Search

Obesity represents a major public health emergency worldwide, and its etiology is shaped by a complex interplay of environmental and genetic factors. Over the last decade, polygenic risk scores (PRS) have emerged as a promising tool to quantify an individual's genetic risk of obesity. The field of PRS in obesity genetics is rapidly evolving, shedding new lights on obesity mechanisms and holding promise for contributing to personalized prevention and treatment. Challenges persist in terms of its clinical integration, including the need for further validation in large-scale prospective cohorts, ethical considerations, and implications for health disparities. In this review, we provide a comprehensive overview of PRS for studying the genetics of obesity, spanning from methodological nuances to clinical applications and challenges. We summarize the latest developments in the generation and refinement of PRS for obesity, including advances in methodologies for aggregating genome-wide association study data and improving PRS predictive accuracy, and discuss limitations that need to be overcome to fully realize its potential benefits of PRS in both medicine and public health., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Numerous studies have demonstrated that the onset of type 2 diabetes (T2D) is linked to the reduction in ß-cell mass caused by apoptosis, a process initiated by endoplasmic reticulum (ER) stress. The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the ATF6 gene (activating transcription factor 6), a key sensor of ER stress, and T2D susceptibility., Methods: The study involved 3229 unrelated individuals, including 1569 patients with T2D and 1660 healthy controls from Central Russia. Four functionally significant intronic SNPs, namely rs931778, rs90559, rs2341471, and rs7517862, were genotyped using the MassARRAY-4 system., Results: The rs2341471-G/G genotype of ATF6 was found to be associated with an increased risk of T2D (OR = 1.61, 95% CI 1.37-1.90, P FDR  < 0.0001). However, a BMI-stratified analysis showed that this genotype and haplotypes CGGA and TAGA are associated with T2D risk exclusively in subjects with obesity or overweight (P FDR  < 0.05). Despite these patients being found to have higher consumption of high-carbohydrate and high-calorie diets compared to normal-weight individuals (P < 0.0001), the influence of the rs7517862 polymorphism on T2D risk was observed independently of these dietary habits. Functional SNP annotation revealed the following: (1) the rs2341471-G allele is associated with increased ATF6 expression; (2) the SNP is located in a region exhibiting enhancer activity epigenetically regulated in pancreatic islets; (3) the rs2341471-G was predicted to create binding sites for 18 activating transcription factors that are part of gene-regulatory networks controlling glucose metabolism and maintaining proteostasis., Conclusions: The present study revealed, for the first time, a strong association between the rs2341471-G/G ATF6 genotype and an increased risk of type 2 diabetes in people with obesity or overweight, regardless of known dietary risk factors. Further research is needed to support the potential of silencing the ATF6 gene as a means for the treatment and prevention of type 2 diabetes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This cross-sectional study explores the impact of FTO gene single nucleotide polymorphisms (SNPs) rs9939609 and rs1421085 on dietary habits contributing to obesity risk in Thai adults. The study enrolled 384 participants from Bangkok, categorized as non-obese (BMI < 25 kg/m 2 ) or obese (BMI ≥ 25 kg/m 2 ) based on WHO Asia Pacific Guidelines. Genotyping for FTO variants was performed using DNA from blood samples. While both SNPs adhered to Hardy-Weinberg equilibrium, the association between risk alleles and anthropometric measurements was not statistically significant. However, risk allele carriers showed significantly higher intakes of sugar and saturated fat compared to homozygous dominant individuals. In the obese group, the odds ratio for high-sugar intake was 2.22 (95% CI 1.13-4.37, p = 0.021) for rs9939609 risk allele carriers. For high-saturated fat intake, the odds ratio was 1.86 (95% CI 1.02-3.40, p = 0.041). Similar associations were observed for rs1421085. Risk allele carriers also exhibited significantly higher leptin levels (p < 0.043) and a positive correlation with myeloperoxidase levels (p < 0.038). These findings highlight the complex relationship between FTO risk alleles, increased consumption of sugar and saturated fat, and obesity-related parameters. The insights emphasize the importance of considering both genetic and dietary factors in obesity prevention strategies., (© 2024. The Author(s).)

Background: Obesity has become a significant global health issue. This multifaceted condition is influenced by genetic, environmental, and lifestyle factors, significantly influenced by nutrition. Aim : The study's objective is to elucidate the relationship between obesity-related genes, nutrient intake, and the development of obesity and the importance of other metabolic diseases. Methods : A comprehensive literature review spanning the past two decades was conducted to analyze the contributions of genetic variants-including FTO , MC4R , and LEPR -and their associations with dietary habits, highlighting how specific nutrients affect gene expression and obesity risk and how the coexistence of metabolic diseases such as type 2 diabetes and osteoporosis may modulate these factors. Moreover, the role of epigenetic factors, such as dietary patterns that encourage the development of obesity, was explored. Discussion and Conclusions : By understanding the intricate relationships among genetics, nutrients, and obesity development, this study highlights the importance of personalized dietary strategies in managing obesity. Overall, an integrated approach that considers genetic predispositions alongside environmental influences is essential for developing effective prevention and treatment methodologies, ultimately contributing to better health outcomes in diverse populations.

Background and Aims: A number of health issues, including high serum uric acid (SUA) and cardiovascular disease (CVD), have been linked to obesity based on observational evidence, though it's currently unclear how these issues are causally related. In order to determine whether obesity mediates this association, we set out to investigate the causal relationship between SUA, obesity, and CVD., Methods and Results: From publicly available genome-wide association studies, we acquired instrumental variables that had a strong correlation to SUA and body mass index (BMI). We employed multiple two-step Mendelian randomization (MR) analyses, using genetic and clinical data from various publicly available biological databases. The mediating role of BMI was examined through mediation analysis. SUA was genetically correlated with BMI [OR = 1.080, 95% CI: 1.024-1.139, P = 0.005]. There was a positive causal effect of SUA on AF [OR = 0.892, 95% CI: 0.804-0.990, P = 0.032], CAD [OR = 0.942, 95% CI: 0.890-0.997, P = 0.037], and EHT [OR = 1.080, 95% CI: 1.024-1.139, P = 0.005]. Among them, BMI mediated the effects of SUA on AF (42.2%; 95% CI, 35.3%-51.9%), CAD (76.3%; 95% CI, 63.4%-92.0%), and EHT (10.0%; 95% CI, 0%-20.0%)., Conclusion: Our research revealed a causal relationship between high SUA exposure and an increased risk of obesity. Additionally, a high SUA level was linked to an increased risk of various CVDs. Given that individuals with high SUA are more likely to be susceptible to AF, CAD, and EHT, attention must be given to their weight status., Competing Interests: Declaration of competing interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Metabolic diseases result from interactions between genetic and lifestyle factors. Understanding the combined influences of single-nucleotide polymorphisms (SNPs) and lifestyle is crucial. This study employs genetic risk scores (GRS) to assess SNPs, providing insight beyond single gene/SNP studies by revealing synergistic effects. Here, we aim to investigate the association of a 23-SNP GRS with metabolic disease-related traits (obesity and type 2 diabetes) to understand if these associations are altered by lifestyle/dietary factors. For this study, 106 Minangkabau women were included and underwent physical, anthropometric, biochemical, dietary and genetic evaluations. The interaction of GRS with lifestyle factors was analyzed using linear regression models, adjusting for potential confounders. No statistically significant associations were observed between GRS and metabolic traits; however, this study demonstrates a novel interaction observed between 13-SNP GRS and monounsaturated fatty acid (MUFA) intake, and that it had an effect on HbA1c levels ( p = 0.026). Minangkabau women with low MUFA intake (≤7.0 g/day) and >13 risk alleles had significantly higher HbA1c levels ( p = 0.010). This finding has implications for public health, suggesting the need for large-scale studies to confirm our results before implementing dietary interventions in the Indonesian population. Identifying genetic influences on dietary response can inform personalized nutrition strategies to reduce the risk of metabolic disease.

Objective: Whether the role of post-traumatic stress disorder (PTSD) on type 2 diabetes (T2D) is mediated by obesity or other mediating factors is controversial. This study was designed to assess the impact of PTSD on genetic susceptibility to T2D and mediating factors., Methods: The datasets for PTSD, T2D, obesity, hypertension, hyperlipidemia, smoking status, and alcohol consumption were obtained from genome-wide association studies. Mendelian randomization (MR) was used to assess exposure-outcome causality, and inverse variance weighted was used as the primary tool for MR analysis. MR-Egger intercept, Cochran's Q, and leave-one-out sensitivity analysis were employed to assess horizontal pleiotropy, heterogeneity, and robustness, respectively., Results: The MR analysis showed that PTSD was associated with increased genetic susceptibility to T2D (OR, 1.036; 95% CI, 1.008-1.064; p = 0.011), obesity (OR, 1.033; 95% CI, 1.016-1.050; p < 0.001), and hypertension (OR, 1.002; 95% CI, 1.000-1.003; p = 0.015), but not not with genetic susceptibility to hyperlipidemia, alcohol consumption, and smoking status ( p ≥ 0.05). Mediated effect analysis showed that PTSD increased genetic susceptibility to T2D by increasing genetic susceptibility to obesity and hypertension, with obesity accounting for 9.51% and hypertension accounting for 2.09%. MR-Egger intercept showed no horizontal pleiotropy ( p ≥ 0.05). Cochran's Q showed no heterogeneity ( p ≥ 0.05). Leave-one-out sensitivity analysis showed that the results were robust., Conclusion: This MR analysis suggests that PTSD increases the risk of T2D and that this effect is partially mediated by obesity and hypertension. Active prevention and treatment of PTSD can help reduce the risk of T2D., 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 © 2024 Yu, Hu, Yang, Bai, Wu, Tong and Yu.)

Our study aimed to identify sweetness preference-associated single-nucleotide polymorphisms (SNPs), characterize the related genetic loci, and develop SNP-based polygenic risk scores (PRS) to analyze their associations with obesity. For genotyping, we utilized a pooled genome-wide association study (GWAS) dataset of 18,499 females and 10,878 males. We conducted genome-wide association analyses, functional annotation, and employed the weighted method to calculate the levels of PRS from 677 sweetness preference-related SNPs. We used Cox proportional hazards modeling with time-varying covariates to estimate age-adjusted and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for obesity incidence. We also tested the correlation between PRS and environmental factors, including smoking and dietary components, on obesity. Our results showed that in males, the TT genotype of rs4861982 significantly increased obesity risk compared to the GG genotype in the Health Professionals Follow-up Study (HPFS) cohort (HR = 1.565; 95% CI, 1.122-2.184; p = 0.008) and in the pooled analysis (HR = 1.259; 95% CI, 1.030-1.540; p = 0.025). Protein tyrosine phosphatase receptor type O (PTPRO) was identified as strongly associated with sweetness preference, indicating a positive correlation between sweetness preference and obesity risk. Moreover, each 10 pack-year increment in smoking was significantly associated with an increased risk of obesity in the HPFS cohort (HR = 1.024; 95% CI, 1.000-1.048) in males but not in females. In conclusion, significant associations between rs4861982, sweetness preference, and obesity were identified, particularly among males, where environmental factors like smoking are also correlated with obesity risk.

Background: The role of the common FTO gene variant rs9939609 in obesity has been well established, and the FTO gene has a strong association with T2DM. Objective: To investigate the association of FTO gene variant rs9939609 with obesity-related parameters in T2DM and CVD patients. Materials and Methods: In this cross-sectional study, 280 subjects of either sex aged 45.10 ± 9.6 years were randomly divided into four groups, that is, T2DM, T2DM with CVD, nondiabetic with CVD disease, and normal control. These samples were genotyped by ARMS-PCR. The FTO gene association with obesity-related parameters in T2DM and CVD patients was analyzed by SPSS 22. Results: The TT genotype was the most common genotype (46.80%) in our study groups. The minor allele frequency (MAF) was significantly higher in T2DM patients (0.39 vs. 0.28), T2DM patients with CVD (0.43 vs. 0.28), and nondiabetic patients with CVD (0.35 vs. 0.28) as compared to control with p < 0.005. Carriers of the AA genotype of the FTO gene rs9939609 were significantly associated with increased BMI, WC, HbA1C, SBP, DBP, and TGs and lowered HDL cholesterol as compared to the TA and TT genotypes in T2DM and CVD patients with p < 0.005. The FTO gene variant rs9939609 showed a significant association with T2DM and CVD. The AA genotype odds ratio (OR) in T2DM was 1.48 (1.06-2.32), p = 0.006, and in CVD, it was 1.56 (1.04-2.4), p = 0.003. Conclusion: The FTO gene variant rs9939609 has a strong association with T2DM and CVD. The AA genotype of FTO gene variants rs9939609 showed a strong association with most of the risk factors of CVD and T2DM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Mazhar Hussain et al.)

Although prior studies have shown that adiponectin synthesis is genetically determined and that its levels influence susceptibility to T2D, the results in this regard have been inconsistent. This study aims, to investigate the relationship between adiponectin gene variants with the risk of developing T2D among Tunisian women and in relation to their BMI status. A cohort of 491 Tunisian T2D women and 373 non-diabetic subjects participated in the study. Nine ADIPOQ variants namely rs16861194, rs17300539, rs266729, rs822395, rs822396, rs2241766, rs1501299, rs2241767 and rs3774261 were selected and genotyped using the TaqMan® SNP genotyping assay. Fasting serum adiponectin levels were quantified using ELISA. The results showed that only the rs17300539 variant exhibited a significant association with the risk of T2D. However, upon considering T2D group stratification based on BMI (normal weight [18-24.99 Kg/m 2 ], overweight [25-29.99 Kg/m 2 ] and obese [30-34.99 Kg/m 2 ]), the ADIPOQ rs2241766 variant emerged as a contributing risk factor for increased BMI in obese women with T2D. Linear regression analysis revealed that the minor allele (A), (GA) and (AA) genotypes of rs17300539 as well as the (G) allele and (GG) genotype of rs2241766 were significantly associated with hypoadiponectinemia in T2D subjects. Two haplotypes namely GGCAATGAA and AGCCGTGGA, were identified as conferring a higher risk of T2D with the GGCAATGAA haplotype also correlating with hypoadiponectinemia. Our study underscores the importance of the rs17300539 variant and the GGCAATGAA haplotype in the risk of T2D and hypoadiponectinemia. Additionally, the presence of the rs2241766 variant highlights its association with 'diabesity' and hypoadiponectinemia among Tunisian T2D women., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity., Methods: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRS LEAP2 ) using linear and logistic regression models. Sex-stratified analyses were also conducted., Results: Five SNPs showed positive associations with obesity-related traits. rs57880964 was associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF-1 concentrations in both men and women. GRS LEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF-1 concentration in both sexes., Conclusions: These findings reveal sex-specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF-1 concentration., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Competing Interests: Conflict of Interest The author declares no conflicts of interest.

Purpose of Review: The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care., Recent Findings: Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% -new variants in known genes as well as identification of novel genes- causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity. While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Single nucleotide polymorphisms (SNPs) could increase the susceptibility of individuals to develop obesity and type 2 diabetes (T2DM). Obesity and T2DM are closely related pathophysiologically, thus similar SNPs could mediate both these diseases, but this is rarely reported. Furthermore, limited studies have been performed to summarize SNP data in the Asian population compared to the Western population. In this study, we aimed to summarize SNPs that are associated with the development of obesity and T2DM among Asian populations. We searched six literature databases and Review Manager (RevMan) was used for meta-analysis. The pooled odds ratios (ORs) and 95% CIs were calculated with a random effects model for the heterogeneity among studies. The pooled analysis showed that rs9939609 (FTO gene) and rs17782313 and rs571312 (MC4R gene) are associated with obesity with an odd ratio (OR) of 1.37, 1.36 and 1.29 respectively. For T2DM, five SNPs, rs7903146 and rs12255372 (TCF7L2 gene), rs13266634 and rs11558471 (SLC30A8 gene) and rs2283228 (KCNQ1 gene) have also shown strong associations with T2DM at OR of 1.64, 1.61, 1.22, 1.29 and 1.60 respectively. This data could be used to develop a gene screening panel for assessing obesity and T2DM susceptibility., (© 2024. The Author(s).)

Obesity, a significant public health concern with high prevalence in both adults and children, is a complex disorder arising from the interaction of multiple genes and environmental factors. Advances in genome-wide association studies (GWAS) and sequencing technologies have identified numerous polygenic causes of obesity, particularly genes involved in hunger, satiety signals, adipocyte differentiation, and energy expenditure. This study investigates the relationship between six obesity-related genes ( CLOCK, FTO, GHRL, LEP, LEPR, MC4R ) and their impact on BMI, WC, HC, WHR, and emotional eating behavior in 220 Romanian adults. Emotional eating was assessed using the validated Emotional Eating Questionnaire (EEQ). Our analysis revealed significant variability in obesity-related phenotypes and emotional eating behaviors across different genotypes. Specifically, CLOCK/ CC, FTO/ AA, and LEP/ AA genotypes were strongly associated with higher obesity metrics and emotional eating scores, while GHRL/ TT and MC4R/ CC were linked to increased BMI and WHR. The interplay between genetic predisposition and emotional eating behavior significantly influenced BMI and WHR, indicating a complex relationship between genetic and behavioral factors. This study, the first of its kind in Romania, provides a foundation for targeted interventions to prevent and reduce obesity and suggests potential strategies for gene expression modulation to mitigate the effects of emotional eating. Adopting a 'One Health' approach by creating an evidence base derived from both human and animal studies is crucial for understanding how to control obesity.

Background: Comorbidities such as obesity and type 2 diabetes mellitus (T2DM) have emerged as critical risk factors exacerbating the severity and mortality of COVID-19. Meanwhile, numerous genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with increased susceptibility to severe COVID-19., Aim: This study investigated whether SNPs previously identified by GWAS as risk factors for severe COVID-19 also correlate with common comorbidities-obesity and T2DM-in hospitalized patients with severe COVID-19., Methods: DNA samples from 199 hospitalized COVID-19 patients were genotyped using probe-based PCR for 10 GWAS SNPs previously implicated in severe COVID-19 outcomes (rs143334143 CCHCR1 , rs111837807 CCHCR1 , rs17078346 SLC6A20 - LZTFL1 , rs17713054 SLC6A20 - LZTFL1 , rs7949972 ELF5 , rs61882275 ELF5 , rs12585036 ATP11A , rs67579710 THBS3 , THBS3 - AS1 , rs12610495 DPP9 , rs9636867 IFNAR2 )., Results: The analysis revealed significant associations between certain SNPs and the increased risk of obesity and T2DM in severe COVID-19 patients. Specifically, rs17713054 SLC6A20 - LZTFL1 (risk allele A; odds ratio (OR) = 2.34, 95% confidence interval (CI) = 1.24-4.4, p = 0.007) and rs7949972 ELF5 SNP (risk allele T; OR = 1.79, 95% CI = 1.11-2.91, p = 0.015) were associated with increased risk of obesity. SNP rs9636867 IFNAR2 was associated with a higher risk of T2DM (risk allele G, OR = 8.28, 95% CI = 1.69-40.64, p = 0.027). Using the model-based multifactor dimensionality reduction (MB-MDR) approach, the six most significant gene-gene interaction patterns associated with obesity in severe COVID-19 patients were identified and included five polymorphic loci: rs7949972, rs17713054, rs61882275, rs12585036, and rs143334143, participating in two or more of the most significant G-G interactions ( pperm < 0.05). In total, the best models of G-G interactions associated with T2DM in patients with severe COVID-19 included eight polymorphic loci, six of which, rs7949972, rs61882275, rs12585036, rs143334143, rs67579710, and rs12610495, were involved in two or more of the most significant G-G interactions., Conclusions: Our study provides novel insights into the genetic associations between GWAS-identified SNPs and the risk of obesity and T2DM in patients with severe COVID-19., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

The increased prevalence of metabolic diseases in the Arab countries is mainly associated with genetic susceptibility, lifestyle behaviours, such as physical inactivity, and an unhealthy diet. The objective of this review was to investigate and summarise the findings of the gene-lifestyle interaction studies on metabolic diseases such as obesity and type 2 diabetes in Arab populations. Relevant articles were retrieved from a literature search on PubMed, Web of Science, and Google Scholar starting at the earliest indexing date through to January 2024. Articles that reported an interaction between gene variants and diet or physical activity were included and excluded if no interaction was investigated or if they were conducted among a non-Arab population. In total, five articles were included in this review. To date, among three out of twenty-two Arab populations, fourteen interactions have been found between the FTO rs9939609, TCF7L2 rs7903146, MC4R rs17782313, and MTHFR rs1801133 polymorphisms and diet or physical activity on obesity and type 2 diabetes outcomes. The majority of the reported gene-diet/ gene-physical activity interactions (twelve) appeared only once in the review. Consequently, replication, comparisons, and generalisation of the findings are limited due to the sample size, study designs, dietary assessment tools, statistical analysis, and genetic heterogeneity of the studied sample.

The extent to which modifiable lifestyle factors offset the determined genetic risk of obesity and obesity-related morbidities remains unknown. We explored how the interaction between genetic and lifestyle factors influences the risk of obesity and obesity-related morbidities. The polygenic score for body mass index was calculated to quantify inherited susceptibility to obesity in 338,645 UK Biobank European participants, and a composite lifestyle score was derived from five obesogenic factors (physical activity, diet, sedentary behavior, alcohol consumption, and sleep duration). We observed significant interaction between high genetic risk and poor lifestyles (p interaction  < 0.001). Absolute differences in obesity risk between those who adhere to healthy lifestyles and those who do not had gradually expanded with an increase in polygenic score. Despite a high genetic risk for obesity, individuals can prevent obesity-related morbidities by adhering to a healthy lifestyle and maintaining a normal body weight. Healthy lifestyles should be promoted irrespective of genetic background., Competing Interests: Declaration of interests P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, TenSixteen Bio, and Tourmaline Bio; equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. A.C.F. reports being co-founder of Goodpath, serving as scientific advisor to MyOme and HeartFlow, and receiving a research grant from Foresite Labs, all unrelated to this work. R.D. reported receiving grants from AstraZeneca; grants and non-financial support from Goldfinch Bio; being a scientific co-founder, consultant, and equity holder for Pensieve Health (pending); and being a consultant for Variant Bio, all not related to this work. A.V.K. reports work as a consultant for Marea Therapeutics and Foresite labs and is an employee and equity holder for Verve Therapeutics, all not related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors., Methods: This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes., Results: Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men., Conclusions: A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation., (© 2024. The Author(s).)

Objective: Evidence has been increasingly pointing towards a potential link between phenotypes related to obesity and the incidence of colorectal cancer. However, confirming this as a direct causal connection remains elusive. This investigation aims to elucidate the causative links between obesity-associated phenotypes and the incidence of colorectal cancer., Methods: Employing the Two Sample Mendelian Randomization (TwoSampleMR) R package, analyses were conducted using Mendelian randomization (MR) to discern potential causative links between obesity categories sourced from both the Institute for Education and University (IEU) Open GWAS Project and Zenodo, and colorectal tumors (data obtained from IEU Open GWAS and FinnGen). For primary evaluations, the study utilized the Wald ratio and the Inverse Variance Weighting (IVW) methods, while the MR-Egger approach was integrated for sensitivity assessment. Bidirectional Mendelian Randomization (Bidirectional MR), as well as Linkage Disequilibrium (LD) Score Regression with well-imputed HapMap3 single nucleotide polymorphisms (SNPs), were additionally executed. Sensitivity assessments entailed IVW, MR-Egger methodologies to assess heterogeneity and pleiotropy, along with a leave-one-out strategy. Instrumental variables were chosen judiciously based on predetermined P-value thresholds and F-statistics., Results: Results from MR evaluations did not identify a clear causative link between BMI and colorectal malignancy. Conversely, both measures of obesity, the Waist-Hip Ratio (WHR) and its adjusted form for BMI (WHRadjBMI), displayed a connection to increased risk of colorectal cancer, especially prominent among female subjects. Reverse MR analyses dismissed potential reverse causality between colorectal malignancies and obesity. A significant genetic interplay was observed between WHR, WHRadjBMI, and colorectal cancer instances. Ensuing MR probes spotlighted inflammatory bowel ailment as a protective factor, while salad intake was indicated as a potential risk concerning colorectal malignancies. Sensitivity reviews, which included tests for both pleiotropy and heterogeneity, validated the robustness of the MR findings., Conclusion: Findings from this research indicate that specific obesity-related parameters, notably WHR and WHRadjBMI, carry a causal relationship with an elevated colorectal cancer risk. The impact is distinctly more evident among females. Such insights might be pivotal for public health deliberations, hinting that individuals boasting a high WHR might necessitate intensified colorectal cancer screenings., 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 © 2024 Chen, Yang, Zhao, Tu, Liu and Yuan.)

Objectives: Non-alcoholic fatty liver disease (NAFLD) has significant genetic susceptibility. Adipocytokines play a crucial role in NAFLD development by participating in insulin resistance and hepatic steatosis. However, the association between adipocytokine pathway genes and NAFLD remains unclear. This study aims to explore the association of gene polymorphisms in the adipocytokine pathway and their interactions with NAFLD in obese children., Methods: A case-control study was conducted, dividing obese children into NAFLD and control groups. Peripheral venous blood (2 mL) was collected from each participant for DNA extraction. A total of 14 single nucleotide polymorphisms (SNP) in the adipocytokine pathway were genotyped using multiplex PCR and high-throughput sequencing. Univariate and multivariate Logistic regression analyses were used to assess the association between SNP and NAFLD in obese children. Dominant models were used to analyze additive and multiplicative interactions via crossover analysis and Logistic regression. Generalized multifactor dimensionality reduction (GMDR) was used to detect gene-gene interactions among the 14 SNPs and their association with NAFLD in obese children., Results: A total of 1 022 children were included, with 511 in the NAFLD group and 511 in the control group. After adjusting for age, gender, and BMI, multivariate Logistic regression showed that PPARG rs1801282 was associated with NAFLD in the obese children in 3 genetic models: heterozygote model (CG vs CC, OR =0.58, 95% CI 0.36 to 0.95, P =0.029), dominant model (GG+CG vs CC, OR =0.62, 95% CI 0.38 to 1.00, P =0.049), and overdominant model (CC+GG vs CG, OR =1.72, 95% CI 1.06 to 2.80, P =0.028). PRKAG2 rs12703159 was associated with NAFLD in 4 genetic models: heterozygous model (CT vs CC, OR =1.51, 95% CI 1.10 to 2.07, P =0.011), dominant model (CT+TT vs CC, OR =1.50, 95% CI 1.10 to 2.03, P =0.010), overdominant model (CC+TT vs CT, OR =0.67, 95% CI 0.49 to 0.92, P =0.012), and additive model (CC vs CT vs TT, OR =1.40, 95% CI 1.07 to 1.83, P =0.015). No significant multiplicative or additive interaction between PPARG rs1801282 and PRKAG2 rs12703159 was found in association with NAFLD. GMDR analysis, adjusted for age, gender, and BMI, revealed no statistically significant interactions among the 14 SNPs (all P >0.05)., Conclusions: Mutations in PPARG rs1801282 and PRKAG2 rs12703159 are associated with NAFLD in obese children. However, no gene-gene interactions among the SNP are found to be associated with NAFLD in obese children.

Type 2 diabetes mellitus (T2DM) is a socially significant disease with increasing prevalence worldwide. It is characterized by heterogeneous metabolic disorders and is associated with various risk factors, including BMI, abnormal lipid levels, hypertension, smoking, dietary preferences, physical inactivity, sedentary lifestyle, family history of diabetes, prediabetes or gestational diabetes, inflammation, intrauterine environment, age, sex, ethnicity, and socioeconomic status. Assessing the genetic risk of developing T2DM in specific populations remains relevant. The ADIPOQ gene, encoding adiponectin, is directly related to the risk of developing T2DM, obesity, and cardiovascular diseases. Our study demonstrated significant associations of ADIPOQ gene polymorphisms with the risk of developing T2DM and obesity, as well as with fasting glucose levels and BMI, in the Kazakh population. Specifically, rs266729 was significantly associated with T2DM and obesity in the Kazakh population, while other studied polymorphisms (rs1501299, rs2241766, and rs17846866) did not show a significant association. These findings suggest that ADIPOQ gene polymorphisms may influence T2DM risk factors and highlight the importance of genetic factors in T2DM development. However, further research in larger cohorts is needed to confirm these associations.

Background: Diverticulosis is a normal anatomical variant of the colon present in more than 70% of the westernized population over the age of 80. Approximately 3% will develop diverticulitis in their lifetime. Many patients present emergently, suffer high morbidity rates and require substantial healthcare resources. Diverticulosis is the most common finding at colonoscopy and has the potential for causing a significant morbidity rate and burden on healthcare. There is a need to better understand the aetiology and pathogenesis of diverticular disease. Research suggests a genetic susceptibility of 40-50% in the formation of diverticular disease. The aim of this review is to present the hypothesized functional effects of the identified gene loci and environmental factors., Methods: A systematic literature review was performed using PubMed, MEDLINE and Embase. Medical subject headings terms used were: 'diverticular disease, diverticulosis, diverticulitis, genomics, genetics and epigenetics'. A review of grey literature identified environmental factors., Results: Of 995 articles identified, 59 articles met the inclusion criteria. Age, obesity and smoking are strongly associated environmental risk factors. Intrinsic factors of the colonic wall are associated with the presence of diverticula. Genetic pathways of interest and environmental risk factors were identified. The COLQ, FAM155A, PHGR1, ARHGAP15, S100A10, and TNFSF15 genes are the strongest candidates for further research., Conclusion: There is increasing evidence to support the role of genomics in the spectrum of diverticular disease. Genomic, epigenetic and omic research with demographic context will help improve the understanding and management of this complex disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

The identification of novel screening tools is imperative to empower the early detection of colorectal cancer (CRC). The influence of the long non-coding RNA maternally expressed gene 3 (MEG3) rs941576 single nucleotide polymorphism on CRC susceptibility remains uninvestigated. This research appraised MEG3 rs941576 association with the risk and clinical features of CRC and obesity-related CRC and its impact on serum MEG3 expression and its targets miR-27a/insulin-like growth factor 1 (IGF1)/IGF binding protein 3 (IGFBP3) and miR-181a/sirtuin 1 (SIRT1), along with the potential of these markers in obesity-related CRC diagnosis. 130 CRC patients (60 non-obese and 70 obese) and 120 cancer-free controls (64 non-obese and 56 obese) were enrolled. MEG3 targets were selected using bioinformatics analysis. MEG3 rs941576 was associated with magnified CRC risk in overall (OR (95% CI) 4.69(1.51-14.57), P = 0.0018) and stratified age and gender groups, but not with obesity-related CRC risk or MEG3/downstream targets' expression. Escalated miR-27a and IGFBP3 and reduced IGF1 serum levels were concomitant with MEG3 downregulation in overall CRC patients versus controls and obese versus non-obese CRC patients. Serum miR-181a and SIRT1 were upregulated in CRC patients versus controls but weren't altered in the obese versus non-obese comparison. Serum miR-181a and miR-27a were superior in overall and obesity-related CRC diagnosis, respectively; meanwhile, IGF1 was superior in distinguishing obese from non-obese CRC patients. Only serum miR-27a was associated with obesity-related CRC risk in multivariate logistic analysis. Among overall CRC patients, MEG3 rs941576 was associated with lymph node (LN) metastasis and tumor stage, serum MEG3 was negatively correlated with tumor stage, while SIRT1 was correlated with the anatomical site. Significant correlations were recorded between MEG3 and anatomical site, SIRT1 and tumor stage, and miR-27a/IGFBP3 and LN metastasis among obese CRC patients, while IGF1 was correlated with tumor stage and LN metastasis among non-obese CRC patients. Conclusively, this study advocates MEG3 rs941576 as a novel genetic marker of CRC susceptibility and prognosis. Our findings accentuate circulating MEG3/miR-27a/IGF1/IGFBP3, especially miR-27a as valuable markers for the early detection of obesity-related CRC. This axis along with SIRT1 could benefit obesity-related CRC prognosis., (© 2024. The Author(s).)

This review examines the latest epidemiological and molecular pathogenic findings of metabolic-associated hepatocellular carcinoma (HCC). Its increasing prevalence is a significant concern and reflects the growing burden of obesity and metabolic diseases, including metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, and type 2 diabetes. Metabolic-associated HCC has unique molecular abnormality and distinctive gene expression patterns implicating aberrations in bile acid, fatty acid metabolism, oxidative stress, and proinflammatory pathways. Furthermore, a notable frequency of single nucleotide polymorphisms in genes such as patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, and membrane-bound O-acyltransferase domain-containing 7 has been observed. The tumor immune microenvironment of metabolic-associated HCC is characterized by unique phenotypes of macrophages, neutrophils, and T lymphocytes. Additionally, the pathogenesis of metabolic-associated HCC is influenced by abnormal lipid metabolism, insulin resistance, and dysbiosis. In conclusion, deciphering the intricate interactions among metabolic processes, genetic predispositions, inflammatory responses, immune regulation, and microbial ecology is imperative for the development of novel therapeutic and preventative measures against metabolic-associated HCC., Competing Interests: T.T. and T.K. have received speaker bureaus from Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., and AstraZeneca., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objective: It is well established that melanocortin-4 receptor ( MC4R ) rs17782313 locus polymorphism is associated with increased obesity risk and that obesity is strongly associated with an enhanced risk of all metabolic syndrome (MS) components. Thus, in this study, we examined the association between the MC4R rs17782313 locus polymorphism and the risk of the remaining MS components, namely, diabetes, hypertension, low high-density lipoprotein (HDL), and hypertriglyceridemia. Methods: We performed an extensive literature screening across six scientific databases, namely, PubMed, Embase, Web of Science, Medline, ScienceDirect, CNKI, and WanFang employing a specific search strategy. Eligible studies were selected for inclusion in our meta-analysis, and odds ratio (OR) values and 95% confidence interval (CI) were computed through fixed- or random-effects models to examine correlation strength. In addition, we performed subgroup analyses involving adjustment factors (unadjusted body mass index [BMI], adjusted BMI), race (Caucasian, Asian), and source of controls (population, hospital). Results: Twenty-two eligible studies were selected from 846 articles, involving 28,018 patients and 98,994 normal participants. Based on this meta-analysis, the MC4R rs17782313 locus polymorphism was associated with an augmented risk of diabetes (allele contrast model T vs. C: OR = 1.05, 95% CI = 1.03-1.08; dominant model TT vs. TC + CC: OR = 1.07, 95% CI = 1.03-1.11) and hypertension (dominant model TT vs. TC + CC: OR = 1.16, 95% CI = 1.03-1.31) risk. However, based on this analysis, the MC4R rs17782313 locus polymorphism was not associated with low HDL and hypertriglyceridemia risk. Conclusions: Based on this analysis, the MC4R rs17782313 locus polymorphism is associated with enhanced risks of diabetes and hypertension, while the associations with low HDL and hypertriglyceridemia require further exploration.

The global obesity pandemic presents a pressing health challenge, with an increasing prevalence shaped by an intricate interplay of genetics and environment. Brain-derived neurotrophic factor (BDNF) plays a pivotal role in regulating feeding behavior and energy expenditure. BDNF single nucleotide polymorphisms have been linked to obesity risk. We hypothesized that BDNF rs925946 is positively associated with obesity susceptibility in the Israeli population. We aimed to study BDNF rs925946 association with obesity susceptibility and its interaction with environmental factors, including eating habits, sugar-sweetened beverages, and physical activity. A data cohort of 4668 Israeli adults (≥18 years, Jewish) was analyzed. Participants' genotypic data for the BDNF rs925946 and lifestyle and eating behavior questionnaire data were analyzed for the association between obesity predisposition and gene-environment interactions. Female (n = 3259) BDNF rs925946 T-allele carriers had an elevated obesity odd (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.03-1.4, P = .02). BDNF rs925946 genotype interacted significantly with physical inactivity, sugar-sweetened beverage consumption, and eating habits score to enhance obesity odds (OR = 1.4; 95% CI, 1.14-1.7; OR = 1.54, 95% CI, 1.1-2.15; and OR = 1.4; 95% CI, 1.2-2.11, respectively). Our data demonstrated a significant association between BDNF rs925946 T-allele female carriers and a higher obesity predisposition, affected by modifiable lifestyle factors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Genome-wide association studies have identified several genetic variants associated with nonalcoholic fatty liver disease. To emphasize metabolic abnormalities in fatty liver, metabolic (dysfunction)-associated fatty liver disease (MAFLD) has been introduced; thus, we aimed to investigate single-nucleotide polymorphisms related to MAFLD and its subtypes. A genome-wide association study was performed to identify genetic factors related to MAFLD. We used a Korean population-based sample of 2282 subjects with MAFLD and a control group of 4669. We replicated the results in a validation sample which included 639 patients with MAFLD and 1578 controls. Additionally, we categorized participants into three groups, no MAFLD, metabolic dysfunction (MD)-MAFLD, and overweight/obese-MAFLD. After adjusting for age, sex, and principal component scores, rs738409 [risk allele G] and rs3810622 [risk allele T], located in the PNPLA3 gene, showed significant associations with MAFLD (P-values, discovery set = 1.60 × 10 -15 and 4.84 × 10 -10 ; odds ratios, 1.365 and 1.284, validation set = 1.39 × 10 -4 , and 7.15 × 10 -4 , odds ratios, 1.299 and 1.264, respectively). An additional SNP rs59148799 [risk allele G] located in the GATAD2A gene showed a significant association with MAFLD (P-values, discovery set = 2.08 × 10 -8 and validation set = 0.034, odds ratios, 1.387 and 1.250). rs738409 was significantly associated with MAFLD subtypes ([overweight/obese-MAFLD; odds ratio (95% confidence interval), P-values, 1.515 (1.351-1.700), 1.43 × 10 -12 and MD-MAFLD: 1.300 (1.191-1.416), 2.90 × 10 -9 ]. There was a significant relationship between rs3810622 and overweight/obese-MAFLD and MD-MAFLD [odds ratios (95% confidence interval), P-values, 1.418 (1.258, 1.600), 1.21 × 10 -8 and 1.225 (1.122, 1.340), 7.06 × 10 -6 , respectively]; the statistical significance remained in the validation set. PNPLA3 was significantly associated with MAFLD and MAFLD subtypes in the Korean population. These results indicate that genetic factors play an important role in the pathogenesis of MAFLD., (© 2024. The Author(s).)

Aims: The aim of this study was to investigate the impact of three single nucleotide polymorphisms (SNPs) within X-Ray Repair Cross Complementary Group 2 (XRCC2) gene and additional gene- abdominal obesity (AO) interaction with endometrial carcinoma (EC) risk., Methods: Hardy-Weinberg equilibrium was tested for all participants by using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). The best SNP-SNP and gene-AO interaction combination among three SNPs within XRCC2 gene and AO was screened using generalized multifactor dimensionality reduction (GMDR)., Results: We employed the logistic regression analysis showed that rs718282-T allele is associated with increased EC risk, adjusted ORs (95%CI) were 1.67 (1.23-2.04). However, we did not find statistical association between rs3218536, and rs3218384 and EC susceptibility. GMDR analysis was used for SNP-SNP- and gene-abdominal obesity analysis. The cross-validation consistency and the testing accuracy for the interaction were calculated. The two-locus model between rs718282 and AO had a testing accuracy of 60.11%, which was significant at the p  < .001 level, and this two- locus model was considered as the best model. It provided statistical evidence for rs718282 gene-AO interaction effects. The results indicated that AO influenced the EC risk depending on the rs718282 genotypes. Compared with non- AO subjects with rs718282-CC genotype, AO subjects with rs718282-CT or TT genotype had the highest EC risk, OR (95%CI) was 2.83 (1.67 - 4.02), after covariates adjustment., Conclusions: Both the rs718282- T allele, and its interaction with AO were associated with increased EC risk.

Obesity is a worldwide health problem with an increasing trend. This condition has a significant genetic background. H19 lncRNA has been shown to protect from dietary obesity through decreasing levels of monoallelic genes in brown fat. In the current study, we aimed to find the association between two possibly functional H19 polymorphisms, namely rs217727 and rs2839698 and obesity in Iranian population. These polymorphisms have been shown to affect risk of some obesity-related conditions in different populations. The study included 414 obese cases and 392 controls. Notably, both rs2839698 and rs217727 were associated with obesity in the allelic model as well as all supposed inheritance models. In addition, after adjustment for gender, all P values remained significant. For rs2839698, the OR (95% CI) for T allele vs. C allele was 3.29 (2.67-4.05) (P-value < 0.0001). In the co-dominant model, both TT and CT genotypes were found to confer risk of obesity compared with CC genotype (OR (95% CI)= 14.02 (8.39-23.43) and 9.45 (6.36-14.04), respectively). Similarly, combination of TT and CT genotypes had an OR (95% CI) = 10.32 (7.03-15.17) when compared with CC genotype. For rs217727, the T allele was found to exert a protective effect (OR (95% CI) = 0.6 (0.48-0.75)). Moreover, in the co-dominant model, OR (95% CI) values for TT and TC genotypes vs. CC genotype were 0.23 (0.11-0.46) and 0.65 (0.49-0.87), respectively. Taken together, H19 polymorphisms may affect risk of obesity in Iranian population. It is necessary to conduct functional studies to confirm a causal relationship between the rs217727 and rs2839698 polymorphisms and obesity., (© 2023. The Author(s).)

Objectives: To explore the prevalence and associated factors of obesity in Tibetan adults in Qinghai, China, and to determine the association between the FTO (rs1121980 and rs17817449) and MC4R gene (rs17782313 and rs12970134) polymorphisms with obesity., Methods: A cross-sectional survey was conducted in 2015 in Qinghai to selected Tibetan adults aged 20 to 80 years. Prevalence of obesity (BMI ≥ 28 kg/m 2 ) and overweight (BMI 24 ~ 27.9 kg/m 2 ) were evaluated. Multivariable logistic models were used to determine the associated factors. Pair-matched subjects of obesity cases and normal-weight controls were selected for the gene polymorphism analyses. Conditional logistic models were used to assess the association between gene polymorphisms with obesity. Additive and multiplicative gene-environment interactions were tested., Results: A total of 1741 Tibetan adults were enrolled. The age- and sex- standardized prevalence of obesity and overweight was 18.09% and 31.71%, respectively. Male sex, older age, heavy level of leisure-time exercise, current smoke, and heavy level of occupational physical activity were associated with both obesity and overweight. MC4R gene polymorphisms were associated with obesity in Tibetan adults. No significant gene-environment interaction was detected., Conclusion: The prevalence of obesity and overweight in Tibetan adults was high. Both environmental and genetic factors contributed to the obesity prevalent., (© 2024. The Author(s).)

Objectives: Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. However, identifying the causal genes, pathways, and tissues/cell types responsible for these associations remains a challenge, and standardized analysis workflows are lacking. Additionally, due to limited treatment options for obesity, there is a need for the development of new pharmacological therapies. This study aimed to address these issues by performing step-wise utilization of knowledgebase for gene prioritization and assessing the potential relevance of key obesity genes as therapeutic targets., Methods and Results: First, we generated a list of 28,787 obesity-associated SNPs from the publicly available GWAS dataset (approximately 800,000 individuals in the GIANT meta-analysis). Then, we prioritized 1372 genes with significant in silico evidence against genomic and transcriptomic data, including transcriptionally regulated genes in the brain from transcriptome-wide association studies. In further narrowing down the gene list, we selected key genes, which we found to be useful for the discovery of potential drug seeds as demonstrated in lipid GWAS separately. We thus identified 74 key genes for obesity, which are highly interconnected and enriched in several biological processes that contribute to obesity, including energy expenditure and homeostasis. Of 74 key genes, 37 had not been reported for the pathophysiology of obesity. Finally, by drug-gene interaction analysis, we detected 23 (of 74) key genes that are potential targets for 78 approved and marketed drugs., Conclusions: Our results provide valuable insights into new treatment options for obesity through a data-driven approach that integrates multiple up-to-date knowledgebases., (© 2023. The Author(s).)

Background/objectives: Different genetic variants are associated with larger body size in childhood vs adulthood. Whether and when these variants predominantly influence adiposity are unknown. We examined how genetic variants influence total body fat and total lean mass trajectories., Methods: Data were from the Avon Longitudinal Study of Parents and Children birth cohort (N = 6926). Sex-specific genetic risk scores (GRS) for childhood and adulthood body size were generated, and dual-energy X-ray absorptiometry scans measured body fat and lean mass six times between the ages of 9 and 25 years. Multilevel linear spline models examined associations of GRS with fat and lean mass trajectories., Results: In males, the sex-specific childhood and adulthood GRS were associated with similar differences in fat mass from 9 to 18 years; 8.3% [95% confidence interval (CI) 5.1, 11.6] and 7.5% (95% CI 4.3, 10.8) higher fat mass at 18 years per standard deviation (SD) higher childhood and adulthood GRS, respectively. In males, the sex-combined childhood GRS had stronger effects at ages 9 to 15 than the sex-combined adulthood GRS. In females, associations for the sex-specific childhood GRS were almost 2-fold stronger than the adulthood GRS from 9 to 18 years: 10.5% (95% CI 8.5, 12.4) higher fat mass at 9 years per SD higher childhood GRS compared with 5.1% (95% CI 3.2, 6.9) per-SD higher adulthood GRS. In females, the sex-combined GRS had similar effects, with slightly larger effect estimates. Lean mass effect sizes were much smaller., Conclusions: Genetic variants for body size are more strongly associated with adiposity than with lean mass. Sex-combined childhood variants are more strongly associated with increased adiposity until early adulthood. This may inform future studies that use genetics to investigate the causes and impact of adiposity at different life stages., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., (© 2023 by the American Diabetes Association.)

Diet modulates the genetic risk of obesity, but the modulation has been rarely studied using genetic risk scores (GRSs) in children. Our objectives were to identify single nucleotide polymorphisms (SNPs) that drive the interaction of specific foods with obesity and combine these into GRSs. Genetic and food frequency data from Finnish Health in Teens study was utilized. In total, 1142 11-year-old subjects were genotyped on the Metabochip array. BMI-GRS with 30 well-known SNPs was computed and the interaction of individual SNPs with food items and their summary dietary scores were examined in relation to age- and sex-specific BMI z-score (BMIz). The whole BMI-GRS interacted with several foods on BMIz. We identified 7-11 SNPs responsible for each interaction and these were combined into food-specific GRS. The most predominant interaction was witnessed for pizza (p < 0.001): the effect on BMIz was b - 0.130 (95% CI - 0.23; - 0.031) in those with low-risk, and 0.153 (95% CI 0.072; 0.234) in high-risk. Corresponding, but weaker interactions were verified for sweets and chocolate, sugary juice drink, and hamburger and hotdog. In total 5 SNPs close to genes NEGR1, SEC16B, TMEM18, GNPDA2, and FTO were shared between these interactions. Our results suggested that children genetically prone to obesity showed a stronger association of unhealthy foods with BMIz than those with lower genetic susceptibility. Shared SNPs of the interactions suggest common differences in metabolic gene-diet interactions, which warrants further investigation., (© 2023. Springer Nature Limited.)

FABP2 is one of the key genes involved in obesity development across different populations. However, there is no comprehensive report about the FABP2 contribution to obesity incidence among Iranians. Hence, the present study was designed to assess the probable role of FABP2 polymorphisms in obesity incidence in the Tehran Cardio- metabolic Genetic Study (TCGS) representative Iran population. Unrelated adults who had BMI information for at least 3 consecutive phases of the TCGS cohort were included. The control and case groups were defined as individuals who always had long-term persistent normal weight (20 < BMI < 25; n = 1526) and individuals who were long-term persistent obese (30 < BMI < 35; n = 1313), respectively. The logistic regression test was used to assess the possible association between SNPs located in and around the FABP2 gene with obesity. Also, we used Haploview and SHEsis to perform haplotype analysis to detect whether or not this chromosomal region is correlated with obesity. We found a gender-dependent association between the rs10857064 FABP2 and the risk of obesity. The presence of the rs10857064-G allele could significantly increase the risk of obesity only in women, not men (OR = 1.26; 95 % CI: 1.02-1.57; p = 0.03). Through haplotype analysis, we also detected that the TG haplotype containing rs7670862 and rs10857064 could significantly enhance the risk of obesity in women, further supporting the central role of rs10857064 in women's long-term obesity risk. In the current study, we revealed that rs10857064-G FABP2 can significantly predispose women to develop obesity. It highlights the importance of different genetic variants in both genders, which could help us to distinguish more efficient obesity screening tests and treatments based on gender in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The Fat-mass and obesity-associated-gene (FTO gene) and sedentary behavior time are associated with obesity. However, whether sedentary behavior time can modify the genetic predisposition to obesity in the Chilean population is unknown. Therefore, this study investigated the association between sedentary behavior, adiposity markers, and the FTO gene., Methods: This cross-sectional study included 409 participants from the Genes, Environment, Diabetes, and Obesity (GENADIO) study. Adiposity markers studied included body weight, body mass index (BMI), waist circumference (WC), and fat mass. Sedentary behaviors were measured using accelerometers. Using multiple regression, we evaluated the interaction between sedentary behaviors and the FTO gene (rs9939609) on adiposity markers., Results: Sedentary behaviors and the FTO genotype were positively associated with higher body weight, BMI, WC, and fat mass. However, the association between time of sedentary behavior and adiposity markers was higher in carriers of the risk variant for the FTO gene. For each hour of increment in sedentary behaviors, body weight increases by 1.36 kg ([95% CI: 0.27; 2.46], p = 0.015) and 2.95 kg ([95%CI: 1.24; 4.65], p = 0.001) in non-risk carriers (TT) versus risk carriers (AA), respectively. We observed similar results for WC, BMI, and body fat, but the interaction was significant only for WC., Conclusion: The association between sedentary behaviors and adiposity markers, especially body weight and WC, is higher in individuals who carry the risk variant of the FTO gene.

Hundreds of genetic variants for body mass index (BMI) have been identified from numerous genome-wide association studies (GWAS) in different ethnicities. In this study, we aimed to develop a polygenic risk score (PRS) for BMI for predicting susceptibility to obesity and related traits in the Korean population. For this purpose, we obtained base data resulting from a GWAS on BMI using 57,110 HEXA study subjects from the Korean Genome and Epidemiology Study (KoGES). Subsequently, we calculated PRSs in 13,504 target subjects from the KARE and CAVAS studies of KoGES using the PRSice-2 software. The best-fit PRS for BMI (PRS BMI ) comprising 53,341 SNPs was selected at a p -value threshold of 0.064, at which the model fit had the greatest R 2 score. The PRS BMI was tested for its association with obesity-related quantitative traits and diseases in the target dataset. Linear regression analyses demonstrated significant associations of PRS BMI with BMI, blood pressure, and lipid traits. Logistic regression analyses revealed significant associations of PRS BMI with obesity, hypertension, and hypo-HDL cholesterolemia. We observed about 2-fold, 1.1-fold, and 1.2-fold risk for obesity, hypertension, and hypo-HDL cholesterolemia, respectively, in the highest-risk group in comparison to the lowest-risk group of PRS BMI in the test population. We further detected approximately 26.0%, 2.8%, and 3.9% differences in prevalence between the highest and lowest risk groups for obesity, hypertension, and hypo-HDL cholesterolemia, respectively. To predict the incidence of obesity and related diseases, we applied PRS BMI to the 16-year follow-up data of the KARE study. Kaplan-Meier survival analysis showed that the higher the PRS BMI , the higher the incidence of dyslipidemia and hypo-HDL cholesterolemia. Taken together, this study demonstrated that a PRS developed for BMI may be a valuable indicator to assess the risk of obesity and related diseases in the Korean population.

Background and Aims: The fatty acid-binding proteins (FABPs) gene polymorphisms are related to several metabolic properties. We investigated the association of SNPs rs2241883 of FABP 1 gene with obesity to evaluate the role of FABP1 gene in the pathogenesis of obesity in the population of MASHAD study cohort., Methods: In this cross-sectional study, 2731 individuals (1883 Obese and 848 nonobese) aged 35 to 65 years old, were enrolled from the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study cohort. DNA Quantitation was determined using the NanoDrop®-1000 instrument (NanoDrop-Technologies). The rs2241883 polymorphisms were genotyped by double ARMs PCR (double amplification refractory mutation system) reactions. Data analysis was carried out using SPSS 22 and a p < 0.05 was set for statistical significance., Results: The results showed that after adjusting for confounding factors, subjects having the CC genotype for rs2241883 polymorphism were at a higher risk of BMI ≥ 30 mg/kg 2 with OR of 1.79 (CI = 1.05-3.07; p = 0.03) and 1.76 (CI = 1.04-2.99; p = 0.04) comparing with reference group using codominant and dominant models, respectively., Conclusion: The results showed that CC genotype for rs2241883 polymorphism is related to an increased risk of the obesity in dominant and codominant models in a population of MASHAD study cohort., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: To study the associations of Protein Tyrosine Phosphatase-N1 (PTPN1) polymorphisms with obesity-related phenotypes in European adolescents, and the influence of physical activity on these relationships., Methods: Five polymorphisms of PTPN1 were genotyped in 1057 European adolescents (12-18 years old). We measured several phenotypes related to obesity, such as adiposity markers, and biochemical and clinical parameters. Physical activity was objectively measured by accelerometry., Results: The T, A, T, T and G alleles of the rs6067472, rs10485614, rs2143511, rs6020608 and rs968701 polymorphisms, respectively, were associated with lower levels of obesity-related phenotypes (i.e., body mass index, body fat percentage, hip circumference, fat mass index, systolic blood pressure and leptin) in European adolescents. In addition, the TATTG haplotype was associated with lower body fat percentage and fat mass index compared to the AACCA haplotype. Finally, when physical activity levels were considered, alleles of the rs6067472, rs2143511, rs6020608 and rs968701 polymorphisms were only associated with lower adiposity in active adolescents., Conclusions: PTPN1 polymorphisms were associated with adiposity in European adolescents. Specifically, alleles of these polymorphisms were associated with lower adiposity only in physically active adolescents. Therefore, meeting the recommendations of daily physical activity may reduce obesity risk by modulating the genetic predisposition to obesity., Impact: Using gene-phenotype and gene*environment analyses, we detected associations between polymorphisms of the Protein Tyrosine Phosphatase-N1 (PTPN1) gene and obesity-related phenotypes, suggesting a mechanism that can be modulated by physical activity. This study shows that genetic variability of PTPN1 is associated with adiposity, while physical activity seems to modulate the genetic predisposition. This brings insights about the mechanisms by which physical activity positively influences obesity., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Obesity and type 2 diabetes (T2D) are serious health problems linked to neurobehavioral alterations. We compared motor function, anxiety-related behavior, and cerebellar gene expression in TALLYHO/Jng (TH), a polygenic model prone to insulin resistance, obesity, and T2D, and normal C57BL/6 J (B6) mice. Male and female mice were weaned onto chow or high fat (HF) diet at 4 weeks of age (wk), and experiments conducted at young (5 wk) and old (14 - 20 wk) ages. In the open field, distance traveled was significantly lower in TH (vs. B6). For old mice, anxiety-like behavior (time in edge zone) was significantly increased for TH (vs B6), females (vs males), and for both ages HF diet (vs chow). In Rota-Rod testing, latency to fall was significantly shorter in TH (vs B6). For young mice, longer latencies to fall were observed for females (vs males) and HF (vs chow). Grip strength in young mice was greater in TH (vs B6), and there was a diet-strain interaction, with TH on HF showing increased strength, whereas B6 on HF showed decreased strength. For older mice, there was a strain-sex interaction, with B6 males (but not TH males) showing increased strength compared to the same strain females. There were significant sex differences in cerebellar mRNA levels, with Tnfα higher, and Glut4 and Irs2 lower in females (vs males). There were significant strain effects for Gfap and Igf1 mRNA levels with lower in TH (vs B6). Altered cerebellar gene expression may contribute to strain differences in coordination and locomotion., Competing Interests: Conflict of interest No conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to evaluate whether dimensions of sleep quality were associated with homeostatic and hedonic eating behaviors among children with healthy weight (BMI-for-age < 90%) but varying maternal weight status., Methods: A total of 77 children (mean [SD], age: 7.4 [0.6] years; BMI z score: -0.10 [0.7]) with healthy weight and high (n = 32) or low (n = 45) familial obesity risk based on maternal weight status were served an ad libitum meal (homeostatic eating) followed by palatable snacks to assess eating in the absence of hunger (EAH; hedonic eating). Habitual sleep quality was quantified from seven nights of wrist actigraphy. Partial correlations, adjusted for child energy needs, pre-meal hunger, food liking, and socioeconomic status, evaluated associations of sleep with meal intake and EAH. Additionally, sleep-by-obesity risk interactions were assessed., Results: Greater sleep fragmentation was associated with higher homeostatic meal energy intake, but only among children at high familial obesity risk (p value for interaction = 0.001; β high risk = 48.6, p = 0.001). Sleep fragmentation was not associated with total EAH but was related to higher and lower intake of carbohydrates (r = 0.33, p = 0.003) and fat (r = -0.33, p = 0.003), respectively., Conclusions: Adverse associations of poor sleep with energy intake may be amplified among children already predisposed to obesity. Furthermore, that fragmented sleep relates to preferential intake of carbohydrates over fat during EAH may suggest alterations in taste preferences with poor sleep., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: Overweight is the scourge of modern society and a major risk factor for many diseases. For this reason, understanding the genetic component predisposing to high body mass index (BMI) seems to be an important task along with preventive measures aimed at improving eating behavior and increasing physical activity., Methods: We analyzed genetic data of a European cohort (n = 21,080, 47.25% women, East Slavs ancestry >80%) for 5 frequently found genes in the context of association with obesity: IPX3 (rs3751723), MC4R (rs17782313), TMEM18 (rs6548238), PPARG (rs1801282) and FTO (rs9939609)., Results: Our study revealed significant associations of FTO (rs9939609) (β = 0.37 (kg/m 2 )/allele, p = <2 × 10 -16 ), MC4R (rs17782313) (β = 0.28 (kg/m 2 )/allele, p = 5.79 × 10 -9 ), TMEM18 (rs6548238) (β = 0.29 (kg/m 2 )/allele, p = 2.43 × 10 -8 ) with BMI and risk of obesity., Conclusions: The results confirm the contribution of FTO, M4CR, and TMEM18 genes to the mechanism of body weight regulation and control., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The relationship between lifestyle and obesity is a major focus of research. Personalized nutrition, which utilizes evidence from nutrigenomics, such as gene-environment interactions, has been attracting attention in recent years. However, evidence for gene-environment interactions that can inform treatment strategies is lacking, despite some reported interactions involving dietary intake or physical activity. Utilizing gene-lifestyle interactions in practice could aid in optimizing interventions according to genetic risk., Methods: This study aimed to elucidate the effects of gene-lifestyle interactions on body mass index (BMI). Cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study were used. Interactions between a multi-locus genetic risk score (GRS), calculated from 76 ancestry-specific single nucleotide polymorphisms, and nutritional intake or physical activity were assessed using a linear mixed-effect model., Results: The mean (standard deviation) BMI and GRS for all participants (n = 12,918) were 22.9 (3.0) kg/m2 and -0.07 (0.16), respectively. The correlation between GRS and BMI was r(12,916) = 0.13 (95% confidence interval [CI] 0.11-0.15, P < 0.001). An interaction between GRS and saturated fatty acid intake was observed (β = -0.11, 95% CI -0.21 to -0.02). An interaction between GRS and n-3 polyunsaturated fatty acids was also observed in the females with normal-weight subgroup (β = -0.12, 95% CI -0.22 to -0.03)., Conclusion: Our results provide evidence of an interaction effect between GRS and nutritional intake and physical activity. This gene-lifestyle interaction provides a basis for developing prevention or treatment interventions for obesity according to individual genetic predisposition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nakamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2023. The Author(s).)

Type 2 diabetes (T2D) represents a multifactorial metabolic disease with a strong genetic predisposition. Despite elaborate efforts in identifying the genetic variants determining individual susceptibility towards T2D, the majority of genetic factors driving disease development remain poorly understood. With the aim to identify novel T2D risk genes we previously generated an N2 outcross population using the two inbred mouse strains New Zealand obese (NZO) and C3HeB/FeJ (C3H). A linkage study performed in this population led to the identification of the novel T2D-associated quantitative trait locus (QTL) Nbg15 (NZO blood glucose on chromosome 15, Logarithm of odds (LOD) 6.6). In this study we used a combined approach of positional cloning, gene expression analyses and in silico predictions of DNA polymorphism on gene/protein function to dissect the genetic variants linking Nbg15 to the development of T2D. Moreover, we have generated congenic strains that associated the distal sublocus of Nbg15 to mechanisms altering pancreatic beta cell function. In this sublocus, Cbx6 , Fam135b and Kdelr3 were nominated as potential causative genes associated with the Nbg15 driven effects. Moreover, a putative mutation in the Kdelr3 gene from NZO was identified, negatively influencing adaptive responses associated with pancreatic beta cell death and induction of endoplasmic reticulum stress. Importantly, knockdown of Kdelr3 in cultured Min6 beta cells altered insulin granules maturation and pro-insulin levels, pointing towards a crucial role of this gene in islets function and T2D susceptibility.

We propose a model for obesity development that traces a considerable part of its origins to the social domain (mainly different forms of prolonged social adversity), both within and across generations, working in tandem with a genetic predisposition. To facilitate overview of social pathways, we place particular focus on three areas that form a cascading sequence: (A) social adversity within the family (parents having a low education, a low social position, poverty and financial insecurity; offspring being exposed to gestational stress, unmet social and emotional needs, abuse, maltreatment and other negative life events, social deprivation and relationship discord); (B) increasing levels of insecurity, negative emotions, chronic stress, and a disruption of energy homeostasis; and (C) weight gain and obesity, eliciting further social stress and weight stigma in both generations. Social adversity, when combined with genetic predisposition, thereby substantially contributes to highly effective transmission of obesity from parents to offspring, as well as to obesity development within current generations. Prevention efforts may benefit from mitigating multiple types of social adversity in individuals, families, and communities, notably poverty and financial strain, and by improving education levels., (© 2022 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes., Methods and Findings: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed., Conclusions: Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DG is employed part-time by Novo Nordisk. VZ is a paid statistical consultant on PLOS Medicine’s statistical board., (Copyright: © 2022 Zagkos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)