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Aims/hypothesis: The aim of this study was to investigate the concordance of dysglycaemia (prediabetes or diabetes) and cardiometabolic traits between women with a history of gestational diabetes mellitus (GDM) and their spouses. Methods: Using hospital medical records, women with GDM (diagnosed between 2012 and 2016) and their spouses were invited to participate in the study and to attend a scheduled hospital visit in a fasting state. Sociodemographic, anthropometric and medical data were collected, and a 75 g OGTT with serum insulin estimation, HbA1c measurement and fasting lipid profile were performed at the visit. Prediabetes and diabetes were defined using ADA criteria and the metabolic syndrome was defined using IDF criteria. Results: A total of 214 couples participated in the study. Women were tested at a mean ± SD age of 32.4 ± 4.6 years and median (quartile [q]25–q75) of 19.5 (11–44) months following the index delivery, while men were tested at a mean ± SD age of 36.4 ± 5.4 years. A total of 72 (33.6%) couples showed concordance for dysglycaemia, while 99 (46.3%) and 51 (23.8%) couples were concordant for overweight/obesity and the metabolic syndrome, respectively. A total of 146 (68.2%) couples showed concordance for any of the above three factors. The presence of dysglycaemia in one partner was associated with an increased risk of dysglycaemia in the other partner (OR 1.80 [95% CI 1.04, 3.11]). Similarly, being overweight/obese (OR 2.19 [95% CI 1.22, 3.93]) and presence of the metabolic syndrome (OR 2.01 [95% CI 1.16, 3.50]) in one partner was associated with an increased risk of these conditions in the other partner. Both women and men were more likely to have dysglycaemia if they had a partner with dysglycaemia. Women with a partner with dysglycaemia had a significantly higher BMI, waist circumference and diastolic BP, and a significantly higher probability of low HDL-cholesterol (<1.29 mmol/l) and the metabolic syndrome compared with women with a normoglycaemic partner. No such differences were observed for men with or without a partner with dysglycaemia. Conclusions/interpretation: The high degree of spousal concordance found in this study suggests social clustering of glycaemic and cardiometabolic traits among biologically unrelated individuals. This provides us with an opportunity to target the behavioural interventions at the level of the 'married couple', which may be a novel and cost-effective method of combating the current diabetes epidemic. [ABSTRACT FROM AUTHOR]

The rapid rise of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) during the last few decades among South Asians has been largely attributed to a major shift in lifestyles including physical inactivity, unhealthy dietary patterns, and an overall pattern of sedentary lifestyle. Genetic predisposition to these cardiometabolic risk factors may have interacted with these obesogenic environments in determining the higher cardiometabolic disease prevalence. Based on the premise that gene-environment interactions cause obesity and cardiometabolic diseases, we systematically searched the literature and considered the knowledge gaps that future studies might fulfill. We identified only seven published studies that focused specifically on gene-environment interactions for cardiometabolic traits in South Asians, most of which were limited by relatively small sample and lack of replication. Some studies reported that the differences in metabolic response to higher physical activity and low caloric diet might be modified by genetic risk related to these cardiometabolic traits. Although studies on gene lifestyle interactions in cardiometabolic traits report significant interactions, future studies must focus on more precise assessment of lifestyle factors, investigation of a larger set of genetic variants and the application of powerful statistical methods to facilitate translatable approaches. Future studies should also be integrated with findings both using mechanistic studies through laboratory settings and randomized clinical trials for clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear.Objectives: The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood.Methods: BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children.Results: Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index.Conclusions: The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects. [ABSTRACT FROM AUTHOR]

Background: High molecular weight (HMW) adiponectin has antiatherogenic, antiinflammatory and antidiabetic properties and these effects have been linked to its effect on high density lipoprotein cholesterol (HDL-c). Single nucleotide polymorphisms (SNPs) in the adiponectin gene influence adiponectin levels. We examined the relationship between HMW-adiponectin levels and cardiometabolic traits in normoand hyperglycemic mixed ancestry South Africans and correlated these levels to two common polymorphisms. Methods: HMW-adiponectin was determined in 101 subjects from the Cape Town Bellville South community-based study on a mixed ancestry population. Comparisons were made between individuals with normoand hyperglycemia. Two common SNPs, ADIPOQ SNPs rs17300539 and rs266729, known to affect adiponectin levels were also tested for. Levels of HMW-adiponectin were then correlated with cardiometabolic traits in all groups. Results: Levels of HMW-adiponectin were not significantly different in the normoand hyperglycemic groups (median 11.6 vs. 10.5 mg/mL, p=0.3060) and in men and women (8.44 vs. 11.34 mg/mL, p = 0.67). ADIPOQ SNPs rs17300539 and rs266729 did not influence levels of HMW-adiponectin. Robust correlation analyses revealed a significant positive correlation between HMW-adiponectin and HDL-c (r= 0.45; 95%CI: 0 .2 7 -0 .5 9 ), similarly in normoand hyperglycemic participants (p> 0.99). This association was substantially attenuated in robust linear regressions adjusted for age, gender and adiposity. Conclusions: Adiponectin levels in this population were not determined by the commonest SNPs of the adiponectin gene, were unaffected by glycemic status; but were significantly correlated with HDL-c levels. Previous studies have attributed some of the beneficial effects of adiponectin to its effect on HDL-c.

Summary: Recent studies provide evidence of correlations of DNA methylation and expression of protein‐coding genes with human aging. The relations of microRNA expression with age and age‐related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole‐blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10−4 (Bonferroni‐corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age‐associated mRNA expression possibly driven by age‐associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict ‘microRNA age’ that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all‐cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10−5 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole‐blood microRNA expression profiling. Age‐associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age‐related diseases. [ABSTRACT FROM AUTHOR]

Background: Dietary intake of phytonutrients present in fruits and vegetables, such as carotenoids, is associated with a lower risk of obesity and related traits, but the impact of genetic variation on these associations is poorly understood, especially in children. Objective: We estimated common genetic influences on serum carotenoid concentrations and obesity-related traits in Mexican American (MA) children. Design: Obesity-related data were obtained from 670 nondiabetic MA children, aged 6-17 y. Serum α- and β-carotenoid concentrations were measured in ~570 (α-carotene in 565 and β-carotene in 572) of these children with the use of an ultraperformance liquid chromatography-photodiode array. We determined heritabilities for both carotenoids and examined their genetic relation with 10 obesity-related traits [body mass index (BMI), waist circumference (WC), high-density lipoprotein (HDL) cholesterol, triglycerides, fat mass (FM), systolic and diastolic blood pressure, fasting insulin and glucose, and homeostasis model assessment of insulin resistance] by using family data and a variance components approach. For these analyses, carotenoid values were inverse normalized, and all traits were adjusted for significant covariate effects of age and sex. Results: Carotenoid concentrations were highly heritable and significant [α-carotene: heritability (h²) = 0.81, P = 6.7 × 10-11; β-carotene: h² = 0.90, P = 3.5 3 10-15]. After adjusting for multiple comparisons, we found significant (P ≤ 0.05) negative phenotypic correlations between carotenoid concentrations and the following traits: BMI, WC, FM, and triglycerides (range: α-carotene = -0.19 to -0.12; β-carotene = -0.24 to -0.13) and positive correlations with HDL cholesterol (α-carotene = 0.17; β-carotene = 0.24). However, when the phenotypic correlations were partitioned into genetic and environmental correlations, we found marginally significant (P = 0.051) genetic correlations only between β-carotene and BMI (-0.27), WC (-0.30), and HDL cholesterol (0.31) after accounting for multiple comparisons. None of the environmental correlations were significant. Conclusions: The findings from this study suggest that the serum carotenoid concentrations were under strong additive genetic influences based on variance components analyses, and that the common genetic factors may influence β-carotene and obesity and lipid traits in MA children. [ABSTRACT FROM AUTHOR]

Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans -eQTLs) affect expression of remote genes (i.e., trans -eGenes) remains unknown. We hypothesized that some trans -eQTLs regulate expression of distant genes by altering the expression of nearby genes ( cis -eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans -eQTLs (at p < 10 −7 ); more than 80% of them were found to have cis -associated eGenes. Mediation testing suggested that for 35% of trans- eQTL -trans- eGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the trans -eGene via cis -eGene expression. In addition, we identified 13 trans -eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis -eGenes ( ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans- mediators ( TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions. Methods: Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software. Results: All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities ( h ) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction. Conclusions/interpretation: Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease. [ABSTRACT FROM AUTHOR]

Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS ( n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10 -8 ). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saadullah Khani, Cotic, Wang, Abidoph, Mills, Richards-Belle, Perry, Khandaker and Bramon.)

The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology. [ABSTRACT FROM AUTHOR]

Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3′-UTR ( u n t ranslated r egion) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (~ 1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (~ 2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3′-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3′-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations ( n ≈ 58,000–96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits. [ABSTRACT FROM AUTHOR]

Background: Observational studies showed that circulating L-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation. Objectives: We assessed the relation between L-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs3 3972313) associated with circulating L-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-L-ascorbic acid and L-ascorbic acid-outcome associations. Design: A meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737). Results: With the use of a meta-analysis of observational estimates, inverse associations were shown between L-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (20.13-SD change; 95% CI: 20.20-, --0.07-SD change; P = 0.0001) per SD increase in L-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 3 10-6) increase in L-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected. Conclusions: The nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of L-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between L-ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation. [ABSTRACT FROM AUTHOR]

Over the past 8 years, the genetics of complex traits have benefited from an unprecedented advancement in the identification of common variant loci for diseases such as type 2 diabetes (T2D). The ability to undertake genome-wide association studies in large population-based samples for quantitative glycaemic traits has permitted us to explore the hypothesis that models arising from studies in non-diabetic individuals may reflect mechanisms involved in the pathogenesis of diabetes. Amongst 88 T2D risk and 72 glycaemic trait loci, only 29 are shared and show disproportionate magnitudes of phenotypic effects. Important mechanistic insights have been gained regarding the physiological role of T2D loci in disease predisposition through the elucidation of their contribution to glycaemic trait variability. Further investigation is warranted to define causal variants within these loci, including functional characterisation of associated variants, to dissect their role in disease mechanisms and to enable clinical translation. [ABSTRACT FROM AUTHOR]

Context: Observational studies have suggested that higher resting heart rate (RHR) may be associated with increased cardiometabolic risk. However, causal associations are not fully understood., Objective: We aimed to examine the direction, strength, and causality of the associations of RHR with cardiometabolic traits., Methods: We assessed the strength of associations between measured RHR and cardiometabolic traits in 506 211 and 372 452 participants from China Kadoorie Biobank (CKB) and UK Biobank (UKB). Mendelian randomization (MR) analyses were used to make causal inferences in 99 228 and 371 508 participants from CKB and UKB, respectively., Results: We identified significant directionally concordant observational associations between RHR and higher total cholesterol, triglycerides (TG), low-density lipoprotein, C-reactive protein (CRP), glucose, body mass index, waist-hip ratio (WHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) after the Bonferroni correction. MR analyses showed that 10 beat/min higher genetically predicted RHR was trans-ethnically associated with a higher DBP (beta 2.059 [95% CI 1.544, 2.574] mmHg in CKB; 2.037 [1.845, 2.229] mmHg in UKB), higher CRP (0.180 [0.057, 0.303] log mg/L in CKB; 0.154 [0.134, 0.174] log mg/L in UKB), higher TG (0.052 [-0.009, 0.113] log mmol/L in CKB; 0.020 [0.010, 0.030] log mmol/L in UKB) and higher WHR (0.218 [-0.033, 0.469] % in CKB; 0.225 [0.111, 0.339] % in UKB). In the opposite direction, higher genetically predicted SBP, TG, glucose, and WHR, and lower high-density lipoprotein, were associated with elevated RHR., Conclusion: Our large-scale analyses provide causal evidence for associations between RHR and cardiometabolic traits, highlighting the importance of monitoring heat rate as a means of alleviating the adverse effects of metabolic disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early life exposure to famine was associated with adulthood metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), and NAFLD was also affected by cardiometabolic traits. However, the role of cardiometabolic traits in the associations from famine exposure to NAFLD was largely unknown. This study aimed to investigate whether the relationship between early life famine exposure and adulthood NAFLD risk was mediated by cardiometabolic traits. Overall, 7578 subjects aged 56·0 (sd 3·7) years in the Dongfeng-Tongji cohort were included and classified into late-exposed (1952-1954), middle-exposed (1954-1956), early-childhood-exposed (1956-1958), fetal-exposed (1959-1961) and non-exposed (1962-1966, reference) group according to the birth year. NAFLD was diagnosed by experienced physicians via abdominal B-type ultrasound inspection. Mediation analysis was used to evaluate the mediating effects of cardiometabolic traits. Compared with those non-exposed, after multivariable adjustment, participants in fetal-exposed group (OR: 1·37; 95 % CI 1·08, 1·73) had 37 % higher risk to develop NAFLD, and the overall childhood-exposed group had marginally significant association with NAFLD (OR: 1·39; 95 % CI 0·99, 1·94). Stratification analysis found the famine-NAFLD associations more evident in women and those born in areas severely affected by famine. Mediation analysis showed that cardiometabolic traits such as total cholesterol, TAG glucose index, γ-glutamyl transpeptidase, alkaline phosphatase and alanine aminotransferase mediated 6·7-22·2 % of the relation from famine exposure to higher NAFLD risk. Early life exposure to famine was related to increased adulthood NAFLD risk, and this relationship was partly mediated by cardiometabolic traits.

• The study Highlights for the first time the association of known genetic varients with T2DM and CAD and their associations with several cardiometabolic traits among Arab Population. • Most significant associations were found for FTO with BMI and waist circumference, ABO with height, HHEX with T2DM and LPL with CAD. • The current study had some limitations such as low statistical power and sample size (which may produce results with type I error), and lack of adjustment of medication effects due to lack of detailed medication information. The United Arab Emirates (UAE) population has a high rate of type 2 diabetes mellitus (T2DM) and other metabolic risk factors for coronary artery disease (CAD). Previous studies have indicated strong genetic associations between T2DM and CAD. The objective of this study was to replicate previously reported significant genetic associations for T2DM and CAD which were in a genome-wide significance level in a cohort from the Arab population of the UAE, and to investigate the associations of these loci with twelve cardiometabolic traits that may influence the development of T2DM and CAD. A total of nine hundreds and fourteen Emiratis were recruited to this study to investigate associations of 101 loci for T2DM (422 patients and 455 controls), and 53 loci for CAD (160 patients and 245 controls), using logistic regression models which incorporating possible confounding factors. Results are presented using odds ratios with their corresponding 95% confidence intervals and p -values. Linear regression models, which included possible covariates were applied to determine any associations between the T2DM and CAD reported loci with the twelve cardiometabolic traits and results were presented as effect sizes (beta), standard errors, and p -values. Furthermore, the overall risks for all the loci found to be associated with T2DM and CAD were determined using the cumulative effects of the risk alleles. For those found to be associated with the twelve cardiometabolic traits, risks were determined using calculations of their polygenic risk scores. The mean age of the T2DM group was 61.5 ± 11.3 and of the CAD group was 66.2 ± 9.3 years. The prevalence of most of the cardiovascular disease risk factors in this cohort were high: mean body mass index (BMI) = 29.4, T2DM (51.9%), hypertension (60.9%), dyslipidemia (68.8%), and smoking (47.9%). All individuals who were tested for CAD (n = 405) also had a diagnosis of T2DM. The highest association variant for T2DM was in SNP rs1977833 in HHEX (p = 0.0016, OR = 0.56 for allele A), which is a multi-ethnic locus for T2DM. The strongest association with CAD was detected with SNP rs264 in LPL, which encodes lipoprotein lipase (p = 0.009, OR = 1.96 for allele A). For the cardiometabolic traits analyses, most notable associations were those of FTO with BMI and waist circumference; ABO with height; KCNK16 with diastolic blood pressure; PROX1-AS1 , GCKR , and MIR129-LEP with fasting blood glucose; random blood glucose with ZEB2 and THADA ; HbA1c levels with TLE1 and FAM99B loci; HDL-cholesterol levels with BRAF ; and triglyceride levels with ZEB2. Furthermore, accumulation of risk alleles and polygenic scores of the associated loci was clearly associated with increased risks for all tested diseases and traits in this cohort. The present study highlighted many known genetic loci, which are linked to T2DM and CAD and their associations with major cardiometabolic traits in Arab descendants. We confirmed that some loci are associated with T2DM, CAD, and metabolic traits independently of the ethnic background, with a novel association also detected between height and ABO. [ABSTRACT FROM AUTHOR]

Context: Observational studies have demonstrated that early menarche is associated with cardiometabolic diseases, but confounding factors make it difficult to infer causality., Objective: We used Mendelian randomization (MR) to examine whether age at menarche (AAM) is causally associated with type 2 diabetes (T2D), coronary artery disease (CAD) and cardiometabolic traits., Design and Methods: A 2-sample MR analysis was conducted using genome-wide association study (GWAS) summary statistics from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 159 208) for T2D and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) consortium (n = 184 305) for CAD. We used 122 instrumental variables (IVs) extracted from a published GWAS meta-analysis incorporating 182 416 women to determine the causal effect of AAM on cardiometabolic diseases, treating childhood and adult body mass index (BMI) as the confounders. Sensitivity analyses were also performed to detect the pleiotropy of the IVs., Results: Employing the MR approach, we found that later AAM was associated with decreased risk of CAD (OR, 0.92 [95% CI, 0.88-0.96]; P = 2.06 × 10-4) in adults, as well as lower blood levels of log fasting insulin, log homeostatic model assessment of insulin resistance (HOMA-IR), log HOMA of β-cell function (HOMA-B), triglycerides, and diastolic blood pressure, but higher blood level of high-density lipoprotein. However, the associations were substantially attenuated after excluding BMI-related variants. MR analyses provide little evidence on the causal effect between AAM and T2D., Conclusions: Our findings showed that AAM did not appear to have a causal effect on the risk of cardiometabolic diseases in adult life, as their associations observed in epidemiological studies might be largely mediated through excessive adiposity. We propose adiposity might be a primary target in future intervention strategy., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Cardiovascular and metabolic traits (CMT) are influenced by complex interactive processes including diet, lifestyle, and genetic predisposition. The present study investigated the interactions of these risk factors in relation to CMTs in the Turkish population., Methods: We applied bootstrap agglomerative hierarchical clustering and Bayesian network learning algorithms to identify the causative relationships among genes involved in different biological mechanisms (i.e., lipid metabolism, hormone metabolism, cellular detoxification, aging, and energy metabolism), lifestyle (i.e., physical activity, smoking behavior, and metropolitan residency), anthropometric traits (i.e., body mass index, body fat ratio, and waist-to-hip ratio), and dietary habits (i.e., daily intakes of macro- and micronutrients) in relation to CMTs (i.e., health conditions and blood parameters)., Results: We identified significant correlations between dietary habits (soybean and vitamin B12 intakes) and different cardiometabolic diseases that were confirmed by the Bayesian network-learning algorithm. Genetic factors contributed to these disease risks also through the pleiotropy of some genetic variants (i.e., F5 rs6025 and MTR rs180508). However, we also observed that certain genetic associations are indirect since they are due to the causative relationships among the CMTs (e.g., APOC3 rs5128 is associated with low-density lipoproteins cholesterol and, by extension, total cholesterol)., Conclusions: Our study applied a novel approach to integrate various sources of information and dissect the complex interactive processes related to CMTs. Our data indicated that complex causative networks are present: causative relationships exist among CMTs and are affected by genetic factors (with pleiotropic and non-pleiotropic effects) and dietary habits., (Copyright © 2016 Elsevier Inc. All rights reserved.)