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.

OBJECTIVE: The current study aims to investigate the significance of N6-methyladenosine (m6A) methylationrelated genes in the clinical prognosis of childhood relapsed B-cell acute lymphoblastic leukemia (B-ALLL) patient.
METHODS: Transcriptome data and corresponding clinical data on m6A methylation-related genes (including 20 genes) were obtained from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) database.
RESULTS: The bone marrow (BM) samples of 134 newly diagnosed (naive) and 116 relapsed B-ALL from TARGET were enrolled in the current study. Three genes (FTO, HNRNPC, RBM15B) showed significant up-regulation in relapsed B-ALL compared with that in naive B-ALL.The three genes had a significantly worse survival (P < 0.05). The LASSO Cox regression model was used to select the most predictive genes as prognostic indicators, and YTHDC1 and FTO were identified as prognostic factors for relapsed B-ALL. Finally, the results of multivariate regression analysis showed that the risk score of m6A methylation-related genes was an independent prognostic factor in relapsed B-ALL (P < 0.05).
CONCLUSIONS: We found that the expression levels of m6A methylation-related genes were different in naive and relapsed patients with B-ALL and correlated with survival and prognosis.This implies that m6A methylation-related genes may be promising prognostic indicators or therapeutic targets for relapsed B-ALL.

BACKGROUND: N6-methyladenosine (m6A) is one of the most common forms of mRNA modification, which is dynamically regulated by the m6A-related genes; however, its effect in glioblastoma (GBM) is still unknown.
OBJECTIVE: We sought to investigate the association between m6A-related genes (m6A-RGs) and GBM.
METHODS: Transcriptome data and the relevant clinical data were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. The m6A-RGs were identified from differently expressed genes, and COX and lasso regression models were applied to locate the prognosis-related genes.
RESULTS: We identified 15 out of 19 m6A-RGs differentially expressed between GBM and nontumor tissues. We identified two subgroups of GBM (clusters 1 and 2) by applying consensus clustering. Compared with the cluster 1 subgroup, the cluster 1 subgroup correlates with a poorer prognosis, and most of the 19 m6A-RGs are higher expressed in cluster 1. Through univariate Cox and lasso regression model, we identified three m6A-RGs, namely HNRNPC, ALKBH5, and FTO, which were used to construct a Cox regression risk model to predict the prognosis of GBM patients.
CONCLUSIONS: We identified a valuable m6A model for predicting the prognosis of GBM patients, which can provide useful epigenetic biomarkers.

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.

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.

Translation is one of the main gene expression steps targeted by cellular stress, commonly referred to as translational stress, which includes treatment with anticancer drugs. While translational stress blocks the translation initiation of bulk mRNAs, it nonetheless activates the translation of specific mRNAs known as short upstream open reading frames (uORFs)-mRNAs. Among these, the ATF4 mRNA encodes a transcription factor that reprograms gene expression in cells responding to various stresses. Although the stress-induced translation of the ATF4 mRNA relies on the presence of uORFs (upstream to the main ATF4 ORF), the mechanisms mediating this effect, particularly during chemoresistance, remain elusive. Here, we report that ALKBH5 (AlkB Homolog 5) and FTO (FTO: Fat mass and obesity-associated protein), the two RNA demethylating enzymes, promote the translation of ATF4 mRNA in a transformed liver cell line (Hep3B) treated with the chemotherapeutic drug sorafenib. Using the in vitro luciferase reporter translational assay, we found that depletion of both enzymes reduced the translation of the reporter ATF4 mRNA upon drug treatment. Consistently, depletion of either protein abrogates the loading of the ATF3 mRNA into translating ribosomes as assessed by polyribosome assays coupled to RT-qPCR. Collectively, these results indicate that the ALKBH5 and FTO-mediated translation of the ATF4 mRNA is regulated at its initiation step. Using in vitro methylation assays, we found that ALKBH5 is required for the inhibition of the methylation of a reporter ATF4 mRNA at a conserved adenosine (A235) site located at its uORF2, suggesting that ALKBH5-mediated translation of ATF4 mRNA involves demethylation of its A235. Preventing methylation of A235 by introducing an A/G mutation into an ATF4 mRNA reporter renders its translation insensitive to ALKBH5 depletion, supporting the role of ALKBH5 demethylation activity in translation. Finally, targeting either ALKBH5 or FTO sensitizes Hep3B to sorafenib-induced cell death, contributing to their resistance. In summary, our data show that ALKBH5 and FTO are novel factors that promote resistance to sorafenib treatment, in part by mediating the translation of ATF4 mRNA.

FTO alpha-ketoglutarate dependent dioxygenase (FTO) is aberrantly expressed in brain disorders. However, the roles of FTO in neonatal hypoxic-ischemic brain injury (HIE) are still unclear. This study aims to investigate the potential of FTO in neonatal HIE. Oxygen-glucose deprivation (OGD) was used to establish HIE in vitro. mRNA levels were detected by real-time reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Protein expression was detected by Western blot. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), ferrous iron (Fe2+) and glutathione (GSH) was detected by specific kit. m6A sites were analyzed using SRAMP and further verify by methylated RNA immunoprecipitation (MeRIP) assay. Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay. Cell death was determined by propidium iodide (PI) staining. FTO was downregulated in patients with neonatal HIE and OGD-treated neurons. Moreover, FTO mRNA expression was decreased in ferroptosis inducer, especially ferric ammonium citrate (FAC). However, overexpression of FTO inhibited the ferroptosis of neurons. Moreover, FTO-mediated N6-methyladenosine (m6A) modification of ferritin heavy chain 1 (FTH1) suppressed its mRNA expression and stability, inhibiting its protein expression. However, overexpression of FTH1 abrogated the effects of FTO and promoted the ferroptosis of neurons. In summary, FTO functions as a protective role in neonatal HIE via inhibiting FTH1 signaling. Thence, targeting may be a promising strategy for FTO neonatal HIE.

OBJECTIVE: 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).
METHODS: A total of 690 subjects were categorized into control, AF without MetS, and AF with MetS.
RESULTS: 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.
CONCLUSIONS: 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.

Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of patients experience treatment failure due to radioresistance. Therefore, understanding the mechanisms of radioresistance is imperative. HOTAIRM1 is deregulated in various human cancers, yet its role in NPC radioresistance are largely unclear.
This study investigated the association between HOTAIRM1 and radioresistance using CCK8, flow cytometry, and comet assays. Additionally, xenograft mice and patient-derived xenografts (PDX) models were employed to elucidate the biological functions of HOTAIRM1, and transcriptomic RNA sequencing was utilized to identify its target genes.
Our study revealed an upregulation of HOTAIRM1 levels in radioresistant NPC cell lines and tissues. Furthermore, a positive correlation was noted between high HOTAIRM1 expression and increased NPC cell proliferation, reduced apoptosis, G2/M cell cycle arrest, and diminished cellular DNA damage following radiotherapy. HOTAIRM1 modulates the acetylation and stability of the FTO protein, and inhibiting FTO elevates the m6A methylation level of CD44 precursor transcripts in NPC cells. Additionally, silencing the m6A reading protein YTHDC1 was found to increase the expression of CD44V. HOTAIRM1 enhances NPC cell resistance to ferroptosis and irradiation through the HOTAIRM1-FTO-YTHDC1-CD44 axis. Mechanistically, HOTAIRM1 interacts with the FTO protein and induces m6A demethylation of the CD44 transcript. The absence of m6A modification in the CD44 transcript prevents its recognition by YTHDC1, resulting in the transition from CD44S to CD44V. An abundance of CD44V suppresses ferroptosis induced by irradiation and contributes to NPC radioresistance.
In conclusion, the results in this study support the idea that HOTAIRM1 stimulates CD44 alternative splicing via FTO-mediated demethylation, thereby attenuating ferroptosis induced by irradiation and promoting NPC radioresistance.

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.