FTO Gene Research Articles

Oxidative stress-mediated activation of FTO exacerbates impairment of the epithelial barrier by up-regulating IKBKB via N6-methyladenosine-dependent mRNA stability in asthmatic mice exposed to PM2.5

In order to comprehend the underlying mechanisms contributing to the development and exacerbation of asthma resulting from exposure to fine particulate matter (PM2.5), we established an asthmatic model in fat mass and obesity-associated gene knockdown mice subjected to PM2.5 exposure. Histological analyses using hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining revealed that the down-regulation of the fat mass and obesity-associated gene (Fto) expression significantly ameliorated the pathophysiological alterations observed in asthmatic mice exposed to PM2.5. Furthermore, the down-regulation of Fto gene expression effectively attenuated damage to the airway epithelial barrier. Additionally, employing in vivo and in vitro models, we elucidated that PM2.5 modulated FTO expression by inducing oxidative stress. Asthmatic mice exposed to PM2.5 exhibited elevated Fto expression, which correlated with increased levels of reactive oxygen species. Similarly, when cells were exposed to PM2.5, FTO expression was up-regulated in a ROS-dependent manner. Notably, the administration of N-acetyl cysteine successfully reversed the PM2.5-induced elevation in FTO expression. Concurrently, we performed transcriptome-wide Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) analysis subsequent to PM2.5 exposure. Through the implementation of Gene Set Enrichment Analysis and m6A-IP-qPCR, we successfully identified inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) as a target gene regulated by FTO. Interestingly, exposure to PM2.5 led to increased expression of IKBKB, while m6A modification on IKBKB mRNA was reduced. Furthermore, our investigation revealed that PM2.5 also regulated IKBKB through oxidative stress. Significantly, the down-regulation of IKBKB effectively mitigated epithelial barrier damage in cells exposed to PM2.5 by modulating nuclear factor-kappa B (NF-κB) signaling. Importantly, we discovered that decreased m6A modification on IKBKB mRNA facilitated by FTO enhanced its stability, consequently resulting in up-regulation of IKBKB expression. Collectively, our findings propose a novel role for FTO in the regulation of IKBKB through m6A-dependent mRNA stability in the context of PM2.5-induced oxidative stress. Therefore, it is conceivable that the utilization of antioxidants or inhibition of FTO could represent potential therapeutic strategies for the management of asthma exacerbated by PM2.5 exposure.

Effect of Pentaclethra macrophyla Benth. Leaf on expression of P53, IRS, HsD17β2, FTO, and CYP11a genes in letrozole-induced polycystic ovarian syndrome rats

Effect of Pentaclethra macrophyla Benth. Leaf on expression of P53, IRS, HsD17β2, FTO, and CYP11a genes in letrozole-induced polycystic ovarian syndrome rats

Childhood Obesity as Interactions of Environmental and Genetic Factors: A Community – Based Study on Primary School Children of Hanoi, Vietnam

Objective: Obesity is a complex disease that involves interactions between environmental and genetic factors in its pathogenesis. The aims of this present study were to analyse the overall effects of some nutritional, physical and genetic factors with childhood obesity, and to build predictive models of childhood obesity.Material and Methods: A case-control study was conducted on 559 Hanoi primary school children (278 obese cases and 281 normal controls). Genetic analysis was performed to evaluate genotype on the rs6265 gene BDNF, rs6548238 gene TMEM18, rs6499640 gene FTO, and rs17782313 gene MC4R. Univariate and multivariate regression analysis were conducted to compare the two groups of children, so as to draw conclusions regarding influencing factors and to establish predictive models of obesity for Hanoi primary school children.Results: Factors increasing the risk of obesity found included: urban living areas (odds ratio (OR)=1.5), caesarean section (OR=2.1), high birth weight (OR=1.9-3.1), parental overweight and obesity (OR=2.1-5.1), short night sleeping times (OR=2.6), characteristics of child feeding; including early weaning (OR=2.1), gluttony (OR=19.1), no snacking (OR=2.4), controlled eating (OR=2.4) fat food hobbies (OR=2.7), and CC rs6548238-TMEM18 genotype (OR=1.8). A predictive model of childhood obesity for Hanoi primary school children was built, based on the BMI of parents, gluttonous characteristics, unrestricted eating with ROC=0.871.Conclusion: Childhood obesity develops as a result of interaction between eating habits, lifestyle characteristics of the child and genetic characteristics inherited from over nutritious parents. Encouraging parents to manage both their own weight and their children’s eating habits such as allowing children to consume food without undue restriction and reducing gluttony can serve as effective interventions to diminish the prevalence of childhood obesity within the community.

Prevalence, associated factors, and gene polymorphisms of obesity in Tibetan adults in Qinghai, China

ObjectivesTo 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.MethodsA cross-sectional survey was conducted in 2015 in Qinghai to selected Tibetan adults aged 20 to 80 years. Prevalence of obesity (BMI ≥ 28 kg/m2) and overweight (BMI 24 ~ 27.9 kg/m2) 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.ResultsA 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.ConclusionThe prevalence of obesity and overweight in Tibetan adults was high. Both environmental and genetic factors contributed to the obesity prevalent.

Associations Between rs9939609 FTO Polymorphism With Nutrient and Food Intake and Adherence to Dietary Patterns in an Urban Argentinian Population

BackgroundThe A allele of rs9939609 polymorphism at the FTO gene has been consistently associated with higher body mass index in different populations, but conflicting results have been found regarding its contribution to food intake variability. ObjectiveThis study aimed to investigate the association between this genetic variant and nutrient and food intake in an urban Argentinian population. DesignA cross-sectional, analytic investigation was performed between October 2018 and February 2020. Participants/settingsAdults of both sexes residing in La Plata, Argentina, were recruited through social networks (Instagram and Facebook). Of 179 eligible adults, a total of 173 adults were included in the final analyses. Outcome measuresNutrient and food group intake data were obtained by an interview-administered food frequency questionnaire. Height and weight were measured, and genotypes were obtained by real-time polymerase chain reaction. Statistical analysesThe per-allele effect on nutrient and food group intake was assessed by general linear models, adjusting for age, sex, educational level, total energy intake, and body mass index. Dietary patterns were derived by principal component analysis. The association of the A allele with adherence to each dietary pattern was also evaluated by the general linear model. ResultsThe frequency of the risk allele was 27%. A-carriers showed a higher total fat (1.88 [0.55, 3.21] % of total energy intake), saturated fatty acids (0.82 [0.25–1.39] % of total energy intake), and monounsaturated fatty acids (0.66 [0.08, 1.24] % of total energy intake), and a lower carbohydrate (−1.99 [−3.48, −0.50] % of total energy intake) intake than TT homozygous. A-carriers also reported a higher “milk and yogurt” (1.08 [0.24, 1.91] % of total energy intake), “animal fats” (1.09 [0.14–2.03] % of total energy intake), and fat-rich ultraprocessed foods (2.10 [0.52, 3.67] % of total energy intake) intake in comparison with TT homozygous. Furthermore, A-carriers showed higher adherence to the Western dietary pattern. ConclusionThe A allele contributed to nutrient and food intake variability in the studied population and was associated with the consumption of saturated fatty acids–enriched foods.

Relationship of rs6499640 and rs17817449 Polymorphisms in the FTO Gene with Type 2 Diabetes

Relationship of rs6499640 and rs17817449 Polymorphisms in the FTO Gene with Type 2 Diabetes

Variability of the SNP rs9939609 in the FTO Gene and Ancestry in Latin American Populations

Introduction: Obesity is a complex condition influenced by genetic and environmental factors. The FTO gene has been associated with obesity through several single nucleotide polymorphisms (SNPs), particularly rs9939609, related to higher body mass index (BMI) and risk of obesity. FTO variants influence the regulation of appetite and energy metabolism by affecting RNA methylation and the expression of key genes in adipogenesis.Objective: To investigate the association between the FTO rs9939609 SNP and genetic ancestry proportions in Latin American populations.Methods: Genotypes for rs9939609 were obtained using VcfTools and the 1000 Genomes Project database. Samples from Latin America were selected, covering four mixed populations: Colombians (n=94), Mexicans (n=64), Peruvians (n=85) and Puerto Ricans (n=104), totaling 347 individuals. To estimate genetic ancestry proportions, 446 SNPs from a panel of ancestry informative markers (AIMs) were used.Results: Individuals with the AA genotype of SNP rs9939609 have a higher proportion of Native American ancestry and a lower proportion of European ancestry compared to TT and AT genotypes. The variability in the proportions of ancestry according to the genotype of the SNP rs9939609 suggests a possible genetic stratification in the Latin American populations studied.Conclusions: These findings highlight the importance of considering ancestral composition in genetic studies related to obesity. More research is needed to understand how gene-environment interactions contribute to obesity in various populations, which could lead to more effective and targeted intervention strategies

Contributing role of metabolic genes APOE, FTO, and LPL in the development of atrial fibrillation: insights from a case-control study.

The aim of the study was to examine the expression profile of genes (APOE, FTO, and LPL) associated with metabolic syndrome (MetS) in subjects with concomitant atrial fibrillation (AF). A total of 690 subjects were categorized into control, AF without MetS, and AF with MetS. The expression profiles of the APOE, FTO, and LPL genes were decreased in AF subjects and AF subjects with MetS as compared to the controls. In AF without the MetS group, an inverse relationship was found between the expression of the LPL gene with body mass index (BMI) and a positive relationship with creatine kinase-MB, whereas expression of the FTO gene was inversely associated with fasting blood glucose and positively with cardiac troponin I in AF suffering from MetS. Expression of the LPL gene was directly linked with systolic blood pressure (SBP) and high-density lipoprotein-cholesterol (HDL-C), whereas an inverse correlation with heart rate and expression of the FTO gene in AF with MetS were shown. The expression of the LPL gene was inversely related to BMI in subjects with AF. The expression of the LPL gene was positively correlated with SBP and HDL-C and negatively correlated with heart rate, while the expression of the FTO gene was an important predictor of AF with MetS. The decreased expression of APOE, FTO, and LPL genes in AF with and without MetS indicates their potential contributing role in the pathogenesis of AF.

The Role of FTO Risk Haplotype in Overweight/Obesity and Lipid Parameters-Results From the Central China Population Study.

Background: Fat mass and obesity-associated gene (FTO) genes rs9939609 is strongly associated with obesity and rs17817449 is an important and potential gene for obesity, have been well established. We aim to evaluate the relationship between FTO gene and overweight/obesity and confirm the influence of obesity on glucose and lipid metabolism parameters. Methods: We investigated 183 normal weight subjects and 193 individuals with overweight/obesity. Firstly, the effect of overweight/obesity on glucose and lipid metabolism parameters was analyzed. Then, the FTO genes rs9939609 and rs17817449 were counted to explore whether polymorphisms were associated with overweight/obesity and metabolic parameters. Results: Significant differences existed in glucose and lipid parameters between the group with overweight/obesity and control group. The rs9939609 and rs17817449 were strongly correlated with overweight/obesity. Haplotype analysis revealed that GA and GT haplotypes had 2.99 and 1.81 fold risk of overweight/obesity. FTO polymorphism also has effects on glucose and lipid metabolism parameters. Conclusions: There is a linkage imbalance between rs9939609 and rs17817449 in a Central China general population cohort, which also reflected the influence of FTO gene on the risk of overweight/obesity and total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) disorders. The new findings could provide new clues to predict obesity and metabolic diseases.

Investigation of genetic markers associated to type 2 diabetes mellitus in Santarém-Pará.

Genetic, epigenetic and environmental factors play an important role in the genesis of Type 2 Diabetes Mellitus (T2D). In the genetic context, one of the strategies used to investigate possible associations with diabetes is the search for Single Nucleotide Polymorphisms (SNPs), involving the comparison of alelle frequencies, the phenotypic variations and other relevant factors, such as environmental influences and lifestyle choices, Thus, the aim of this study was to find the relationship of risk variants for T2D in SNPs (rs4994) in the ADRB3 gene; (rs1799854) in the ABCC8 gene; (rs7901695 and rs12255372) in the TCF7L2 gene; and (rs8050136) in the FTO gene in a sample of the population of the municipality of Santarém (PA), Brazilian Amazon, in the northern region of Brazil. ABCC8 (rs1799854 C>T) showed a statistically significant association with T2D. Each chosen gene and SNP has been previously implicated in T2D risk according to existing scientific literature, owing to their roles in glucose regulation and body fat.

RNA m6A dynamic modification mediated by nucleus-localized FTO is involved in follicular reserve.

In eukaryotic organisms, the most common internal modification of messenger RNA (mRNA) is N6-methyladenosine (m6A). This modification can be dynamically and reversibly controlled by specific enzymes known as m6A writers and erasers. The fat-mass and obesity-associated protein (FTO) catalyzes RNA demethylation and plays a critical role in various physiological and pathological processes. Our research identified dynamic alterations in both m6A and FTO during the assembly of primordial follicles, with an inverse relationship observed for m6A levels and nuclear-localized FTO expression. Application of Fto small interfering RNA (siRNA) altered the expression of genes related to cell proliferation, hormone regulation, and cell chemotaxis, and affected RNA alternative splicing. Overexpression of the full-length Fto gene led to changes in m6A levels, alternative splicing of Cdk5, cell proliferation, cell cycle progression, and proportion of primordial follicles. Conversely, overexpression of Fto lacking a nuclear localization signal (NLS) did not significantly alter m6A levels or primordial follicle assembly. These findings suggest that FTO, localized in the nucleus but not in the cytoplasm, regulates RNA m6A demethylation and plays a role in cell proliferation, cell cycle progression, and primordial follicle assembly. These results highlight the potential of m6A and its eraser FTO as possible biomarkers and therapeutic targets.

Association of the FTO gene with obesity and cancer in dogs

Nowadays, obesity is one of the most serious problems that significantly affect health in both human and animal populations. Fat mass and obesity-associated gene (FTO), increases the risk of obesity and other metabolic diseases such as cancer, with taking part in many complex molecular pathways. On the other hand, environmental and genetic factors cause changes in FTO gene variants and expression levels, which result in phenotypic differences. Advanced knowledge on the genetic basis of human FTO gene and its association with cancer and obesity, has paved the way for the investigation of FTO gene in animals as well. In this review, we summarized current state of knowledge about the FTO gene, which is considered as an important marker of obesity in humans, as well as obesity, cancer and the association of FTO polymorphisms with these diseases in dogs by considering humans with other animal species. Understanding the molecular background of the FTO gene in dogs will be leading to the development of individual treatment methods and prediction of possible phenotypic effects in other species.

Nutrigenetics: unravelling the genetic contributions to obesity, cardiovascular diseases, and diabetes mellitus

In this review, we aim to explore the field of nutrigenetics and its potential impact on obesity, cardiovascular diseases, and diabetes mellitus. Current dietary approaches in nutritional science often overlook the individual’s genetic profile, limiting the effectiveness of personalized diets. Nutrigenetics aims to incorporate genetic data into nutritional interventions to optimize disease prevention and treatment strategies. Regarding obesity, genetic factors, including multiple genes and alleles, influence body weight and predisposition to obesity. The FTO and MC4R genes, for example, have been linked to weight gain and appetite regulation. Similarly, genetic variations in the APO-A and APO-E gene families affect lipid metabolism and susceptibility to cardiovascular diseases. Genetic variations in genes such as MTHFR and PPAR-γ2 have been associated with increased cardiovascular risk, while dietary factors, such as the consumption of fruits and vegetables, can reduce the likelihood of developing these diseases. In diabetes mellitus, both type 1 and type 2, genetic factors also play a significant role. Genes like IGF2BP2 and PRKAA2 impact insulin resistance and glucose metabolism. Although nutrigenetics is still a developing field, it has the potential to revolutionize personalized nutrition plans and improve health outcomes.

FTO is a major genetic link between breast cancer, obesity, and diabetes.

Breast cancer (BC), obesity, and type 2 diabetes mellitus (T2DM) are three complex diseases and health problems that are prevalent worldwide. The aim of this study was to investigate the common genetic associations between these diseases by referring back to the previous genome-wide association studies (GWAS). To this end, significant GWAS variants and common variants associated with BC, obesity, or diabetes were identified from the GWAS catalog. To perform candidate variants, the 1000-Genomes Project was used to find variants with linkage disequilibrium. Common variants between each category were identified (common candidate haplotypic variants). Finally, these variants and their associated genes were examined for SNP function analysis, gene expression, gene-gene correlation, and pathway analysis. The results identified 7 variants associated with both T2DM and BC, 8 variants associated with both obesity and BC, and 167 variants associating obesity with T2DM. 91 variants and 4 haplotypic blocks such as CTC were identified on the FTO gene associated with obesity, BC, and T2DM. The results of TCGA data showed that FTO in gene expression was correlated with 6 other genes in the DNA repair pathway in BC subjects. This study suggests that the FTO gene is one of the major genes shared by BC, T2DM, and obesity based on two DNA repair and inflammatory mechanisms. These results may provide a new perspective on the important role of the FTO gene and repair mechanism in the relationship between BC, obesity, and T2DM for future studies.

FTO and MC4R polymorphisms, and selected pre-, peri- and postnatal factors as determinants of body mass index and fatness in children: a thorough analysis of the associations

BackgroundOverweight and obesity among children have become significant global health concerns. Previous studies have highlighted the potential role of genetic factors, particularly polymorphisms in the FTO and MC4R genes, as well as environmental factors in the development of childhood obesity. This study aimed to investigate the relationships between genetic, socioeconomic and perinatal factors, adverse childhood events (ACEs), and lifestyle, and their impact on overweight, obesity and body composition parameters in children. Additionally, we explored potential interactions between genetic factors and ACEs.MethodsFour hundred fifty-six children aged 6–12 years participated in our study. Information on the socioeconomic status, perinatal factors, ACEs and lifestyle of the children was collected with a questionnaire completed by their parents/guardians. We examined the children’s body weight and conducted an electrical bioimpedance analysis. Overweight and obesity were diagnosed based on the International Obesity Task Force and McCarthy criteria. We genotyped two selected polymorphisms in the FTO and MC4R genes using the TaqMan SNP allelic discrimination method.ResultsHigher BMI (Body Mass Index) z scores were related to higher paternal BMI and lower maternal age at the child’s birth. Higher FMI (Fat Mass Index) z scores were associated with higher paternal BMI, increased gestational weight, lower maternal education and the presence of the FTO risk allele. Higher FatM (fat mass in kg) z scores were linked to lower maternal education, lower maternal age at the child’s birth, higher maternal body weight gain, paternal BMI and the presence of the FTO risk allele. Moreover, interaction effects were observed on BMI z scores between ACE and FTO AA, and on FMI z scores and FatM z scored between ACE and MC4R CC.ConclusionsThe contribution of environmental factors is more strongly related to changes in body composition than genetic ones. Additionally, the presence of the risk allele combined with unfavourable environmental factors like ACEs leads to visible interaction effects, resulting in increased BMI z scores and FMI z scores in children.

Sex and Race Differences in Obesity-Related Genetic Susceptibility and Risk of Cardiometabolic Disease in Older US Adults

The fat mass and obesity-associated gene (FTO) is associated with obesity phenotypes, but the association is inconsistent across populations. Within-population differences may explain some of the variability observed. To investigate sex differences in the association between FTO single-nucleotide variants (SNVs) and obesity traits among self-identified non-Hispanic Black and non-Hispanic White US adults, to examine whether the SNVs were associated with cardiometabolic diseases, and to evaluate whether obesity mediated the association between FTO SNVs and cardiometabolic diseases. This cross-sectional study used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a US population-based cohort study with available genetic data (assayed in 2018) and phenotypic data at baseline (enrolled 2003-2007). Participants were aged 45 to 98 years at baseline. Data were analyzed from October 2021 to October 2022. Eleven SNVs in the FTO gene present among both Black and White participants. Objectively measured obesity indicators (body mass index and waist-to-height ratio), objectively measured and/or self-reported cardiometabolic diseases (hypertension, stroke history, heart disease, and diabetes), and self-reported social-economic and psychosocial status. A total of 10 447 participants (mean [SD] age, 64.4 [9.7] years; 5276 [55.8%] women; 8743 [83.7%] Black and 1704 [16.3%] White) were included. In the White group, 11 FTO SNVs were significantly associated with obesity, hypertension, and diabetes using linear models (eg, body mass index: β = 0.536; 95% CI, 0.197-0.875), but none of the FTO SNVs were associated with obesity traits in the Black group. White males had a higher risk of obesity while White females had a higher risk of hypertension and diabetes. However, 1 FTO SNV (rs1121980) was associated with a direct increase in the risk of heart disease in Black participants not mediated by obesity (c' = 0.145 [SE, 0.0517]; P = .01). In this cross-sectional study of obesity phenotypes and their association with cardiometabolic diseases, the tested FTO SNVs reflected sex differences in White participants. Different patterns of associations were observed among self-identified Black participants. Therefore, these results could inform future work discovering risk alleles or risk scores unique to Black individuals or further investigating genetic risk in all US residents.

Type 2 diabetes linked FTO gene variant rs8050136 is significantly associated with gravidity in gestational diabetes in a sample of Bangladeshi women: Meta-analysis and case-control study.

Gestational diabetes mellitus (GDM) is a growing public health concern that has not been extensively studied. Numerous studies have indicated that a variant (rs8050136) of the fat mass-associated gene, FTO, is associated with both GDM and Type 2 diabetes mellitus(T2DM). We conducted a meta-analysis on the association between the FTO single nucleotide polymorphism (SNP) rs8050136 and T2DM, followed by a case-control study on the association of the said SNP and GDM in a sample of Bangladeshi women. A total of 25 studies were selected after exploring various databases and search engines, which were assessed using the Newcastle-Ottawa Scale (NOS). The MetaGenyo web tool was used to conduct this meta-analysis. A case-control study was performed on 218 GDM patients and 284 controls to observe any association between FTO rs8050136 and GDM. Genotyping was performed using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS) method, and statistical analyses were performed using various statistical softwares. In the meta-analysis 26231 cases and 43839 controls were examined. Pooled association analyses revealed a statistically significant relationship between the FTO rs8050136 polymorphism and an elevated risk of T2DM under all genetic models (P<0.05). In the case-control study, synergistic analyses of the SNP and gravida with GDM revealed a significant (P<0.01) association with an increase in odds by 1.6 to 2.4 folds in multigravida and decrease in odds by 2 folds in primigravida. A positive family history of diabetes and the minor allele of this SNP collectively increased the risk of developing GDM by many-fold (1.8 to 2.7 folds). However, after accounting for family history of diabetes and gravidity, analyses showed no significant association with GDM. Our meta-analysis revealed a significant association between SNP rs8050136 of FTO with T2DM, and this variant was substantially associated with an increased risk of GDM in a sample of Bangladeshi multigravida women.

Interaction of common variants of FTO gene and Dietary Inflammatory Index on obesity measures: Tehran Lipid and Glucose Study

BackgroundThis study aimed to examine the interaction of Dietary Inflammatory Index (DII) and fat mass and obesity-associated gene (FTO) single-nucleotide polymorphisms (SNPs) on change in obesity measures.MethodsA total of 4480...

A bidirectional Mendelian randomisation study to evaluate the relationship between body constitution and hearing loss

Hearing loss and hearing disorders represent possible mediating pathways in the associations between noise exposures and non-auditory health outcomes. In this context, we assessed whether the noise-obesity associations should consider hearing functions as possible mediators and applied Mendelian randomisation (MR) to investigate causal relationships between body constitution and hearing impairments. We obtained genetic associations from publicly available summary statistics from genome-wide association studies in European ancestry adult populations (N= from 210,088 to 360,564) for (i) body constitution: body mass index (BMI), waist circumference (WC) and body fat percentage (BFP), and (ii) hearing loss: sensorineural hearing loss, noise-induced hearing loss, and age-related hearing impairment (ARHI). We employed colocalisation analysis to investigate the genetic associations for BMI and ARHI liability within an FTO locus. We conducted bi-directional MR for the ‘forward’ (from body constitution to hearing) and ‘reverse’ directions. We applied the random effects inverse variance-weighted method as the main MR method, with additional sensitivity analyses. Colocalisation analysis suggested that BMI and ARHI shared a causal variant at the FTO gene. We did not find robust evidence for causal associations from body constitution to hearing loss and suggested that some associations may be driven by FTO variants. In the reverse analyses, ARHI was negatively associated with BMI [effect size – 0.22 (95% CI – 0.44 to – 0.01)] and BFP [effect size – 0.23 (95% CI – 0.45 to 0.00)], supporting the notion that ARHI may diminish body constitution. Finally, our data suggest that there is no strong evidence that hearing explains the association between noise exposure and body constitution.

Digital lifestyle treatment improves long-term metabolic control in type 2 diabetes with different effects in pathophysiological and genetic subgroups

To address the unmet need for scalable solutions for lifestyle treatment, we developed a new digital method to promote behavioral change. Here we report that patients with type-2 diabetes in Sweden (n = 331) exposed to the intervention have significantly improved HbA1c during a median follow-up of 1038 days (4 mmol/mol compared with matched controls; P = 0.009). This is paralleled by reduced body weight, ameliorated insulin secretion, increased physical activity, and cognitive eating restraints. Participants with high BMI and insulin resistance have an even larger response, as have non-risk allele carriers for the FTO gene. The findings open a new avenue for scalable lifestyle management with sustained efficacy and highlight a previously unrecognized opportunity for digital precision treatment based on genetics and individual pathophysiology. ClinicalTrials.gov NCT04624321.