There is an urgent need for a better molecular understanding of the pathophysiology underlying development and progression of diabetic nephropathy. The aim of the current study was to identify novel ...associations between serum lipidomics and diabetic nephropathy. Non-targeted serum lipidomic analyses were performed with mass spectrometry in 669 individuals with type 1 diabetes. Cross-sectional associations of lipid species with estimated glomerular filtration rate (eGFR) and urinary albumin excretion were assessed. Moreover, associations with register-based longitudinal follow-up for progression to a combined renal endpoint including ≥30% decline in eGFR, ESRD and all-cause mortality were evaluated. Median follow-up time was 5.0-6.4 years. Adjustments included traditional risk factors and multiple testing correction. In total, 106 lipid species were identified. Primarily, alkyl-acyl phosphatidylcholines, triglycerides and sphingomyelins demonstrated cross-sectional associations with eGFR and macroalbuminuria. In longitudinal analyses, thirteen lipid species were associated with the slope of eGFR or albuminuria. Of these lipids, phosphatidylcholine and sphingomyelin species, PC(O-34:2), PC(O-34:3), SM(d18:1/24:0), SM(d40:1) and SM(d41:1), were associated with lower risk of the combined renal endpoint. PC(O-34:3), SM(d40:1) and SM(d41:1) were associated with lower risk of all-cause mortality while an SM(d18:1/24:0) was associated with lower risk of albuminuria group progression. We report distinct associations between lipid species and risk of renal outcomes in type 1 diabetes, independent of traditional markers of kidney function.
Accumulating evidence showed a bidirectional association between post-traumatic stress disorder and inflammation. However, whether the association is causal remains unclear. We aimed to evaluate the ...causal relationships between inflammatory cytokines and post-traumatic stress disorder using two-sample bi-directional Mendelian randomization analysis.
Single nucleotide polymorphism from genome-wide association studies of inflammatory cytokines, C-reactive protein, and post-traumatic stress disorder (23,212 patients and 151,447 controls) was selected as instrumental variables. The causal associations were estimated by inverse variance weighting with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods.
We observed suggestive associations of genetically predicted interleukin-17 (IL-17) and RANTES with post-traumatic stress disorder. One standard deviation (SD) increase in genetically predicted level of IL-17 lowered the risk of post-traumatic stress disorder with an odds ratio (OR) of 0.902 (95 % CI = 0.828, 0.984, P = 0.02). One SD higher genetically predicted RANTES (CCL5) concentration increased post-traumatic stress disorder risk (OR = 1.067, 95 % CI = 1.005, 1.133, P = 0.032). However, we found no evidence of causal associations of post-traumatic stress disorder with the selected inflammatory cytokines and biomarkers. We observed no evidence supporting the presence of pleiotropy. The results of sensitivity analyses demonstrated the same directions and similar effect sizes as the primary findings.
Potential pleiotropy, possible weak instruments, and low statistical power limited our findings.
Inflammation was suggestively causally associated with the risk of post-traumatic stress disorder, and inflammatory cytokines had no downstream effect on post-traumatic stress disorder. Further studies are needed to explain the mechanisms of systemic inflammation and neuroinflammation in post-traumatic stress disorder.
•Evidence suggests a bidirectional causality between inflammation and PTSD.•We performed two-sample bidirectional Mendelian randomization approach to detect the causal associations between inflammation and PTSD.•We observed suggestive evidence that genetically increased RANTES was causally associated with a higher risk of PTSD.•Genetically elevated IL-17 showed the potential protective effect for PTSD.•Altered inflammatory cytokines concentrations had no downstream effect on PTSD.
Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota-derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations ...and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes.
Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models.
After 15.0 (6.7-19.3) (median interquartile range) years of follow-up, we recorded all-cause and cardiovascular mortality (
= 363 and 120, respectively), combined CVD (
= 406), coronary outcome (myocardial infarction and coronary intervention) (
= 163), stroke (
= 115), hospitalization for heart failure (
= 81), and end-stage renal disease (
= 144). In univariate analyses, higher TMAO concentrations were associated with all end points (
≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (
≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (
= 0.29;
< 0.001).
In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function.
To identify novel pathophysiological signatures of longstanding type 1 diabetes (T1D) with and without albuminuria we investigated the gut microbiome and blood metabolome in individuals with T1D and ...healthy controls (HC). We also mapped the functional underpinnings of the microbiome in relation to its metabolic role.
One hundred and sixty-one individuals with T1D and 50 HC were recruited at the Steno Diabetes Center Copenhagen, Denmark. T1D cases were stratified based on levels of albuminuria into normoalbuminuria, moderate and severely increased albuminuria. Shotgun sequencing of bacterial and viral microbiome in stool samples and circulating metabolites and lipids profiling using mass spectroscopy in plasma of all participants were performed. Functional mapping of microbiome into Gut Metabolic Modules (GMMs) was done using EggNog and KEGG databases. Multiomics integration was performed using MOFA tool.
Measures of the gut bacterial beta diversity differed significantly between T1D and HC, either with moderately or severely increased albuminuria. Taxonomic analyses of the bacterial microbiota identified 51 species that differed in absolute abundance between T1D and HC (17 higher, 34 lower). Stratified on levels of albuminuria, 10 species were differentially abundant for the moderately increased albuminuria group, 63 for the severely increased albuminuria group while 25 were common and differentially abundant both for moderately and severely increased albuminuria groups, when compared to HC. Functional characterization of the bacteriome identified 23 differentially enriched GMMs between T1D and HC, mostly involved in sugar and amino acid metabolism. No differences in relation to albuminuria stratification was observed. Twenty-five phages were differentially abundant between T1D and HC groups. Six of these varied with albuminuria status. Plasma metabolomics indicated differences in the steroidogenesis and sugar metabolism and circulating sphingolipids in T1D individuals. We identified association between sphingolipid levels and Bacteroides sp. abundances. MOFA revealed reduced interactions between gut microbiome and plasma metabolome profiles albeit polar metabolite, lipids and bacteriome compositions contributed to the variance in albuminuria levels among T1D individuals.
Individuals with T1D and progressive kidney disease stratified on levels of albuminuria show distinct signatures in their gut microbiome and blood metabolome.
Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with ...common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
Abstract The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study ...aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers ( P < 5 × 10 –8 ). Notably, SNP rs17793860 surpassed our study-wide significance threshold ( P < 1.19 × 10 –9 ). Additionally, rs4530093 was linked to bacterial beta diversity ( P < 5 × 10 –8 ). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors.
Subjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was ...to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM.
We included subjects from a Danish cohort of T1DM subjects (Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e'≥12 or E/e' 8-12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed.
One-hundred forty-six subjects had diastolic dysfunction and 18 systolic dysfunction. Compared to the control group, patients with myocardial dysfunction had longer duration of diabetes (p = 0.005), and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p < 0.001), albuminuria (p < 0.001), and incidence of advanced retinopathy (p < 0.001). The supervised classification model identified a specific pattern associated with myocardial dysfunction, with a capacity to discriminate patients with myocardial dysfunction from controls. PLS-DA showed that triglyceride-rich lipoproteins (TGRLs), such as VLDL (total VLDL particles, large VLDL subclass and VLDL-TG content) and IDL (IDL cholesterol content), as well as the plasma concentration of GlycA, were associated with the presence of subclinical myocardial dysfunction.
Proatherogenic TGRLs and the proinflammatory biomarker Glyc A are strongly associated to myocardial dysfunction in T1DM. These findings suggest a pivotal role of TGRLs and systemic inflammation in the development of subclinical myocardial dysfunction in T1DM.
Abstract
Background
Plasma copeptin is a surrogate of arginine vasopressin (AVP) secretion and is associated with a risk of renal and cardiovascular disease. We investigated associations between ...copeptin and renal events, cardiovascular events and mortality in type 1 diabetes (T1D).
Methods
We conducted a prospective cohort study on 658 individuals with T1D from Steno Diabetes Center Copenhagen. Plasma copeptin concentrations and conventional risk factors were assessed at baseline. The five endpoints were traced through national registries and electronic laboratory records.
Results
Baseline mean age was 55 ± 13 years and estimated glomerular filtration rate (eGFR) was 81 ± 26 mL/min/1.73 m2. The median follow-up was 6.2 years (interquartile range 5.8–6.7); 123 participants reached a combined renal endpoint decline in eGFR ≥30%, end-stage kidney disease (ESKD) or all-cause mortality, 93 had a decrease in eGFR ≥30%, 21 developed ESKD, 94 experienced a combined cardiovascular endpoint and 58 died from all causes. Higher copeptin was associated with all endpoints in unadjusted Cox regression analyses. Upon adjustment for baseline eGFR, the associations were attenuated and remained significant only for the combined renal endpoint and decrease in eGFR ≥30%. Results were similar upon further adjustment for other risk factors, after which hazard ratios for the two renal endpoints were 2.27 (95% confidence interval 1.08–4.74) and 4.49 (1.77–11.4), respectively, for the highest versus the lowest quartile of copeptin.
Conclusions
Higher copeptin was an independent risk marker for a combined renal endpoint and decline in renal function. AVP may be a marker of renal damage or a factor whose contribution to renal and cardiovascular risk is partially mediated by renal damage.
Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in ...T1D.
In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m
per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m
per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform.
At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m
. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 (
= 0.039). Observations were confirmed in the validation subset.
Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D.
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