65 research outputs found
Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
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
A Mendelian randomization cytokine screen reveals IL-13 as causal factor in risk of severe COVID-19
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
DNA methylation at birth and lateral ventricular volume in childhood:a neuroimaging epigenetics study
Background: Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest. Methods:In this study, we conducted the first epigenome-wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1-weighted brain scans at 10 years), based on data from a large population-based birth cohort, the Generation R Study (N = 840). Employing both probe-level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross-sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all-male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114). Results: At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome-wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV – but not individual top hits – showed significant cross-sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC. Conclusions: This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.</p
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  < 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
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
Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment
SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5′ and 3′ flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5′ or 3′ prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function
Investigating the impact of poverty on mental illness in the UK Biobank using Mendelian Randomization
It is unclear whether poverty and mental illness are causally related. Using UK Biobank and Psychiatric Genomic Consortium data, we examined evidence of causal links between poverty and nine mental illnesses (attention deficit and hyperactivity disorder (ADHD), anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder and schizophrenia). We applied genomic structural equation modelling to derive a poverty common factor from household income, occupational income and social deprivation. Then, using Mendelian randomization, we found evidence that schizophrenia and ADHD causally contribute to poverty, while poverty contributes to major depressive disorder and schizophrenia but decreases the risk of anorexia nervosa. Poverty may also contribute to ADHD, albeit with uncertainty due to unbalanced pleiotropy. The effects of poverty were reduced by approximately 30% when we adjusted for cognitive ability. Further investigations of the bidirectional relationships between poverty and mental illness are warranted, as they may inform efforts to improve mental health for all
Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population
BACKGROUND: Serum calciprotein particle maturation time (T(50)), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T(50) and study their association with cardiovascular disease and mortality. METHODS: We performed a genome-wide association study of serum T(50) in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T(50) on cardiovascular outcomes. Finally, we examined associations between T(50) loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. RESULTS: We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10(−101)), rs2077119 (p = 3.34 × 10(−18)), and rs9870756 (p = 3.10 × 10(−8)), together explaining 18.3% of variation in serum T(50). MR did not demonstrate a causal effect of T(50) on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T(50), was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01–1.28)] and all-cause mortality alone [1.14 (1.00–1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06–1.84), relative excess risk due to interaction 0.54 (0.01–1.08)]. CONCLUSIONS: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T(50) levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease
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