Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.

BACKGROUND: Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA). METHODS: We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10-16, as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors. RESULTS: Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10-7) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10-5), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects. CONCLUSIONS: We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis.

Role of rs9939506 polymorphism of FTO gene in resistance to eating in male adolescents.

BACKGROUND: Single Nucleotide Polymorphisms (SNPs) of the Fat mass and obesity-associated (FTO) gene may be associated with obesity by regulating appetite. The present study aimed to investigate the relationship between FTO genotype and resistance to eating in male adolescents. METHODS: The present cross-sectional study included 246 adolescent boys in Tehran, Iran, who were assessed for self-efficacy related to weight control using the Weight Efficacy Lifestyle (WEL), questionnaire, food intake using the Food Frequency Questionnaire (FFQ), physical activity using the International Physical Activity Questionnaire (IPAQ), and anthropometric indices using Bio-Impedance Analyzer (BIA). Moreover, the participants underwent genotyping for the rs9930506 polymorphism of the FTO gene, and the relationship between FTO genotype and resistance to eating was investigated using different models of multiple linear regression. RESULTS: According to our findings, there was a significant reverse relationship between the FTO rs9930506 genotype and resistance to eating (ß: -0.16, P = 0.01). Moreover, the relationship was still significant after adjusting for age, nutritional knowledge, BMI, and mother's BMI, educational level, and occupational status. CONCLUSION: According to our results, the FTO genotype had a significant effect on resistance to eating and food desires. However, there is a need for further studies to evaluate the underlying mechanisms of the effects of the FTO gene on appetite and obesity.

FTO Gene Polymorphisms at the Crossroads of Metabolic Pathways of Obesity and Epigenetic Influences.

In this review, we summarize the current state of knowledge on the fat mass and obesity-associated (FTO) gene and its role in obesity. The FTO-encoded protein is involved in multiple molecular pathways contributing to obesity as well as other metabolic complexities. This review emphasizes the epigenetic influence on the FTO gene as a new approach in the treatment and management of obesity. Several known substances have a positive effect on reducing FTO expression. Depending on which variant of the single nucleotide polymorphism (SNP) is present, the profile and level of gene expression changes. Implementation of environmental change measures could lead to reduced phenotypic manifestation of FTO expression. Treating obesity through FTO gene regulation will have to include various complex signal pathways in which FTO takes part. Identification of FTO gene polymorphisms may be useful for the development of individual obesity management strategies, including the recommendation of taking certain foods and supplements.

Associations between FTO rs9939609 polymorphism, serum vitamin D, mental health, and eating behaviors in overweight adults.

Background: Despite the significant role of the Fat Mass and Obesity-Associated (FTO) gene in obesity, the underlying mechanisms are not fully elucidated. Besides, vitamin D deficiency and obesity are mostly seen together, and it can be hypothesized that this nutrient may have an impact in the role of FTO genotype in adiposity.Objective: Thus, this study aimed to investigate the association of FTO rs9939609 gene polymorphism with eating behaviors, eating disorders, and general mental health in overweight adults, considering their vitamin D intake as a mediate confounding factor.Methods: This cross-sectional study was carried out on 197 overweight adults in Shiraz, Iran. Genotyping was performed through amplification refractory mutation system polymerase chain reaction (ARMS PCR). Mental health, vitamin D intake, eating behaviors and disorders were assessed by the validated questionnaires.Results: The risk allele of the FTO rs9939609 polymorphism (A) was significantly associated with a higher risk of eating behavior and mental health disorders (all P < 0.05). After considering vitamin D intake, the AA genotype carriers had significantly higher risks for poorer eating behavior (P = 0.002), mental health (P = 0.007), and general mental health (P = 0.039) compared with the TT carriers if they had insufficient vitamin D intake.Conclusion: In conclusion, these results indicated that the A-allele of the FTO rs9939609 polymorphism may be associated with poorer eating behaviors, mental health, and higher risk of eating disorders. It was also identified that the effect of FTO rs9939609 A risk allele on eating behavior and mental health may be limited to people with insufficient vitamin D intake.

FTO-rs9939609 Polymorphism is a Predictor of Future Type 2 Diabetes: A Population-Based Prospective Study.

The study aimed to evaluate the contribution of the FTO A/T polymorphism (rs9939609) to the prediction of the future type 2 diabetes (T2D). A population-based prospective study included 1443 nondiabetic subjects at baseline, and they were examined for developing T2D after 5-year follow-up. Cox proportional hazards model was used to evaluate the hazard ratio (HR) of rs9939609 to the future T2D in the models adjusted for the confounding factors including socio-economic status, lifestyle factors (smoking and drinking history, sporting habits, and leisure time), and clinical patterns (obese status, blood pressures, and dyslipidemia) at baseline. The area under receiver operating characteristic curve (AUC) was used to measure the power to predict individuals with T2D. The FTO-rs9939609 polymorphism was a significant predictor of future T2D in the model unadjusted, and it remained significant in the final model after adjustment for the confounding factors, showing an additive effect of the A-allele (HR = 1.35, 95% CI = 1.02-1.78, P = 0.036, AUC = 0.676). For normoglycemic subjects at baseline, the similar final adjusted model reported the increased HR per A-allele (HR = 1.50, 95% CI = 1.09-2.07, P = 0.012, AUC = 0.697). Five-year changes in BMI, waist circumference, and systolic blood pressure did not remove the contribution of rs9939609 to increased HR of T2D. The population attributable risk for risk genotype was 13.6%. In conclusion, the study indicates that the FTO-rs9939609 polymorphism is an important genetic predictor for future T2D in Vietnamese population.

Association of FTO variant with parental history of type 2 diabetes mellitus in adults.

OBJECTIVE: To find out the association between fat mass and obesity-associated gene polymorphism and risk factors frequently associated with type 2 diabetes mellitus. METHODS: The case-control study was conducted from January 2020 to March 2021 at the Ziauddin University, Karachi, and comprised deoxyribonucleic acid samples for fat mass and obesity-associated gene polymorphism from non-diabetic Pakistani population. Group A comprised non-diabetics with parental history of type 2 diabetes mellitus and Group B had controls without parental history of type 2 diabetes mellitus. Analysis was based on restriction fragment length polymorphism and polymerase chain reaction. Data was analysed using SPSS 25. RESULTS: Of the 150 subjects, 75(50%) each were in Group A and Group B. There were 40 (53.3%) males and 35 (46.7%) females in Group A compared to 35 (46.7%) males and 40(53.3%) females in Group B. Overall, 48% subjects were single and 52 % were married. A difference in frequency of fat mass and obesity-associated gene (rs9939609) alleles, such as TT, AA TA, was noted between the groups (p>0.999). TA allele was found to be associated with Group A (33) 44% (p=0.40), while TT allele was associated with Group B (41) 54% (p=0.414). AA allele was equally distributed between the groups (6) 8% (p=1.00). CONCLUSIONS: The TT allele of fat mass and obesity-associated gene was found to be an independent allele associated with the risk of developing type 2 diabetes mellitus.

The association between fat mass and obesity-associated (FTO) genotype and serum vitamin D level in breast cancer patients.

The preventive effect of vitamin D against breast cancer can be influenced by gene polymorphisms. This study aimed to investigate the association between serum level of 25(OH) vitamin D and FTO genotype in breast cancer patients. A cross-sectional study was carried out on 180 newly diagnosed patients with breast cancer in Tehran, Iran. The blood samples were collected from the participants in order to assess the FTO gene rs9939609 polymorphism by the tetra-primer amplification refractory mutation system (Tetra-ARMS) PCR method. The serum level of 25(OH) vitamin D was measured using the direct competitive enzyme-linked immunosorbent assay (ELISA) method. The association between vitamin D and the FTO genotype in patients with breast cancer was assessed after adjustment for cofounders. The frequency of TT, AT and AA genotypes in the breast cancer patients were 43% (n = 77), 49% (n = 89) and 8% (n = 14), respectively. All patients with higher than 40 ng/dl of serum 25(OH) vitamin D had one or two copies of FTO rs9939609 risk allele (p = 0.019). No linear association was found between the number of FTO risk allele and the level of serum vitamin D. All patients with high serum level of 25(OH) vitamin D had one or two copies of FTO rs9939609 risk allele. FTO gene polymorphisms may counteract the beneficial effects of vitamin D in breast cancer prevention. Further studies can help to better understand the genetic factors predisposing to breast cancer and their effect on the association between vitamin D and breast cancer.

Association of serum 25-OH-vitamin D level with FTO and IRX3 genes expression in obese and overweight boys with different FTO rs9930506 genotypes.

BACKGROUND: The roles of FTO gene and the level of serum 25-OH-vitamin D in obesity are frequently reported. This study aimed to investigate the interactions of serum 25-OH-vitamin D level, FTO and IRX3 genes expression, and FTO genotype in obese and overweight boys. METHODS: This study was carried out on the 120 male adolescents with overweight in Tehran, Iran. Blood samples were collected from the participants in order to evaluate the serum level of 25-OH-vitamin D, the expression level of FTO and IRX3 genes, and FTO genotype for rs9930506 at baseline and after 18 weeks of the study. RESULTS: In general, no significant association was found between serum 25-OH-vitamin D level and IRX3 and FTO genes expression. The results of linear regression on the relationship between 25-OH-vitamin D serum level and FTO and IRX3 genes expression based on FTO genotypes for rs9930506 indicated that in AA/AG genotype carriers, serum 25-OH-vitamin D level was positively associated with FTO gene expression (B = 0.07, p = 0.02) and inversely associated with IRX3 gene expression (B = - 0.07, p = 0.03). In GG carriers, serum 25-OH-vitamin D level was not associated with expression of IRX3 and FTO genes. CONCLUSION: There are significant interactions between 25-OH-vitamin D and the expression of FTO and IRX3 genes in the subset of obese patients with specific genotypes for FTO rs9930506. There was no association between serum 25-OH-vitamin D levels and the expression of FTO and IRX genes in individuals with a homozygous genotype for the risk allele of the FTO gene polymorphism.

Genetic effects of FTO gene insertion/deletion (InDel) on fat-tail measurements and growth traits in Tong sheep.

Tong sheep is a kind of famous fat-tailed sheep in China, which no longer meets market demands because of the large amount of fat deposition in tail. Fat mass and obesity associated (FTO) gene regulates fatty acid transport and fat metabolism to affect obesity and is also reported to regulate phenotypic traits in healthy animals. To identify the insertion/deletion (InDel) variations of the FTO gene and evaluate their effects on fat-tail measurements and growth traits, 166 healthy individuals from Tong sheep were identified and analyzed. Herein, 10 novel InDel polymorphisms were founded in the Tong sheep FTO gene, which displayed intermediate polymorphism (0.25 < PIC < 0.5) and were in Hardy-Weinberg equilibrium (p > .05). Correlation analysis of 78 Tong sheep phenotypic traits data and InDel polymorphisms showed that eight InDel loci were significantly associated with partial growth traits (p < .05), four InDel loci were significantly correlated with fat-tail measurements (p < .05). In particular, individuals with genotype DD showed better phenotypic traits than individuals with other genotypes at male sheep InDel 5 and InDel 8 loci, which had small tail-fat dimensions while having good growth traits. These results confirmed potential usefulness of FTO gene in marker-assisted selection programs of Tong sheep breeding.

FTO gene-lifestyle interactions on serum adiponectin concentrations and central obesity in a Turkish population.

The aim of the study was to investigate whether lifestyle factors modify the association between fat mass and obesity-associated (FTO) gene single nucleotide polymorphisms (SNPs) and obesity in a Turkish population. The study included 400 unrelated individuals, aged 24-50 years recruited in a hospital setting. Dietary intake and physical activity were assessed using 24-hour dietary recall and self-report questionnaire, respectively. A genetic risk score (GRS) was developed using FTO SNPs, rs9939609 and rs10163409. Body mass index and fat mass index were significantly associated with FTO SNP rs9939609 (p = 0.001 and p = 0.002, respectively) and GRS (p = 0.002 and p = 0.003, respectively). The interactions between SNP rs9939609 and physical activity on adiponectin concentrations, and SNP rs10163409 and dietary protein intake on increased waist circumference were statistically significant (Pinteraction = 0.027 and Pinteraction = 0.044, respectively). Our study has demonstrated that the association between FTO SNPs and central obesity might be modified by lifestyle factors in this Turkish population.

Association and interaction of the FTO rs1421085 with overweight/obesity in a sample of Pakistani individuals.

PURPOSE: Genetic variants determine the predisposition of an individual to obesity in a given environment. The present study was conducted to seek an association of the FTO variant rs1421085 with overweight/obesity and related traits in 612 Pakistani subjects in a case-control manner (overweight/obese = 306 and non-obese = 306). Moreover, interaction effects of the rs1421085 and overweight/obesity on multiple metabolic traits were also investigated, which were never explored before in Pakistani as well as in any other population. MATERIALS AND METHODS: Anthropometric traits were measured by standard procedures, while metabolic parameters were determined by biochemical assays. Genotyping of the rs1421085 was carried out by TaqMan allelic discrimination assay. The data were analysed using SPSS software version 19. RESULTS: The study revealed a significant association of the rs1421085 with overweight/obese phenotype with respect to over-dominant model indicated by h-index. The CT genotype of the rs1421085 was observed to increase the risk of being overweight/obese by 1.583 times (95% CI 1.147-2.185, p = 0.005). The CT genotype was also found to be associated with higher values of all anthropometric variables (except height and waist-to-hip ratio). Moreover, the interaction between the CT genotype of the rs1421085 and overweight/obesity was found to influence several metabolic parameters (raised blood pressure, product of triglyceride and glucose index, triglyceride levels, LDL-C, VLDL-C, coronary risk index, atherogenic index, and triglyceride-to-HDL-C ratio). CONCLUSION: In conclusion, the rs1421085 was found to be associated with overweight/obesity and related anthropometric traits independent of age and gender in Pakistani population. Moreover, this variant was found to influence various metabolic traits in the presence of overweight/obesity. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Dietary Carbohydrate Promotes Cell Survival in Cancer Via the Up-Regulation of Fat Mass and Obesity-Associated Gene Expression Level.

Cancer cells are mainly dependent on glycolysis for their growth and survival. Dietary carbohydrates play a critical role in the growth and proliferation of cancer and a low-carbohydrate diet may help slow down the growth of tumours. However, the exact mechanisms behind this effect are unclear. This review study aimed to investigate the effect of fat mass and obesity-associated (FTO) gene in the association between dietary carbohydrates and cancer. This study was carried out using keywords such as polymorphism and/or cancer and/or dietary carbohydrate and/or FTO gene. PubMed and Science Direct databases were used to collect all related articles published from 1990 to 2018. Recent studies showed that the level of FTO gene expression in cancer cells is dramatically increased and may play a role in the growth of these cells through the regulation of the cellular metabolic pathways, including the phosphoinositide 3-kinases/protein kinaseB (PI3K/AKT) signaling pathway. Dietary carbohydrate may influence the FTO gene expression by eliminating the inhibitory effect of adenosine monophosphate-activated protein kinase (AMPK) on the FTO gene expression. This review summarised what has been recently discovered about the effects of dietary carbohydrate on cancer cells and tried to determine the mediating role of the FTO gene in these effects.

Establishing a genetic link between FTO and VDR gene polymorphisms and obesity in the Emirati population.

BACKGROUND: Obesity is a metabolic disease that is widely prevalent with approximately 600 million people classified as obese worldwide. Its etiology is multifactorial and involves a complex interplay between genes and the environment. Over the past few decades, obesity rates among the Emirati population have been increasing. The aim of this study was to investigate the association of candidate gene single nucleotide polymorphisms (SNPs), namely FTO (rs9939609) and VDR (rs1544410), with obesity in the UAE population. METHODS: This is a case-control study in which genomic DNA was extracted from saliva samples of 201 obese, 115 overweight, and 98 normal subjects in the United Arab Emirates (UAE). Genotyping for the variants was performed using TaqMan assay. RESULTS: The mean Body Mass Index (BMI) ± SD for the obese, overweight, and normal subjects was 35.76 ± 4.54, 27.53 ± 1.45, and 22.69 ± 1.84 kg/m2, respectively. Increasing BMI values were associated with increase in values of HbA1c, systolic and diastolic blood pressure. There was a significant association observed between the FTO SNP rs9939609 and BMI (p = 0.028), with the minor allele A having a clear additive effect on BMI values. There was no significant association detected between BMI and rs1544410 of VDR. Moreover, significant interaction between the FTO rs9939609 and physical activity reduced the "AA" genotype effect on increase in BMI (p = 0.027). CONCLUSIONS: Our study findings indicate that the minor allele A of the rs9939609 has a significant association with increasing BMI values. Moreover, our findings support the fact that increasing BMI is associated with increasing risks of other comorbidities such as higher blood pressure, poorer glycemic control, and higher triglycerides. In addition, physical activity was found to attenuate the effect of the "AA" genotype on the predisposition to higher BMI values.

Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). RESULTS: Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. CONCLUSIONS: To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

Association between FTO gene polymorphisms and HDL cholesterol concentration may cause higher risk of cardiovascular disease in patients with acromegaly.

INTRODUCTION: Cardiovascular diseases are main cause of morbidity and mortality in acromegaly. Polymorphisms of FTO gene are associated with obesity and increased risk of CVD (independently of BMI). Aim of this study was to investigate the allele frequencies of two FTO gene polymorphisms: rs9939609 and rs9930506 in patients with acromegaly and to examine the association of FTO gene polymorphisms with BMI and selected metabolic parameters. MATERIALS AND METHODS: Identification of two single nucleotide polymorphisms of FTO gene was carried out in 51 patients with acromegaly using the minisequencing method. RESULTS: The risk-allele frequencies of rs9939609 and rs9930506 polymorphisms were 0.471 and 0.529, respectively and they were higher than in general European population. There is no association of FTO gene polymorphisms with BMI, glucose, total cholesterol, LDL cholesterol and triglyceride. The risk alleles were associated with decreased HDL cholesterol concentration. Homozygotes for the rs9939609-risk allele had 1.25-fold lower HDL cholesterol concentration than carriers of the TT genotype (p = 0.0024). The estimated average decrease in HDL cholesterol concentration per risk allele for rs9930506 was 11.2%. Nevertheless, statistically significant differences were observed only between AG versus GG and AA versus GG genotypes. Homozygotes for the rs9930506-risk allele had 1.27-fold lower HDL cholesterol concentration than carriers of the AA genotype (p = 0.007). CONCLUSION: The risk-allele frequencies of studied polymorphisms in acromegaly were higher than in general European population. There is an association between FTO gene polymorphisms and HDL cholesterol concentration, suggesting FTO gene polymorphisms may be associated with higher CVD risk in patients with acromegaly.

Effect of FTO rs9930506 on obesity and interaction of the gene variants with dietary protein and vitamin E on C-reactive protein levels in multi-ethnic Malaysian adults.

BACKGROUND: Individual variations of obesity-related traits can be a consequence of dietary influence on gene variants. METHODS: This cross-sectional study aimed to evaluate (i) the effect of FTO rs9930506 on obesity and related parameters and (ii) the influence of diet on the above association in Malaysian adults. In total, 79 obese and 99 nonobese Malaysian adults were recruited. RESULTS: In comparison with Chinese and Malays, Indians had significantly higher waist circumference (P ≤ 0.001 and P = 0.016), waist-hip ratio (P = 0.001 and P < 0.001), body fat percentage (P = 0.001 and P = 0.042), fasting insulin (P = 0.001 and P = 0.001), homeostatic model assessment-insulin resistance (P = 0.001 and P = 0.001) and lower high-density lipoprotein-cholesterol levels (P < 0.001 and P < 0.001), respectively. Indians consumed significantly lower dietary cholesterol (P = 0.002), percentage energy from protein (P < 0.001) and higher fibre (P = 0.006) compared to the other two groups. Malaysian Indians expressed the highest risk allele frequency (G) of FTO rs9930506 compared to the Malays and the Chinese (P < 0.001). No significant association was found between FTO rs9930506 and obesity (dominant model). Risk allele carriers (G) consumed significantly lower vitamin E (P = 0.020) and had a higher fibre intake (P = 0.034) compared to the noncarriers (A). Gene-diet interaction analysis revealed that risk allele carriers (G) had lower high sensitivity C-reactive protein (hsCRP) levels with higher energy from protein (≥14% day-1 ; P = 0.049) and higher vitamin E (≥5.4 mg day-1 ; P = 0.038). CONCLUSIONS: The presence of the risk allele (G) of FTO rs9930506 was not associated with an increased risk of obesity. Malaysian Indians had a significantly higher frequency of the risk allele (G). Indian participants expressed higher atherogenic phenotypes compared to Chinese and Malays. FTO rs9930506 may interact with dietary protein and vitamin E and modulate hsCRP levels.

[Assessment of the sufficiency of Moscow population with folic acid, depending on the combined effect of polymorphism of MTHFR and FTO genes].

The results of assessing the sufficiency of folic acid of the residents of the Moscow region have been presented depending on rs1801133 MTHFR gene polymorphism and rs9939609 FTO gene polymorphism. A total of 326 people were examined, including 74 men and 252 women aged 20 to 65 years. The results of determining the level of folic acid in blood serum showed insufficiency of this vitamin among the population of the Moscow region of the Russian Federation. The expressed vitamin deficit (level <3,0 ng/ml) was detected in 24.2% of the surveyed residents, in 22.8% folic acid level was at the lower bound of the norm (3.0-4.5 ng/ml). The results of genotyping showed a statistically significant association of low folic acid level with rs1801133 MTHFR gene polymorphism in carriers of A allele of rs9939609 FTO gene polymorphism both in the homozygous state (genotype AA) and in the heterozygous (genotype AT) state, OR=4.26; CI (1.40-12.9), p=0.008, as well as with rs9939609 FTO gene polymorphism in carriers of the T allele of rs1801133 MTHFR gene polymorphism both in the homozygous (genotype TT) and heterozygous (CT genotype) state, OR=3.29; CI (1.07-10.1), p=0.03. In carriers of 3 alleles of risk of folic acid deficiency [rs9939609 FTO gene polymorphism and rs1801133 MTHFR gene polymorphism (genotypes CT/AA and TT/AT)] blood serum level of folic acid was below the norm, that indicated folate deficiency in this category of persons.

[The association of rs993609 polymorphisms of gene FTO and rs659366 polymorphisms of gene UCP2 with obesity among Arctic Russian population].

It is known that particular qualities of the prevalence of obesity, characteristic for the population of the Far North, are connected with the presence of genetic polymorphisms. The association of two polymorphisms (rs993609 of FTO gene and rs659366 of UCP2 gene) with obesity was studied in 175 people living on the territory of the Russian Arctic (Yamalo-Nenets Autonomous District). The incidence of obesity risk allele (A) of FTO gene rs9939609 polymorphism in the surveyed population of the Arctic (30.8%) was lower by 15% than that of the population of the central regions of Russia, Caucasian Americans and Europeans, but was higher by 18-20% than in Alaska inhabitants. The frequency of the A allele of the FTO gene was significantly 1.4-fold lower in indigenous Arctic people than in the alien population (p<0.05), that had significantly higher content of body fat (by 12%) than the indigenous population, including the Nenets (p<0.05). Рositive association had been identified between T allele rs659366 polymorphism of UCP2 gene and obesity risk in the surveyed who lived in the Arctic zone. Thus, the inhabitants of the Far North revealed the presence of genetic variants that contribute to heat production.

FTO gene variant modulates the neural correlates of visual food perception.

Variations in the fat mass and obesity associated (FTO) gene are currently the strongest known genetic factor predisposing humans to non-monogenic obesity. Recent experiments have linked these variants to a broad spectrum of behavioural alterations, including food choice and substance abuse. Yet, the underlying neurobiological mechanisms by which these genetic variations influence body weight remain elusive. Here, we explore the brain structural substrate of the obesity-predisposing rs9939609 T/A variant of the FTO gene in non-obese subjects by means of multivariate classification and use fMRI to investigate genotype-specific differences in neural food-cue reactivity by analysing correlates of a visual food perception task. Our findings demonstrate that MRI-derived measures of morphology along middle and posterior fusiform gyrus (FFG) are highly predictive for FTO at-risk allele carriers, who also show enhanced neural responses elicited by food cues in the same posterior FFG area. In brief, these findings provide first-time evidence for FTO-specific differences in both brain structure and function already in non-obese individuals, thereby contributing to a mechanistic understanding of why FTO is a predisposing factor for obesity.

Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH.