Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes T2D, n = 775; cardiovascular ...disease CVD, n = 551; random subcohort n = 1137) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk.
Background
Mitochondria play an important role in cellular metabolism, and their dysfunction is postulated to be involved in metabolic disturbances. Mitochondrial DNA is present in multiple copies ...per cell. The quantification of mitochondrial DNA copy number (mtDNA‐CN) might be used to assess mitochondrial dysfunction.
Objectives
We aimed to investigate the cross‐sectional association of mtDNA‐CN with type 2 diabetes and the potential mediating role of metabolic syndrome.
Methods
We examined 4812 patients from the German Chronic Kidney Disease (GCKD) study and 9364 individuals from the Cooperative Health Research in South Tyrol (CHRIS) study. MtDNA‐CN was measured in whole blood using a plasmid‐normalized qPCR‐based assay.
Results
In both studies, mtDNA‐CN showed a significant correlation with most metabolic syndrome parameters: mtDNA‐CN decreased with increasing number of metabolic syndrome components. Furthermore, individuals with low mtDNA‐CN had significantly higher odds of metabolic syndrome (OR = 1.025; 95% CI = 1.011–1.039, P = 3.19 × 10−4, for each decrease of 10 mtDNA copies) and type 2 diabetes (OR = 1.027; 95% CI = 1.012–1.041; P = 2.84 × 10−4) in a model adjusted for age, sex, smoking and kidney function in the meta‐analysis of both studies. Mediation analysis revealed that the association of mtDNA‐CN with type 2 diabetes was mainly mediated by waist circumference in the GCKD study (66%) and by several metabolic syndrome parameters, especially body mass index and triglycerides, in the CHRIS study (41%).
Conclusions
Our data show an inverse association of mtDNA‐CN with higher risk of metabolic syndrome and type 2 diabetes. A major part of the total effect of mtDNA‐CN on type 2 diabetes is mediated by obesity parameters.
Menarche signifies the primary event in female puberty and is associated with changes in self-identity. It is not clear whether earlier puberty causes girls to spend less time in education. ...Observational studies on this topic are likely to be affected by confounding environmental factors. The Mendelian randomization (MR) approach addresses these issues by using genetic variants (such as single nucleotide polymorphisms, SNPs) as proxies for the risk factor of interest. We use this technique to explore whether there is a causal effect of age at menarche on time spent in education. Instruments and SNP-age at menarche estimates are identified from a Genome Wide Association Study (GWAS) meta-analysis of 182,416 women of European descent. The effects of instruments on time spent in education are estimated using a GWAS meta-analysis of 118,443 women performed by the Social Science Genetic Association Consortium (SSGAC). In our main analysis, we demonstrate a small but statistically significant causal effect of age at menarche on time spent in education: a 1 year increase in age at menarche is associated with 0.14 years (53 days) increase in time spent in education (95% CI 0.10–0.21 years, p = 3.5 × 10
−8
). The causal effect is confirmed in sensitivity analyses. In identifying this positive causal effect of age at menarche on time spent in education, we offer further insight into the social effects of puberty in girls.
Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this ...disorder, although the majority of these genes are still unknown.
We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect.
Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes.
We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.
High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure ...diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 × 10(-10)). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P-values from 8.3 × 10(-03) to 9.3 × 10(-11)). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction.
Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic ...factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI 1.15, 1.27, P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI 1.06, 1.12, P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI 1.9, 3.2, P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI 1.3, 2.7, P = 1.2x10-9; and 1.6 minutes per allele, 95% CI 1.1, 2.2, P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, ...with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.
We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron.
Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it ...difficult to infer causality.
The Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium.
There was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m
(95% CI 0.25-0.51 kg/m
). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data.
MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.
Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T ...(Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.
High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of ...various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2786 in discovery and n = 1185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (Phewas) were also explored to further investigate these association results. We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the ROC curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach. We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.
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