Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Regulation of TRIB1 abundance in hepatocyte models in response to proteasome inhibition.

Tribbles related homolog 1 (TRIB1) contributes to lipid and glucose homeostasis by facilitating the degradation of cognate cargos by the proteasome. In view of the key metabolic role of TRIB1 and the impact of proteasome inhibition on hepatic function, we continue our exploration of TRIB1 regulation in two commonly used human hepatocyte models, transformed cell lines HuH-7 and HepG2. In both models, proteasome inhibitors potently upregulated both endogenous and recombinant TRIB1 mRNA and protein levels. Increased transcript abundance was unaffected by MAPK inhibitors while ER stress was a weaker inducer. Suppressing proteasome function via PSMB3 silencing was sufficient to increase TRIB1 mRNA expression. ATF3 was required to sustain basal TRIB1 expression and support maximal induction. Despite increasing TRIB1 protein abundance and stabilizing bulk ubiquitylation, proteasome inhibition delayed but did not prevent TRIB1 loss upon translation block. Immunoprecipitation experiments indicated that TRIB1 was not ubiquitylated in response to proteasome inhibition. A control bona fide proteasome substrate revealed that high doses of proteasome inhibitors resulted in incomplete proteasome inhibition. Cytoplasm retained TRIB1 was unstable, suggesting that TRIB1 lability is regulated prior to its nuclear import. N-terminal deletion and substitutions were insufficient to stabilize TRIB1. These findings identify transcriptional regulation as a prominent mechanism increasing TRIB1 abundance in transformed hepatocyte cell lines in response to proteasome inhibition and provide evidence of an inhibitor resistant proteasome activity responsible for TRIB1 degradation.

Homozygous Familial Hypercholesterolemia in Canada: An Observational Study.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH. Objectives: The aim of the study was to obtain a comprehensive registry of HoFH in Canada, known to have several founder effect regions, and describe the clinical characteristics and cardiovascular outcomes of this population over time. Methods: Clinical and genetic data on patients with HoFH were collected via a standardized questionnaire sent to academic sites participating in the Familial Hypercholesterolemia Canada network. Results: A total of 48 patients with HoFH were enrolled. The median age at diagnosis was 12 years (interquartile range [IQR]: 5-24) and untreated LDL-C levels were 15.0 mmol/L (IQR: 10.5-18.6 mmol/L; 580 mg/dL IQR: 404-717 mg/dL). At last follow-up visit, median age was 40 years (IQR: 26-54 years). Treated LDL-C levels were 6.75 mmol/L (IQR: 4.73-9.51 mmol/L; 261 mg/dL IQR: 183-368 mg/dL) with 95.5% of patients on statins, 88.6% on ezetimibe, 34.1% on proprotein convertase subtilisin/kexin type 9 inhibitors, 27.3% on lomitapide, 13.6% on evinacumab, and 56.8% were treated with low-density lipoprotein apheresis or plasmapheresis. Deaths were reported in 7 (14.5%) and major adverse cardiovascular events were observed in 14.6% of patients with the average onset at 30 years (IQR: 20-36 years). Aortic stenosis was reported in one-half the patients (47.9%) and 10 (20.8%) underwent aortic valve replacement. Conclusions: This HoFH patient registry in Canada will provide important new health-related knowledge about the phenotypic manifestations and determinants of cardiovascular risk in this population, allowing for closer examination of quality of life and burden to the health care system.

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

BACKGROUND: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene (LDLR) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia. METHODS: To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls. RESULTS: Rare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene (NOS3), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80-3.26; P=5.50×10-9). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86-4.65]; P=5.00×10-6) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14-1.51]; P=2.00×10-4) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk. CONCLUSIONS: Beyond LDLR, we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.

Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.

BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss. METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention. FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training. INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes. FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).

Profound Elevation in LDL Cholesterol Level Following a Ketogenic Diet: A Case Series.

The ketogenic diet (KD) is currently popular for the achievement of weight loss and improvement in glycemic variables. The diet allows consumption of foods high in fat and protein, with strict limitation of carbohydrates. We present a case series of substantial increases in total cholesterol and low-density lipoprotein cholesterol following the initiation of a KD, with improvements in cholesterol levels once the KD was stopped. Novel teaching points include the need for lipid monitoring in patients who choose to follow a KD and for raising awareness of the extreme lipid response that can occur in some patients, particularly lean individuals.

À l'heure actuelle, le régime cétogène (RC) est populaire pour obtenir une perte de poids et améliorer les variables de la glycémie. Le régime repose sur la consommation d'aliments riches en matières grasses et en protéines, et une stricte limitation des aliments riches en glucides. Nous présentons une série de cas dont le cholestérol total et le cholestérol à lipoprotéines de faible densité avaient augmenté de façon substantielle après l'adoption du RC, et dont les concentrations de cholestérol s'étaient améliorées après l'arrêt du RC. Parmi les nouveaux points à retenir figurent la nécessité d'effectuer le bilan lipidique chez les patients qui choisissent de suivre un RC et la conscientisation à la réponse lipidique extrême que l'on peut observer chez certains patients, particulièrement chez les personnes minces.

Targeting skeletal muscle mitochondrial health in obesity.

Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.

Genome-wide screening identifies DNA methylation sites that regulate the blood proteome.

Background: Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Materials & methods: Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins. Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of the ABO locus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure. Conclusion: This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight.

Our lifestyle choices and interactions with the world around us are continuously printed in our DNA through a biochemical process known as epigenomic modification. Excessive epigenomic modification at a DNA site may cause disease. To prevent or treat disease, it is important to find such sites and remove the excessive epigenomic modification with medications or lifestyle changes. Here the authors searched for DNA sites that undergo epigenomic modification. The authors also investigated the mechanism whereby these sites cause disease. The authors found that there are DNA sites where reverting the epigenomic modification could have a big impact on the body. The authors have made these findings publicly available.

A novel anti-inflammatory role links the CARS2 locus to protection from coronary artery disease.

BACKGROUND AND AIMS: Genome-wide association studies (GWAS) identified a coronary artery disease (CAD) risk locus on 13.q34 tagged by rs61969072 (T/G). This variant lies in an intergenic region, proximal to ING1, CARKD and CARS2 but its causal relationship to CAD is unknown. METHODS AND RESULTS: We first demonstrated that rs61969072 and tightly linked single nucleotide polymorphisms (SNPs) associate with CARS2 but not ING1 or CARKD expression in carotid endarterectomy samples, with reduced CARS2 abundance in carriers of the CAD risk allele (G). THP-1 monocytes were differentiated and polarized to proinflammatory (M1) and anti-inflammatory (M2) macrophages. CARS2 gene expression decreased in M1 and increased in M2 macrophages, consistent with a role for CARS2 in inflammation. Gene expression profiling revealed an increase in pro-inflammatory markers in response to CARS2 siRNA knockdown in THP-1 derived macrophages, accompanied by an increased abundance of inflammatory cytokines in the cell supernatant. Functional enrichment analysis of impacted transcripts identified the anti-inflammatory IL10 signalling pathway. Western blot analysis of CARS2 silenced macrophages revealed reduced STAT3 phosphorylation in response to IL-10 and increased expression of LPS-induced genes that are repressed by IL-10, indicating a role for CARS2 in anti-inflammatory signalling. Finally, to simulate vessel wall conditions, macrophages, and smooth muscle cells (SMC) were maintained in co-culture. Significantly, CARS2 silencing in macrophages altered the SMC phenotype, decreasing expression of contractile genes and increasing expression of inflammatory genes. CONCLUSIONS: These data highlight a novel anti-inflammatory novel role for CARS2 in human macrophages and SMCs that may underlie the protective effect of a common GWAS-identified variant.

Association of muscle fiber type with measures of obesity: A systematic review.

Obesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity. Here, we systematically reviewed literature investigating this topic from PubMed, Web of Science, and EMBASE. Of these, 32 articles were included in our final review and analysis. Most studies (22/32) reported a significant relationship between muscle fiber-type proportion and a measure of obesity. Overall, there was a significant negative relationship between the proportion of type I fibers and body mass index (BMI) and a significant positive relationship between the proportion of type IIX fibers and BMI. Moreover, between-group comparisons indicated a greater prevalence of type IIX fibers and a lower prevalence of type I fibers in patients living with obesity relative to lean individuals. These significant relationships were confirmed in a meta-analysis of these data. The causal nature of these associations remains to be evaluated.

Common Polymorphism That Protects From Cardiovascular Disease Increases Fibronectin Processing and Secretion.

BACKGROUND: Fibronectin (FN1) is an essential regulator of homodynamic processes and tissue remodeling that have been proposed to contribute to atherosclerosis. Moreover, recent large-scale genome-wide association studies (GWAS) have linked common genetic variants within the FN1 gene to coronary artery disease risk. METHODS: Public databases were analyzed by 2-Sample Mendelian Randomization. Expression constructs encoding short FN1 reporter constructs and full-length plasma FN1 variants were introduced in various cell models. Secreted and cellular levels were then analyzed and quantified by SDS-PAGE and fluorescence microscopy. Mass spectrometry and glycosylation analyses were performed to probe possible posttranscriptional differences. RESULTS: Bioinformatic analyses revealed that common coronary artery disease risk single nucleotide polymorphisms in the FN1 locus associate with circulating levels of FN1 and that higher FN1 (fibronectin 1) protein levels in plasma are linked to lower coronary artery disease risk. The coronary artery disease-associated FN1 locus encompasses a common polymorphism that translates a L15Q variant situated within the FN1 signal peptide. Introduction of FN1 reporter constructs, differing at position 15, revealed differences in secretion, with the FN1 Q15 variant being less well secreted. Moreover, the L15Q polymorphism was found to alter glycosylation in some cell models but not in human plasma. CONCLUSIONS: In addition to providing novel functional evidence implicating FN1 in cardioprotection, these findings demonstrate that a common variant within a secretion signal peptide regulates protein function.

miR1908-5p regulates energy homeostasis in hepatocyte models.

We previously identified genomic variants that are quantitative trait loci for circulating miR-1908-5p and then showed this microRNA to causally associate with plasma levels of LDL-C, fasting blood glucose and HbA1c. The link to LDL-C was subsequently validated and clarified by the identification of a miR1908-5p-TGFB-LDLR regulatory axis. Here, we continue our investigations on miR1908-5p function by leveraging human primary hepatocytes and HuH-7 hepatoma models. Expression of miR1908-5p was shown to be sensitive to glucose and agents affecting glucose metabolism. Transcriptome-wide changes in primary hepatocytes and HuH-7 cells treated with a miR1908-5p mimic were investigated by enrichment approaches to identify targeted transcripts and cognate pathways. Significant pathways included autophagy and increased mitochondrial function. Reduced activation and/or levels of several key energy and metabolic regulators (AKT, mTOR, ME1, G6PD, AMPK and LKB) were subsequently confirmed in mimic treated HuH-7 cells. These effects were associated with reduced NADPH to NADP+ ratio in HuH-7 cells. LKB1 was validated as a direct target of miR1908-5p, the reintroduction of which was however insufficient to compensate for the impact of the miR1908-5p mimic on AMPK and ACC1. These findings implicate miR1908-5p in metabolic and energy regulation in hepatocyte models via multiple, independent, pathways.

Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians.

A better understanding of the central role of inflammation in the development of coronary artery disease (CAD) has been the impetus for the evaluation of therapeutic strategies targeting the interleukin-1ß/interleukin-6 cytokine signaling pathway, involved in both chronic atherogenesis and in triggering of atherosclerotic plaque rupture. As an inexpensive pharmacologic agent with relatively few adverse effects that tend to be mild and tolerable, the role of colchicine in secondary prevention of atherothrombotic events has been the focus of multiple recent large-scale randomized controlled trials involving patients with stable CAD (Low-Dose Colchicine [LoDoCo] and LoDoCo2 trials), a recent myocardial infarction (Colchicine Cardiovascular Outcome Trial [COLCOT], Colchicine in Patients With Acute Coronary Syndrome [COPS], and Colchicine and Spironolactone in Patients With Myocardial Infarction/Synergy Stent Registry [CLEAR SYNERGY] trials), and undergoing percutaneous coronary interventions (Colchicine in Percutaneous Coronary Intervention [COLCHICINE-PCI] trial). Based on this evidence, low-dose colchicine (0.5 mg once daily) should be considered in patients with recent myocardial infarctions-within 30 days and, ideally, within 3 days-or with stable CAD to improve cardiovascular outcomes. Colchicine should not be used in patients with severe renal or hepatic disease because of the risk of severe toxicity. No serious adverse effect was associated with the combined use of colchicine and high-intensity statin therapy in large trials. The impact of colchicine in high-risk populations of patients with peripheral arterial disease and in those with diabetes for the primary prevention of CAD remains to be established.

Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity.

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

A Common Polymorphism in the FADS1 Locus Links miR1908 to Low-Density Lipoprotein Cholesterol Through BMP1.

OBJECTIVE: Leveraging microRNA-Seq data and the 1000 Genomes imputed genotypes, we identified rs174561 as a strong microRNA quantitative trait loci for circulating microRNA-1908-5p with higher miR-1908-5p and reduced LDL (lowdensity lipoprotein)-cholesterol, fasting glucose and A1c concentrations in carriers of the rs-174561-C allele. Here, we have investigated the molecular mechanism(s) linking miR-1908-5p to LDL-C concentrations. APPROACH AND RESULTS: Transfection experiments demonstrate that the presence of the C allele significantly increases miR- 1908-5p abundance relative to the T allele. LDLR mRNA and low-density lipoprotein receptor (LDLR) total protein were unchanged in response to differential miR-1908-5p expression. However, the ratio of the cleaved to full-length form of LDLR decreased with miR-1908-5p mimic and increased with miR-1908-5p inhibitor treatment. BMP1 (bone morphogenetic protein 1) is a protease responsible for LDLR cleavage, and we show that miR-1908-5p mimic reduces BMP1 mRNA. Using a reporter array, we identified the TGF-ß (transforming growth factor-beta) signaling pathway activity to be reduced by miR- 1908-5p mimic treatment, and this was associated with reduced TGFB1 expression. TGF-ß signaling increases BMP1, and we further demonstrate that the effect of miR-1908-5p on LDLR cleavage is abolished by exogenous TGF-ß treatment. CONCLUSIONS: These findings uncover a mechanism whereby miR-1908-5p reduces TGFB1 abundance resulting in lower expression of BMP1, ultimately leading to reduced LDLR cleavage. Cleavage of the mature LDLR is known to reduce cell surface affinity for LDL, thereby linking miR-1908-5p to lower circulating LDL-cholesterol levels.

Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

[This corrects the article DOI: 10.1371/journal.pgen.1008629.].

2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.

The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment.

Convergence of biomarkers and risk factor trait loci of coronary artery disease at 3p21.31 and HLA region.

Here we seek to identify molecular biomarkers that mediate the effect of risk factors on coronary artery disease (CAD). We perform a SNP-based multiomics data analysis to find biomarkers (probes) causally associated with the risk of CAD within known genomic loci for its risk factors. We identify 78 biomarkers, the majority (64%) of which are methylation probes. We detect the convergence of several CNS and lifestyle trait loci and their biomarkers at the 3p21.31 and human leukocyte antigen (HLA) regions. The 3p21.31 locus was the most populated region in the convergence of biomarkers and risk factors. In this region, we noted as the BSN gene becomes methylated the level of stomatin (STOM) in blood increases and this contributes to higher risk of CAD. In the HLA locus, we identify several methylation biomarkers associated with various CAD risk factors. SNPs in the CFB gene display a trans-regulatory impact on the GRIA4 protein level. A methylation site upstream of the APOE gene is associated with a higher protein level of S100A13 which in turn leads to higher LDL-C and greater CAD risk. We find UHRF1BP1 and ILRUN mediate the effect of obesity on CAD whereas methylation sites within NOS3 and CKM mediate the effect of their associated-risk factors on CAD. This study provides further insight into the biology of CAD and identifies a list of biomarkers that mediate the impact of risk factors on CAD. A SNP-based initiative can unite data from various fields of omics into a single network of knowledge.

Factors affecting weight loss variability in obesity.

Current obesity treatment strategies include diet, exercise, bariatric surgery, and a limited but growing repertoire of medications. Individual weight loss in response to each of these strategies is highly variable. Here we review research into factors potentially contributing to inter-individual variability in response to treatments for obesity, with a focus on studies in humans. Well-recognized factors associated with weight loss capacity include diet adherence, physical activity, sex, age, and specific medications. However, following control for each of these, differences in weight loss appear to persist in response to behavioral, pharmacological and surgical interventions. Adaptation to energy deficit involves complex feedback mechanisms, and inter-individual differences likely to arise from a host of poorly defined genetic factors, as well as differential responses in neurohormonal mechanisms (including gastrointestinal peptides), metabolic efficiency and capacity of tissues, non-exercise activity thermogenesis, thermogenic response to food, and in gut microbiome. A better understanding of the factors involved in inter-individual variability in response to therapies will guide more personalized approaches to the treatment of obesity.