The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk. The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

The seven human APOBEC3 (hA3) genes encode polynucleotide cytidine deaminases that play vital roles in restricting replication of viruses and retrotransposons. However, off-target A3 deamination of the cellular genome is a major source of somatic mutations in human cancer. The ability to study A3 biology in vivo is hindered by the fact that the solitary murine Apobec3 gene (mA3) encodes a cytoplasmic enzyme, with no apparent mutagenic activity. Transgenic expression of individual hA3 genes in mice has helped to confirm their oncogenic potential but important questions including which hA3 genes are active in different tissue contexts and how they function in concert when under control of their cognate promoters cannot be addressed using these models. Here we describe humanization of the mouse mA3 locus by integration of a modified BAC clone encompassing the entire 7-gene hA3 locus from human chromosome 22 replacing mA3 on mouse chromosome 15. APOBEC3 mice are viable and fertile and hA3 gene expression in cells and tissues correlates strongly with expression in corresponding human cells and tissues, indicating human-like regulation of hA3 gene expression in the mice. Splenocytes from this line display a functional human A3 response to Friend Murine Leukaemia Virus (F-MLV) infection. We propose that the Hs-APOBEC3 mouse will uniquely model the function of the complete hA3 locus in a living organism and that it will serve as a useful background upon which to model human cancer, as well as assisting drug discovery efforts. ### Competing Interest Statement The authors have declared no competing interest.

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

BACKGROUND:Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. OBJECTIVE:The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. METHODS:AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. RESULTS:Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. CONCLUSION:Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.

Twenty single-nucleotide polymorphisms that are known to be associated with an increased risk of Alzheimer's disease were categorized into immunity, lipid metabolism and endocytosis pathways. Cytokines are known to play a significant role in AD pathogenesis. Till now no studies have evaluated the relationship between immune, lipid and endocytotic polygenic risk scores, cytokines and glucose metabolism in Mild Cognitive Impairment (MCI). Imaging and cytokine data was obtained from the ADNI dataset. Pearson correlation was calculated on 138 MCI subjects to investigate the relationship between cytokines and the differential polygenetic risk scores. The data of 72 subjects was used to calculate correlations between fluorodeoxyglucose (FDG)-positron emission tomography (PET) measurements and the cytokines. Higher immune and endocytosis risk scores were associated with lower concentrations of multiple cytokines at baseline, while a higher lipid risk score related to higher concentrations of various cytokines, as detailed in Table 1. The total risk score inversely correlated only to pro-inflammatory cytokines, while the risk scores of the different pathways were also shown to be associated to anti-inflammatory and apoptotic cytokines. Interestingly, FDG-PET showed associations with anti-inflammatory cytokine concentrations globally throughout the brain. Bilateral temporal and angular metabolism was shown to be associated to pro-inflammatory, anti-inflammatory and apoptotic cytokines, where glucose metabolism of the posterior cingulate only showed further associations with pro-inflammatory cytokines at both time points.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Background and aims: In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011. Methods: Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients. Results: Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA. Conclusions: The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias.

Aim: The association between lipoprotein(a) (Lp(a)) and coronary artery calcium score (CAC) in asymptomatic individuals is unclear although both are risk factors for atherosclerosis. The influence of ethnicity on this relationship is unestablished. The study objective was to evaluate the influence of Lp(a) on CAC in asymptomatic individuals in our multi-ethnic tertiary clinic.

OBJECTIVE:Imprinted genes are crucial for the growth and development of fetal and juvenile mammals. Altered imprinted gene dosage causes a variety of human disorders, with growth and development during these crucial early stages strongly linked with future metabolic health in adulthood. Neuronatin (Nnat) is a paternally expressed imprinted gene found in neuroendocrine systems and white adipose tissue and is regulated by the diet and leptin. Neuronatin expression is downregulated in obese children and has been associated with stochastic obesity in C57BL/6 mice. However, our recent studies of Nnat null mice on this genetic background failed to display any body weight or feeding phenotypes but revealed a defect in glucose-stimulated insulin secretion due to the ability of neuronatin to potentiate signal peptidase cleavage of preproinsulin. Nnat deficiency in beta cells therefore caused a lack of appropriate storage and secretion of mature insulin. METHODS:To further explore the potential role of Nnat in the regulation of body weight and adiposity, we studied classical imprinting-related phenotypes such as placental, fetal, and postnatal growth trajectory patterns that may impact upon subsequent adult metabolic phenotypes. RESULTS:Here we find that, in contrast to the lack of any body weight or feeding phenotypes on the C57BL/6J background, deletion of Nnat in mice on 129S2/Sv background causes a postnatal growth restriction with reduced adipose tissue accumulation, followed by catch up growth after weaning. This was in the absence of any effect on fetal growth or placental development. In adult 129S2/Sv mice, Nnat deletion was associated with hyperphagia, reduced energy expenditure, and partial leptin resistance. Lack of neuronatin also potentiated obesity caused by either aging or high fat diet feeding. CONCLUSIONS:The imprinted gene Nnat plays a key role in postnatal growth, adult energy homeostasis, and the pathogenesis of obesity via catch up growth effects, but this role is dependent upon genetic background.

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone- and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat-null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole-animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.

Aim: Evolocumab and Alirocumab are the currently licensed PCSK9 inhibitors. The most common adverse effects reported with them are nasopharyngitis and injection site reactions. To our knowledge, this is the first case report of liver enzyme (LFTs) elevation with Evolocumab. Reintroducing Alirocumab in the same patient did not increase the LFTs.

Revealing the relationship between dysfunctional genes in blood and brain tissues from patients with Alzheimer's Disease (AD) will help us to understand the pathology of this disease. In this study, we conducted the first such large systematic analysis to identify differentially expressed genes (DEGs) in blood samples from 245 AD cases, 143 mild cognitive impairment (MCI) cases, and 182 healthy control subjects, and then compare these with DEGs in brain samples. We evaluated our findings using two independent AD blood datasets and performed a gene-based genome-wide association study to identify potential novel risk genes. We identified 789 and 998 DEGs common to both blood and brain of AD and MCI subjects respectively, over 77% of which had the same regulation directions across tissues and disease status, including the known ABCA7, and the novel TYK2 and TCIRG1. A machine learning classification model containing NDUFA1, MRPL51, and RPL36AL, implicating mitochondrial and ribosomal function, was discovered which discriminated between AD patients and controls with 85.9% of area under the curve and 78.1% accuracy (sensitivity = 77.6%, specificity = 78.9%). Moreover, our findings strongly suggest that mitochondrial dysfunction, NF-κB signalling and iNOS signalling are important dysregulated pathways in AD pathogenesis.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Aim: In June 2016, the National Institute for Health and Care Excellence (NICE) recommended the use of evolocumab in patients with 1)Non-familial hypercholesterolemia with LDL C persistently above 4.0mmol/l and high risk of CVD or LDL-C above 3.5mmol/litre and very high risk of CVD; 2)Heterozygous familial hypercholesterolaemia (FH) either if LDL-C is above 5.0mmol/l without CVD or above 3.5mmol/l with high risk of CVD. In line with the criteria for heterozygotes, NHS England commissioned evolocumab for the treatment of homozygous FH in September 2016. Here we review the prescribing patterns and treatment efficacy of evolocumab on LDL-C and Lipoprotein(a) from a tertiary care lipid service.

This corrects the article DOI: 10.1038/sdata.2017.179.

Sporadic Alzheimer's disease (AD) constitutes 95% of cases and has an unknown aetiology. Apolipoprotein E (APOE) remains the major genetic risk factor for sporadic AD. However, modifiable risk factors like diabetes, hypertension, obesity, physical inactivity, depression, and smoking play significant role in AD. Qrisk2 is a cardiovascular disease (CVD) risk score developed in the UK to calculate the likelihood of developing CVD over the next ten years. To date, no studies have evaluated the influence of CVD risk calculated by Qrisk2 on biomarkers and clinical progression in cognitively normal (CN), and early and late mild cognitive impairment (EMCI and LMCI) subjects. Using the ADNI cohort, we selected 614 participants among CN, EMCI and LMCI, having 2-year follow-up and necessary information to calculate the Qrisk2 score. CSF, Amyloid PET (AV45-PET), [18F]FDG PET data were analysed. ADAS13 and CDR-SB were used as cognitive measures. The Qrisk2–2016 calculator was used to run a modified Qrisk2 score. Multiple regression analysis was performed to evaluate the influence of Qrisk2 scores on top of APOE4 on neurodegenerative markers. Subjects were classified according to APOE4 genotype, and Qrisk2 score (high-risk ≥20%, low-risk <20%). EMCI: in both APOE4 carriers and non-carriers, amyloid load was significantly higher and FDG uptake was significantly lower in high-risk compared to low-risk group at baseline. LMCI: in APOE4 non-carriers FDG uptake in high-risk group significantly deteriorated from baseline to follow up. CN: In APOE4 non-carriers, high-risk group showed significantly lower FDG uptake at baseline and follow up, compared to low-risk group. In APOE4 carriers, FDG uptake significantly decreased longitudinally in the high-risk group. Multiple regression analysis found for Qrisk2 and APOE4 status an independent predictive value on FDG uptake, ADAS13 and CDR-SB changes. We demonstrated for the first time that Qrisk2 is associated with significant changes in cognitive function and cerebral glucose metabolism independent of APOE4 in prodromal AD. This study suggests that CVD risk is associated with progressive neuronal damage, and prevention and treatment of cardiovascular risk is one of the most effective way of preventing AD.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.