPRETATION: A number of differentially methylated CpGs reported to be associated with type 2 diabetes in the EWAS literature were replicated in blood and show promise for clinical use as disease biomarkers. However, more prospective studies are needed to support the robustness of these findings.</p