Genetically predicted waist circumference and risk of atrial fibrillation.

INTRODUCTION: Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis. METHODS: In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 -8 ). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR-Egger, and weighted median regression) were used to ensure that our results more reliable. RESULTS: All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30-1.58, P = 2.51 × 10 -13 ). The results of MR-Egger and weighted median regression exhibited similar trends (MR-Egger OR = 1.40 [95% CI, 1.08-1.81], P = 1.61 × 10 -2 ; weighted median OR = 1.39 [95% CI, 1.21-1.61], P = 1.62 × 10 -6 ). MR-Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. CONCLUSIONS: Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.

Abdominal Obesity Genetic Variants Predict Waist Circumference Regain After Weight Loss.

Although many individuals are able to achieve weight loss, maintaining this loss over time is challenging. We aimed to study whether genetic predisposition to general or abdominal obesity predicts weight regain after weight loss. We examined the associations between genetic risk scores for higher BMI and higher waist-to-hip ratio adjusted for BMI (WHRadjBMI) with changes in weight and waist circumference up to 3 years after a 1-year weight loss program in participants (n = 822 women, n = 593 men) from the Look AHEAD (Action for Health in Diabetes) study who had lost ≥3% of their initial weight. Genetic predisposition to higher BMI or WHRadjBMI was not associated with weight regain after weight loss. However, the WHRadjBMI genetic score did predict an increase in waist circumference independent of weight change. To conclude, a genetic predisposition to higher WHRadjBMI predicts an increase in abdominal obesity after weight loss, whereas genetic predisposition to higher BMI is not predictive of weight regain. These results suggest that genetic effects on abdominal obesity may be more pronounced than those on general obesity during weight regain. ARTICLE HIGHLIGHTS: Nearly all individuals who intentionally lose weight experience weight regain. Individuals with a higher genetic risk for abdominal adiposity experience increased regain in waist circumference after weight loss. Genetic predisposition to higher BMI does not predict weight regain after weight loss.

Waist circumference mediates the association between rs1260326 in GCKR gene and the odds of lean NAFLD.

While non-alcoholic fatty liver disease (NAFLD) has been widely studied, the pathophysiology of lean NAFLD, the critical NAFLD subgroup, remains elusive. This study aimed to clarify the association between polymorphisms of GCKR, waist circumference, and the odds of lean NAFLD in the elderly Chinese Han population who live in the Zhangjiang community center of Shanghai, China. Three single nucleotide polymorphisms (SNPs), including rs1260326, rs780093, and rs780094, were genotyped in MassARRAY Analyzer. The association between SNPs with waist circumference in five genetic models was analyzed and rechecked by the logistic regression analysis. Mediation models were established to evaluate whether the waist circumstance can mediate the association between SNPs and lean NAFLD. In this study, the frequency of the C allele of rs1260326, rs780093, and rs780094 was significantly lower in lean NAFLD individuals than in lean non-NAFLD ones. The association between rs1260326 in GCKR and the odds of lean NAFLD was mediated via waist circumference after adjusting gender and age in the elderly Chinese Han population (ß = 1.196, R2 = 0.043, p = 0.020). For the first time, this study examined the mediating effect of waist circumference on the association between rs1260326 in GCKR and the odds of lean NAFLD (ß = 0.0515, 95% CI 0.0107-0.0900, p = 0.004). It may contribute to illustrating the pathogenesis of lean NAFLD and indicate that waist circumference management might improve lean NAFLD control.

The genetic predisposition increases the chances of schoolchildren maintaining higher adiposity levels after three years.

BACKGROUND: The behavior of anthropometrics and the relationship with genetic factors through a long-term perspective should be better explored. This study aims to verify the odds of maintaining the nutritional status classification after three years, according to the rs9939609 polymorphism (FTO gene). METHODS: It was a retrospective longitudinal study with 355 schoolchildren (7-17 years). Body mass index, body-fat percentage (BF%), and waist circumference (WC) were measured at baseline and follow-up. The FTO gene was evaluated from blood collection and genotyping performed by real-time polymerase chain reaction. Odds ratios and 95% confidence intervals were calculated. RESULTS: For those homozygous with the A allele, the odds of being at less favorable classification at follow-up were 2.29 (1.24; 4.22) and 4.05 (2.08; 7.86) times higher than expected for BF% and WC, respectively, whereas the odds of being in the more favorable classification at follow-up were 0.34 (0.12; 0.93) and 0.11 (0.01; 0.78) for BF% and WC, respectively. The odds of being at less favorable classification were higher for AA carriers with less favorable classification at baseline for BF% and WC compared to AT and TT carriers. CONCLUSIONS: Schoolchildren with a genetic predisposition to obesity and unfavorable anthropometric profile at baseline had more chances of maintaining their nutritional status after three years of follow-up.

Genetic Predisposition of Both Waist Circumference and Hip Circumference Increased the Risk of Venous Thromboembolism.

BACKGROUND: Obesity, especially abdominal obesity, is an independent indicator of increased cardiovascular risk. Observational studies have shown an observational association between obesity and venous thromboembolism (VTE). As a type of VTE, pulmonary embolism (PE) is also associated with obesity. However, it is unclear whether the observed associations are causal or caused by confounding bias or reverse causality. METHODS: We performed a two-sample test by obtaining the exposure dataset of waist circumference (WC) and hip circumference (HC) from the Neale Laboratory Consortium's genome-wide association study summary data and the summary-level outcome data of VTE and PE from FinnGen Biobank of European ancestry to determine the causal effect of WC and HC on VTE and PE. RESULTS: All three Mendelian randomization methods displayed a positive association between WC/HC and VTE/PE. WC and HC were positively associated with VTE (odds ratio [OR] = 1.803 per 1 standard deviation [SD] increase in WC, 95% confidence interval [CI] = 1.393-2.333; p < 0.001; OR = 1.479 per 1 SD increase in HC, 95% CI = 1.219-1.796; p < 0.001, respectively). Furthermore, we found a causal association between genetically predicted WC/HC and a higher risk of PE (OR = 1.929 per 1 SD increase in WC, 95% CI = 1.339-2.778, p < 0.001; OR = 1.431 per 1 SD increase in HC, 95% CI =1.095-1.869; p = 0.009, respectively). CONCLUSION: There is a significant causal relationship between WC/HC and VTE/PE, which is consistent with observational studies. Taking measures to reduce WC/HC of obesity may help reduce the incidence of VTE/PE.

The weight of childhood adversity: evidence that childhood adversity moderates the impact of genetic risk on waist circumference in adulthood.

OBJECTIVE: The present study tested the interactive effects of childhood adversity and polygenic risk scores for waist circumference (PRS-WC) on waist circumference (WC). Consistent with a diathesis-stress model, we hypothesize that the relationship between PRS-WC and WC will be magnified by increasing levels of childhood adversity. METHODS: Observational study of 7976 adults (6347 European Americans and 1629 African Americans) in the Health and Retirement Study with genotyped data. PRS-WC were calculated by the HRS administrative core using the weighted sum of risk alleles based on a genome-wide association study conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. Childhood adversity was operationalized using a sum score of three traumatic events that occurred before the age of 18 years. RESULTS: There was a statistically significant interaction between PRS-WC and childhood adversity for European Americans, whereby the magnitude of PRS-WC predicting WC increased as the number of adverse events increased. CONCLUSIONS: This study supports the idea of the interactive effects of genetic risks and childhood adversity on obesity. More epidemiological studies, particularly with understudied populations, are needed to better understand the roles that genetics and childhood adversity play on the development and progression of obesity.

Causality of anthropometric markers associated with polycystic ovarian syndrome: Findings of a Mendelian randomization study.

INTRODUCTION: Using body mass index (BMI) as a proxy, previous Mendelian randomization (MR) studies found total causal effects of general obesity on polycystic ovarian syndrome (PCOS). Hitherto, total and direct causal effects of general- and central obesity on PCOS have not been comprehensively analyzed. OBJECTIVES: To investigate the causality of central- and general obesity on PCOS using surrogate anthropometric markers. METHODS: Summary GWAS data of female-only, large-sample cohorts of European ancestry were retrieved for anthropometric markers of central obesity (waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR)) and general obesity (BMI and its constituent variables-weight and height), from the IEU Open GWAS Project. As the outcome, we acquired summary data from a large-sample GWAS (118870 samples; 642 cases and 118228 controls) within the FinnGen cohort. Total causal effects were assessed via univariable two-sample Mendelian randomization (2SMR). Genetic architectures underlying causal associations were explored. Direct causal effects were analyzed by multivariable MR modelling. RESULTS: Instrumental variables demonstrated no weak instrument bias (F > 10). Four anthropometric exposures, namely, weight (2.69-77.05), BMI (OR: 2.90-4.06), WC (OR: 6.22-20.27), and HC (OR: 6.22-20.27) demonstrated total causal effects as per univariable 2SMR models. We uncovered shared and non-shared genetic architectures underlying causal associations. Direct causal effects of WC and HC on PCOS were revealed by two multivariable MR models containing exclusively the anthropometric markers of central obesity. Other multivariable MR models containing anthropometric markers of both central- and general obesity showed no direct causal effects on PCOS. CONCLUSIONS: Both and general- and central obesity yield total causal effects on PCOS. Findings also indicated potential direct causal effects of normal weight-central obesity and more complex causal mechanisms when both central- and general obesity are present. Results underscore the importance of addressing both central- and general obesity for optimizing PCOS care.

The Association Between Puberty Timing and Body Mass Index in a Longitudinal Setting: The Contribution of Genetic Factors.

We analyzed the contribution of genetic factors on the association between puberty timing and body mass index (BMI) using longitudinal data and two approaches: (i) genetic twin design and (ii) polygenic scores (PGS) of obesity indices. Our data were derived from Finnish cohorts: 9080 twins had information on puberty timing and BMI and 2468 twins also had genetic data. Early puberty timing was moderately associated with higher BMI in childhood in both boys and girls; in adulthood these correlations were weaker and largely disappeared after adjusting for childhood BMI. The largest proportion of these correlations was attributable to genetic factors. The higher PGSs of BMI and waist circumference were associated with earlier timing of puberty in girls, whereas weaker associations were found in boys. Early puberty is not an independent risk factor for adult obesity but rather reflects the association between puberty timing and childhood BMI contributed by genetic predisposition.

What is the role of cardiorespiratory fitness and sedentary behavior in relationship between the genetic predisposition to obesity and cardiometabolic risk score?

BACKGROUND: Genetic factors along with inadequate lifestyle habits are associated with the development of cardiometabolic alterations. Thus, the present study aimed to examine the role of sedentary behavior on the relationship between rs9939609 polymorphism (fat mass and obesity-associated gene-FTO) and cardiometabolic risk score according to cardiorespiratory fitness (CRF) levels in children and adolescents. METHODS: A cross-sectional study with 1215 children and adolescents (692 girls), aged between 6 and 17 years. Screen time as a marker of sedentary behavior was evaluated through a self-reported questionnaire and CRF was estimated using the 6-min walking and running test. The genotyping of the FTO rs9939609 polymorphism was performed using a real-time polymerase chain reaction. Clustered cardiometabolic risk score (cMetS) was calculated by summing z-scores of total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, glucose, systolic blood pressure, and waist circumference, and dividing it by five. Moderation analyses were tested using multiple linear regression models. RESULTS: The coefficient of the interaction term of FTO (rs9939609) and screen time indicated that screen time was a significant moderator on the relationship between FTO rs9939609 polymorphism and cMetS (p = 0.047) in children and adolescents classified with low CRF (ß = 0.001; 95% CI = 0.001; 0.002). It was observed a significant association between genotype risk (AA) of FTO polymorphism and cMetS, in participants that spent more than 378 min a day in front of screen-based devices (ß = 0.203; 95% CI = 0.000; 0.405). No interaction term was found for those with high CRF. CONCLUSIONS: High sedentary behavior seems to influence the relationship between genetic predisposition to obesity and cardiometabolic risk factors in children and adolescents with low CRF.

Genetic Predictors of Change in Waist Circumference and Waist-to-Hip Ratio With Lifestyle Intervention: The Trans-NIH Consortium for Genetics of Weight Loss Response to Lifestyle Intervention.

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with waist circumference (WC) and waist-to-hip ratio (WHR) adjusted for BMI (WCadjBMI and WHRadjBMI), but it remains unclear whether these SNPs relate to change in WCadjBMI or WHRadjBMI with lifestyle intervention for weight loss. We hypothesized that polygenic scores (PS) comprised of 59 SNPs previously associated with central adiposity would predict less of a reduction in WCadjBMI or WHRadjBMI at 8-10 weeks in two lifestyle intervention trials, NUGENOB and DiOGenes, and at 1 year in five lifestyle intervention trials, Look AHEAD, Diabetes Prevention Program, Diabetes Prevention Study, DIETFITS, and PREDIMED-Plus. One-SD higher PS related to a smaller 1-year change in WCadjBMI in the lifestyle intervention arms at year 1 and thus predicted poorer response (ß = 0.007; SE = 0.003; P = 0.03) among White participants overall and in White men (ß = 0.01; SE = 0.004; P = 0.01). At average weight loss, this amounted to 0.20-0.28 cm per SD. No significant findings emerged in White women or African American men for the 8-10-week outcomes or for WHRadjBMI. Findings were heterogeneous in African American women. These results indicate that polygenic risk estimated from these 59 SNPs relates to change in WCadjBMI with lifestyle intervention, but the effects are small and not of sufficient magnitude to be clinically significant.

Prospective associations between leukocyte telomere length and adiposity in childhood.

Leukocyte telomere length (LTL) is associated with obesity and may be involved in its aetiology, but few studies have focused on children and most have been cross-sectional. We assessed the relation of LTL with adiposity development in a prospective study of Colombian children. We quantified LTL at enrollment in 722 children aged 5-12 years and measured anthropometry annually for a median 6 years. Using mixed effects models, we estimated changes in adiposity measures including BMI and waist circumference (WC)-for-age z-scores in relation to baseline LTL z-score. In girls, longer LTL was linearly related to a lower increase in WC z-score from age 6 to 16 years. Every 1 SD LTL was associated with an adjusted 0.13 units lower increase in WC (95% CI: -0.23, -0.03; p = 0.01). In conclusion, longer LTL among girls in middle childhood is associated with smaller increases in WC, an indicator of abdominal adiposity.

ALDH2, ADCY3 and BCMO1 polymorphisms and lifestyle-induced traits are jointly associated with CAD risk in Chinese Han people.

BACKGROUNDS: To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then used the polymerase chain reaction (PCR)-ligase detection reaction (LDR) to genotype the targeted 102 SNPs. METHODS: We adopted elastic net algorithm to build an association model that considered simultaneously genetic and lifestyle/clinical factors associated with CAD in Chinese Han population. RESULTS: In this study, we developed an all covariates-based model to explain the risk of CAD, which incorporated 8 lifestyle/clinical factors and a gene-score variable calculated from 3 significant SNPs (rs671, rs6751537 and rs11641677), attaining an area under the curve (AUC) value of 0.71. It was found that, in terms of genetic variants, the AA genotype of rs671 in the additive (adjusted odds ratio (OR) = 2.51, p = 0.008) and recessive (adjusted OR = 2.12, p = 0.021) models, the GG genotype of rs6751537 in the additive (adjusted OR = 3.36, p = 0.001) and recessive (adjusted OR = 3.47, p = 0.001) models were associated with increased risk of CAD, while GG genotype of rs11641677 in additive model (adjusted OR = 0.39, p = 0.044) was associated with decreased risk of CAD. In terms of lifestyle/clinical factors, the history of hypertension (unadjusted OR = 2.37, p < 0.001) and dyslipidemia (unadjusted OR = 1.82, p = 0.007), age (unadjusted OR = 1.07, p < 0.001) and waist circumference (unadjusted OR = 1.02, p = 0.05) would significantly increase the risk of CAD, while height (unadjusted OR = 0.97, p = 0.006) and regular intake of chicken (unadjusted OR = 0.78, p = 0.008) reduced the risk of CAD. A significantinteraction was foundbetween rs671 and dyslipidemia (the relative excess risk due to interaction (RERI) = 3.36, p = 0.05). CONCLUSION: In this study, we constructed an association model and identified a set of SNPs and lifestyle/clinical risk factors of CAD in Chinese Han population. By considering both genetic and non-genetic risk factors, the built model may provide implications for CAD pathogenesis and clues for screening tool development in Chinese Han population.

Diverse effect of MC4R risk alleles on obesity-related traits over a lifetime: Evidence from a well-designed cohort study.

This population-based longitudinal study is the first investigation that assesses the association of common MC4R SNPs with the obesity-related parameters over time and determines the effect of risk alleles during the three adulthood life periods (early, middle, and late) in a large Iranian cohort, a population with a unique genetic make-up that has been understudied and relatively unexplored. We obtained the genotype of 5370 unrelated adults who participated in the ongoing Tehran Cardiometabolic Genetic Study (TCGS) cohort project for the common MC4R SNPs. Linear regression and linear mixed model analyses were performed to examine the effect of MC4R polymorphisms on maximum BMI and other obesity-related factors over time. We recognized that several SNPs associated with the maximum BMI and the increased BMI, waist circumference, and waist-hip ratio across Iranian adults over a lifetime. Interestingly, we found that rs9954571-A has a yet unreported protective role against obesity-related factors, including BMI, waist circumference, waist-hip ratio, and triglyceride level. Additionally, a survey of the impact of the MC4R risk score throughout the adulthood life periods indicated that the MC4R risk score is influenced both the elevated BMI and waist circumference only during the early adulthood period. Our findings can expand our knowledge about the MC4R genetic variant's contributions to adulthood obesity and highlight the importance of evaluating the genetic components affecting obesity over a lifetime, which could be considered for obesity clinical screening and treatment.

Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals.

BACKGROUND: The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. METHODS: We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. RESULTS: EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change. CONCLUSION: Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.

Plasma Cortisol and Risk of Atrial Fibrillation: A Mendelian Randomization Study.

CONTEXT: Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally. OBJECTIVE: To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design. METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants). RESULTS: One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38). CONCLUSION: Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.

A genome-wide methylation study of body fat traits in the Norfolk Island isolate.

BACKGROUND AND AIMS: Natural variation in body fat is explained by both genetic and environmental effects. Epigenetic mechanisms such as DNA methylation can mediate these effects causing changes in gene expression leading to onset of obesity. Studies of genetic isolates have the potential to provide new epigenetic insights with advantages such as reduced genetic diversity and environmental exposures. METHODS AND RESULTS: This was an exploratory study of genome-wide DNA methylation in relation to body fat traits in 47 healthy adults from the genetic isolate of Norfolk Island. Quantitative body fat traits (body fat percentage, body mass index, hip circumference, waist circumference, waist-hip-ratio and weight) were carefully measured. DNA methylation data was obtained from peripheral blood using Illumina 450K arrays. Multi-trait analysis was performed using Principal Component Analysis (PCA). CpG by trait association testing was performed using stepwise linear regressions. Two components were identified that explained approximately 89% of the phenotypic variance. In total, 5 differential methylated positions (DMPs) were identified at genome-wide significance (P≤ 2.4 × 10-7), which mapped to GOT2-CDH8, LYSMD3, HIBADH, ADGRD1 and EBF4 genes. Gene set enrichment analysis of 848 genes containing suggestive DMPs (P≤ 1.0 × 10-4) implicated the Cadherin (28 genes, Padj = 6.76 × 10-7) and Wnt signaling pathways (38 genes, Padj = 7.78 × 10-6). CONCLUSION: This study provides new insights into the epigenetically influenced genes and pathways underlying body fat variation in a healthy cohort and provides targets for consideration in future studies of obesity risk.

Effects of Gene-Environment Interaction on Obesity among Chinese Adults Born in the Early 1960s.

The prevalence of obesity has been increasing sharply and has become a serious public health problem worldwide. Gene-environment interaction in obesity is a relatively new field, and little is known about it in Chinese adults. This study aimed to provide the effects of gene-environment interaction on obesity among Chinese adults. A stratified multistage cluster sampling method was conducted to recruit participants from 150 surveillance sites. Subjects born in 1960, 1961 and 1963 were selected. An exploratory factor analysis was used to classify the environmental factors. The interaction of single nucleotide polymorphisms (SNPs) and environmental factors on body mass index (BMI) and waist circumference were analyzed using a general linear model. A multiple logistic regression model combined with an additive model was performed to analyze the interaction between SNPs and environmental factors in obesity and central obesity. A total of 2216 subjects were included in the study (mean age, 49.7 years; male, 39.7%, female, 60.3%). Engaging in physical activity (PA) could reduce the effect of MC4R rs12970134 on BMI (ß = -0.16kg/m2, p = 0.030), and also reduce the effect of TRHR rs7832552 and BCL2 rs12454712 on waist circumference (WC). Sedentary behaviors increased the effects of SNPs on BMI and WC, and simultaneously increased the effects of FTO rs9939609 and FTO rs8050136 on obesity and central obesity. A higher socioeconomic status aggravated the influence of SNPs (including FTO rs9939609, BNDF rs11030104, etc.) on BMI and WC, and aggravated the influence of SEC16B rs574367 on central obesity. The MC4R rs12970134 association with BMI and the FTO rs8050136 association with central obesity appeared to be more pronounced with higher energy intake (ß = 0.140 kg/m2, p = 0.049; OR = 1.77, p = 0.004, respectively). Engaging in PA could reduce the effects of SNPs on BMI and WC; nevertheless, a higher socioeconomic status, higher dietary energy intake and sedentary behaviors accentuated the influences of SNPs on BMI, WC, obesity and central obesity. Preventative measures for obesity should consider addressing the gene-environment interaction.

Chromosomal regions strongly associated with waist circumference and body mass index in metabolic syndrome in a family-based study.

Obesity is the most crucial phenotype in metabolic syndrome (MetS), and waist circumference (WC) and body mass index (BMI) are two common indexes to define obesity. It is an accepted fact that genetic and environmental interaction influence obesity and MetS. Microsatellites are a subcategory of tandem repeats with a length of 1 to 10 nucleotides. Tandem repeats make up repetitive genomic regions. Differences in the number of tandem repeats or their variation (alleles) result in microsatellite polymorphisms. Thus, we attempted to find microsatellite variation associated with WC and BMI in a family-based study. Twelve microsatellite markers were selected to investigate possible genes or chromosomal regions in 91 families with at least one affected MetS. The cut-off values for BMI and WC were considered 25 kg/m2 and 90 cm, respectively. In all members of the families, the strongest association was observed between the marker D11S1304 (allele 1) with both WC and BMI, independently, by the biallelic model in the family-based association test analysis (P < 0.05). Besides, when we compared high- and low-level groups in members with MetS, the markers D8S1743 and D11S1304 (allele 1) showed a strong association with WC (P = 0.0080) and BMI (P = 0.0074), respectively. When the simultaneous detection of the high WC and MetS status was used as a trait, the strongest association was observed with the marker D8S1743 (P = 0.0034). Moreover, when BMI with the high MetS status was used as a trait, the strongest association was observed with the marker D8S1743 (allele 4) (P = 0.0034). The obtained results showed a relationship between obesity and MetS with markers on the selected regions on chromosomes 8 and 11, and to a lesser degree, on chromosome 12.

Causal relationship between dietary macronutrient composition and anthropometric measures: A bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: The question whether the proportion of energy provided by fat and carbohydrates in the diet is associated with body mass index (BMI) and waist circumference (WC) is an important public health issue, but determining causality is difficult in epidemiological studies. OBJECTIVES: Using a two-sample bidirectional Mendelian randomization (MR) in both a univariable and multivariable setting, we aimed to determine whether the relative proportion of different macronutrients in the diet (in % of total energy intake (E%)) is causally related to BMI and WC and vice versa. METHODS: All analyses were based on genome-wide association studies including 268,922 Europeans with dietary data (SSGAC Consortium) and at least 232,101 with anthropometric measures (GIANT Consortium). An inverse-variance weighted approach using modified second-order weights within the radial regression framework was performed. Radial MR-Egger, weighted median and mode, Robust Adjusted Profile Score (RAPS), and Pleiotropy RESidual Sum and Outlier (PRESSO) methods were used in sensitivity analyses to verify MR assumptions. Additionally, multivariable MR was conducted to account for inter correlation between macronutrient intakes. All estimates represent the standard deviation (SD) change in each outcome per one SD change in the respective exposure. RESULTS: We found that genetically predicted relative carbohydrate intake (E%) reduced BMI (ß = -0.529; 95% CI: -0.745, -0.312; P-value = 2⋅10-6) and WC (ß = -0.459; 95% CI: -0.656, -0.262; P-value = 5⋅10-6). Both effects were also supported by the multivariable approach: ß = -0.441 (95% CI: -0.772, -0.109; P-value = 0.009) for BMI and ß = -0.410 (95% CI: -0.667, -0.154; P-value = 0.002) for WC. Genetically predicted dietary intake of fat (E%) was weaker and positively related to both anthropometric measures. We obtained evidence that a higher BMI and WC increased the relative dietary intake of fat and protein (E%). For example, each SD higher BMI increased protein intake (E%) by 0.114 SD (95% CI: 0.081, 0.147; P-value = 9⋅10-12) and each SD higher WC increased protein intake (E%) by 0.078 SD (95% CI: 0.035, 0.121; P-value = 4⋅10-4). Sensitivity analyses confirmed these findings revealing consistent effect estimates. CONCLUSIONS: Using genetic information to improve causal inference we found evidence, that a low relative carbohydrate proportion (E%) and a high proportion of fat (E%) in the diet is causally related to a higher BMI and a higher WC. Further research considering carbohydrate, fat, and protein quality and possible consequences on micronutrient intake is needed to define the implications for dietary intake recommendations.

Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia.

BACKGROUND: Lipid metabolism disorders, especially hypertriglyceridemia (HTG), are risk factors for non-alcoholic fatty liver disease (NAFLD). However, the association between genetic factors related to HTG and the risk of NAFLD has been scarcely studied. METHODS: A total of 185 subjects with moderate HTG were prospectively included. We investigated the association between genetic factors' (five allelic variants with polygenic hypertriglyceridemia) clinical and biochemical biomarkers with NAFLD severity. The five allelic variants' related clinical and biochemical data of HTG were studied in all the subjects. NAFLD was assessed by abdominal ultrasound and patients were divided into two groups, one with no or mild NAFLD and another with moderate/severe NAFLD. RESULTS: Patients with moderate/severe NAFLD had higher weight and waist values and a higher prevalence of insulin resistance than patients with no or mild NAFLD. Moderate/severe NAFLD was independently associated with APOA5 rs3134406 and ZPR1 rs964184 variants, and also showed a significant inverse relationship with lipoprotein(a) [Lp(a)] concentrations. CONCLUSIONS: APOA5 rs3135506 and ZPR1 rs964184 variants and lipoprotein(a) are associated with moderate/severe NAFLD. This association was independent of body weight, insulin resistance, and other factors related to NAFLD.