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AimsRare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants.MethodsThis is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years.ResultsTwenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up.ConclusionsApproximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients. Aims: Rare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants. Methods: This is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years. Results: Twenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up. Conclusions: Approximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients.

Body mass index (BMI) is a highly heritable polygenic trait. It is also affected by various environmental and behavioral risk factors. We used a BMI polygenic risk score (PRS) to study the interplay between the genetic and environmental factors defining BMI. First, we generated a BMI PRS that explained more variance than a BMI genetic risk score (GRS), which was using only genome-wide significant BMI-associated variants (R2= 13.1% compared to 6.1%). Second, we analyzed interactions between BMI PRS and seven environmental factors. We found a significant interaction between physical activity and BMI PRS, even when the well-known effect of theFTOregion was excluded from the PRS, using a small dataset of 6,179 samples. Third, we stratified the study population into two risk groups using BMI PRS. The top 22% of the studied populations were included in a high PRS risk group. Engagement in self-reported physical activity was associated with a 1.66 kg/m2decrease in BMI in this group, compared to a 0.84 kg/m2decrease in BMI in the rest of the population. Our results (i) confirm that genetic background strongly affects adult BMI in the general population, (ii) show a non-linear interaction between BMI genetics and physical activity, and (iii) provide a standardized framework for future gene-environment interaction analyses.

Overweight in children is strongly associated with parental body mass index (BMI) and overweight. We assessed parental transmitted and non-transmitted genetic contributions to overweight in children from the Danish National Birth Cohort by constructing genetic risk scores (GRSs) from 941 common genetic variants associated with adult BMI and estimating associations of transmitted maternal/paternal and non-transmitted maternal GRS with child overweight. Maternal and paternal BMI (standard deviation (SD) units) had a strong association with childhood overweight [Odds ratio (OR): 2.01 (95% confidence interval (CI) 1.74; 2.34) and 1.64 (95% CI 1.43; 1.89)]. Maternal and paternal transmitted GRSs (SD-units) increased odds for child overweight equally [OR: 1.30 (95% CI 1.16; 1.46) and 1.30 (95% CI 1.16; 1.47)]. However, both the parental phenotypic and the GRS associations may depend on maternal BMI, being weaker among mothers with overweight. Maternal non-transmitted GRS was not associated with child overweight [OR 0.98 (95% CI 0.88; 1.10)] suggesting no specific influence of maternal adiposity as such. In conclusion, parental transmitted GRSs, based on adult BMI, contribute to child overweight, but in overweight mothers other genetic and environmental factors may play a greater role.

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment(1). The origins of specific compounds are known, including metabolites that are highly heritable(2,3), or those that are influenced by the gut microbiome(4), by lifestyle choices such as smoking(5), or by diet(6). However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts(7,8) that were not available to us when we trained the algorithms. We used feature attribution analysis(9) to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.The levels of 1,251 metabolites are measured in 475 phenotyped individuals, and machine-learning algorithms reveal that diet and the microbiome are the determinants with the strongest predictive power for the levels of these metabolites.

Fetal intrauterine growth is influenced by complex interactions between the maternal genes, environment and fetal genes. The aim of this study was to assess the effect of GWAS-identified genetic variants associated with birth weight on intrauterine fetal growth in 665 children. Fetal growth was estimated by two-dimensional ultrasound scans at 20, 25 and 32 weeks of gestation and growth trajectories were modeled using mixed linear regression. A genetic risk score (GRS) of birth weight-raising variants was associated with intrauterine growth showing an attenuating effect on the unconditional daily reduction in proportional weight gain of 8.92 × 10−6 percentage points/allele/day (p = 2.0 × 10−4), corresponding to a mean difference of 410 g at 40 weeks of gestation between a child with lowest and highest GRS. Eight variants were independently associated with intrauterine growth throughout the pregnancy, while four variants were associated with fetal growth in the periods 20–25 or 25–32 weeks of gestation, indicating that some variants may act in specific time windows during pregnancy. Four of the intrauterine growth variants were associated with type 2 diabetes, hypertension or BMI in the UK Biobank, which may provide basis for further understanding of the link between intrauterine growth and later risk of metabolic disease.

Background Dislipidaemia and increased levels of apolipoprotein B (apoB) in individuals with obesity are risk factors for development of cardiovascular disease (CVD). The aim of this study was to investigate the effect of weight loss and weight maintenance with and without liraglutide treatment on plasma lipid profiles and apoB. Methods Fifty-eight individuals with obesity (body mass index 34.5 ± 3.0 kg/m2 [mean ± SD]) were included in this study. After 8 weeks on a very low-calorie diet (800 kcal/day), participants were randomized to weight maintenance with meal replacements with or without liraglutide (1.2 mg daily) for 1 year. Plasma samples from before and after weight loss and after 1 year of weight maintenance were subjected to nuclear magnetic resonance-based lipidomics analysis. Results After an 8-week low-calorie diet, study participants lost 12.0 ± 2.9 kg (mean ± SD) of their body weight, which was reflected in their lipid profiles (80 out of 124 lipids changed significantly), including reduced levels of apoB, total cholesterol, free cholesterol, remnant cholesterol, triglycerides, low-density lipoprotein and very low-density lipoprotein subclasses. After 1 year of maintained weight loss, the majority of the lipids had returned to pre-weight loss levels even though weight loss was successfully maintained in both groups. Interestingly, apoB levels remained low in the liraglutide treated group (apoB change: 0.03 ± 0.02 mmol/L, p = 0.4) in contrast to an increase in the control group (apoB change: 0.06 ± 0.07 mmol/L, p = 0.02). Conclusion An 8-week low-calorie diet, in individuals with obesity, reduced plasma levels of lipids and the atherogenic marker apoB. After 1 year of weight maintenance, only study participants treated with liraglutide maintained reduced levels of apoB, despite similar body weight maintenance. Treatment with liraglutide may therefore reduce apoB levels and thus reflect lower CVD risk. Including apoB measurements in clinical practice when monitoring patients with dislipidemia or CVD might prove to be useful.

Key points Obesity during pregnancy and childbirth is associated with labour dystocia leading to instrumental or operative delivery, but the underlying pathophysiological mechanisms remain unclear and insufficient uterine contractility has been suggested. This study examined whether reduced myometrial mitochondrial capacity or quantity could contribute as a pathophysiological mechanism to labour dystocia. Data did not support reduced myometrial mitochondrial capacity or quantity in the myometrium at term in obese women, but a reduced myocyte density with increased triglyceride content was demonstrated, which could lead to poorer uterine contractility. These results add to the understanding of systemic effects of obesity, placing also the myometrium at term as an affected non-adipose tissue. Abstract Obesity is known to increase the risk of labour dystocia and insufficient energy supply, due to reduced mitochondrial capacity or quantity, could be a possible mechanism leading to reduced efficiency of uterine contractility during labour. In the present study of 36 women having an elective Caesarean section at term, obesity did not change mitochondrial phenotype in the myometrial myocyte obtained from uterine biopsies taken at delivery. Respiration rates in isolated mitochondria were unaffected by obesity. No indication of reduced content, investigated by quantification of the complexes of the respiratory chain, or altered regulation, examined by myometrial mRNA levels of genes related to mitochondrial biogenesis and inflammation, was detected. Yet we found increased myometrial triglyceride content in the obese group (2.39 ± 0.26 vs. 1.56 ± 0.20 mm, P = 0.024), while protein content and citrate synthase activity per gram wet weight myometrium were significantly lower in the obese (109.2 ± 7.2 vs. 139.4 ± 5.6 mg g−1, P = 0.002, and 24.8 ± 1.0 vs. 29.6 ± 1.4 U g−1 wet wt, P = 0.008, respectively). These differences were substantiated by our histological findings where staining for nuclei, cytoplasm, glycogen and collagen supported the idea of a smaller muscle content in the myometrium in obese women. In conclusion no indication of myometrial mitochondrial dysfunction in the isolated state was found, but the observed increase of lipid content might play a role in the pathophysiological mechanisms behind labour dystocia in obese women.

OBJECTIVES: The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes.METHODS: In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161).RESULTS: In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( β = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( β = -0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p CONCLUSION: Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.

BACKGROUND: Recent GWAS studies have identified more than 300 SNPs associated with variation in blood pressure. We investigated whether a genetic risk score constructed from these variants is associated with burden of coronary heart disease.METHODS: From 2010-2014, 4,809 individuals admitted to coronary angiography in Capital Region of Copenhagen were genotyped. We calculated hypertension GRS comprised of GWAS identified SNPs associated with blood pressure. We performed logistic regression analyses to estimate the risk of hypertension and prevalent CHD. We also assessed the severity of CHD associated with the GRS. The analyses were performed using GRS quartiles. We used the Inter99 cohort to validate our results and to investigate for possible pleiotropy for the GRS with other CHD risk factors.RESULTS: In COGEN, adjusted odds ratios comparing the 2nd, 3rd and 4th cumulative GRS quartiles with the reference were 1.12(95% CI 0.95-1.33), 1.35(95% CI 1.14-1.59) and 1.29(95% CI 1.09-1.53) respectively, for prevalent CHD. The adjusted multinomial logistic regression showed that 3rd and 4th GRS quartiles were associated with increased odds of developing two(OR 1.33, 95% CI 1.04-1.71 and OR 1.36, 95% CI 1.06-1.75, respectively) and three coronary vessel disease(OR 1.77, 95% CI 1.36-2.30 and OR 1.65, 95% CI 1.26-2.15, respectively). Similar results for incident CHD were observed in the Inter99 cohort. The hypertension GRS did not associate with type 2 diabetes, smoking, BMI or hyperlipidemia.CONCLUSION: Hypertension GRS quartiles were associated with an increased risk of hypertension, prevalent CHD, and burden of coronary vessel disease in a dose-response pattern. We showed no evidence for pleiotropy with other risk factors for CHD.

Background Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG (rs36210421 and rs1805123) on QT interval and plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon during an oral glucose tolerance test (OGTT). We used two population-based cohorts for evaluation of the effect of common variants in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1, GIP, insulin and glucagon during an OGTT. Results Carriers of either the minor A-allele of rs36210421 or the minor G-allele of rs1805123 had ~ 2 ms shorter QT interval per risk allele (p = 0.025 and p = 1.9 × 10− 7). Additionally, both variants were associated with alterations in pancreatic and gut hormone release among carriers. The minor A- allele of rs36210421 was associated with increased GLP-1 and decreased GIP response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release. A genetic risk score combining the two gene variants revealed reductions in glucose-stimulated GIP, as well as suppressed glucagon response to increased glucose levels during an OGTT. Conclusions Two common missense polymorphisms of the Kv11.1 voltage-gated hERG potassium channel are associated with alterations in circulating levels of GIP and glucagon, suggesting that hERG potassium channels play a role in fasting and glucose-stimulated release of GIP and glucagon. Trial registration ClinicalTrials.gov (NCT00289237). Trial retrospectively registered at February 9, 2006. Studies were approved by the Ethical Committee of the Central Denmark Region (journal no. 20080229) and by the Copenhagen County Ethical Committee (KA 98155). Electronic supplementary material The online version of this article (10.1186/s12863-018-0602-2) contains supplementary material, which is available to authorized users.

Key Clinical Message It is important to be aware of the risk of abnormally invasive placenta in patients with a history of Asherman syndrome and uterine scarring. A prenatal diagnosis by ultrasonography is useful when planning of mode of delivery.

Obesity during pregnancy and childbirth is associated with labour dystocia leading to instrumental or operative delivery, but the underlying pathophysiological mechanisms remain unclear and insufficient uterine contractility has been suggested. This study examined whether reduced myometrial mitochondrial capacity or quantity could contribute as a pathophysiological mechanism to labour dystocia. Data did not support reduced myometrial mitochondrial capacity or quantity in the myometrium at term in obese women, but a reduced myocyte density with increased triglyceride content was demonstrated, which could lead to poorer uterine contractility. These results add to the understanding of systemic effects of obesity, placing also the myometrium at term as an affected non-adipose tissue.Obesity is known to increase the risk of labour dystocia and insufficient energy supply, due to reduced mitochondrial capacity or quantity, could be a possible mechanism leading to reduced efficiency of uterine contractility during labour. In the present study of 36 women having an elective Caesarean section at term, obesity did not change mitochondrial phenotype in the myometrial myocyte obtained from uterine biopsies taken at delivery. Respiration rates in isolated mitochondria were unaffected by obesity. No indication of reduced content, investigated by quantification of the complexes of the respiratory chain, or altered regulation, examined by myometrial mRNA levels of genes related to mitochondrial biogenesis and inflammation, was detected. Yet we found increased myometrial triglyceride content in the obese group (2.39 ± 0.26 vs. 1.56 ± 0.20 mm, P = 0.024), while protein content and citrate synthase activity per gram wet weight myometrium were significantly lower in the obese (109.2 ± 7.2 vs. 139.4 ± 5.6 mg g

The TCF7L2 rs7903146 T-allele shows the strongest association with type 2 diabetes (T2D) among common gene variants. The aim of this study was to assess circulating levels of metabolites following a meal test in individuals carrying the high risk rs790346 TT genotype (cases) and low-risk CC genotype (controls). Sixty-two men were recruited based on TCF7L2 genotype, 31 were TT carriers and 31 were age- and BMI-matched CC carriers. All participants consumed a test meal after 12 hours of fasting. Metabolites were measured using proton nuclear magnetic resonance (NMR) spectroscopy. Metabolomic profiling of TCF7L2 carriers were performed for 141 lipid estimates. TT carriers had lower fasting levels of L-VLDL-L (total lipids in large very low density lipoproteins, p = 0.045), L-VLDL-CE (cholesterol esters in large VLDL, p = 0.03), and L-VLDL-C (total cholesterol in large VLDL, p = 0.045) compared to CC carriers. Additionally, TT carriers had lower postprandial levels of total triglycerides (TG) (q = 0.03), VLDL-TG (q = 0.05, including medium, small and extra small, q = 0.048, q = 0.0009, q = 0.04, respectively), HDL-TG (triglycerides in high density lipoproteins q = 0.037) and S-HDL-TG (q = 0.00003). In conclusion, TT carriers show altered postprandial triglyceride response, mainly influencing VLDL and HDL subclasses suggesting a genotype-mediated effect on hepatic lipid regulation.

Objectives To assess the detection rate of triploidy at first-trimester screening for trisomy 21 and evaluate outcome in triploid pregnancies. Methods From 2008 to 2011, 198 427 women with singleton pregnancies underwent first-trimester screening between 11 + 2 and 14 + 0 weeks' gestation. Screening parameters included nuchal translucency, maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). In all triploid fetuses, these parameters were re-evaluated. Karyotypes were established by invasive testing (chorionic villus sampling or amniocentesis) or postabortem and obtained from the Danish Cytogenetic Central Register and the Danish Fetal Medicine Database. Results A total of 30 triploid fetuses underwent first-trimester screening. Twenty-five were diagnosed as a result of abnormal first-trimester scan findings, a detection rate of 83.3%. Twenty-three fetuses were identified due to a high risk for trisomy 13, 18 or 21 and two fetuses due to structural abnormalities. The incidence of triploidy at first-trimester screening was 1:6614. A smaller crown–rump length than that estimated by date of last menstrual period was found in 95% of the fetuses with data available for evaluation. Eight fetuses had a larger biparietal diameter than expected for gestational age. Fetuses with a 69,XXX karyotype had significantly lower multiples of the median values for β-hCG and PAPP-A than did 69,XXY fetuses (P = 0.045 and P = 0.02 forβ-hCG and PAPP-A, respectively). No infants with triploidy were born in the study period. Among the triploid gestations detected on first-trimester screening, 20 (80.0%) women chose termination of pregnancy, four (16.0%) had spontaneous miscarriage and one (4.0%) was stillborn. Conclusion First-trimester screening for trisomy 21 also provides a high detection rate for triploidy. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Increased levels of circulating branched chain amino acids (BCAAs), as well as phenylalanine, and tyrosine have been suggested to be involved in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unknown how these metabolites are affected by weight loss, and during weight-maintaining treatment with glucagon-like peptide-1 receptor agonist (GLP-1 RA). We aimed to characterize changes in metabolites related to protein turnover and glycolysis after a weight loss intervention followed by long term weight maintenance with/without GLP-1 RA. Fifty-eight obese individuals underwent a diet-induced 12 % body weight loss during 8 weeks. Participants were randomized to weight maintenance with or without administration of the GLP-1 RA liraglutide (1.2 mg/day) for 52 weeks. Metabolomic profiling by high-throughput proton nuclear magnetic resonance spectroscopy was used for quantification of metabolites. The weight loss was maintained in both groups and was associated with 9–20 % decreases in plasma concentrations of alanine, phenylalanine, histidine, tyrosine and the BCAAs leucine, isoleucine and valine (p

Statins are a widely used group of drugs which can lower cholesterol levels. Recently, there has been emerging evidence that statins may decrease the formation of cholesterol gallstones and several studies have reported invert association between symptomatic cholesterol gallstones and statin use. Subsequent evidence for decrease in gallstone-associated complications among statin users have not been clearly described. In this review we summarize current evidence for the association between statin use and the risk of gallstone-associated complications.

The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression. Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines. Yet, the interindividual response to therapy and slope of disease progression varies markedly among patients with type 2 diabetes. Gene-gene, gene-environment, and gene-treatment interactions may explain some of the variation in disease progression. Several genetic variants have been suggested to be associated with response to antidiabetic drugs. Some are present in drug receptors or drug metabolizers (OCT genes, KCNJ11, ABCC8, and CYP2C9). Numerous type 2 diabetes risk variants have been identified, but genetic risk score models applying these variants have failed to identify 'disease progressors' among patients with diabetes. Although genetic risk scores are based on a few known loci and only explain a fraction of the heritability of type 2 diabetes, it seems that the genes responsible for the development of diabetes may not be the same driving disease progression after the diagnosis has been made. Pharmacogenetic interactions explain some of the interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards.

Asherman syndrome (AS) was first reported in 1894 by Heinrich Fritz, however it was not until 1948 that Joseph Asherman described the syndrome, frequency, and etiology based on a series of cases of intrauterine adhesions following curettage of a gravid uterus in 29 women with secondary amenorrhea (Asherman 1948; 1950).

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease. ispartof: NATURE vol:600 issue:7889 pages:500-+ ispartof: location:England status: published

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20412-9.