Fat Mass And Obesity-associated Variants Research Articles

Examining the association between the FTO gene and neuroticism reveals indirect effects on subjective well-being and problematic alcohol use

Associations between the fat mass and obesity-associated (FTO) gene and obesity are well-established. However, recent studies have linked FTO to addiction phenotypes and dopaminergic signaling, thus suggesting broader psychiatric implications. We explored this assumption by conducting a phenome-wide association study across 4756 genome-wide association studies, identifying 23–26 psychiatric traits associated with FTO at the multiple-corrected significance level. These traits clustered into four categories: substance use, chronotype/sleep, well-being, and neuroticism. To validate these findings, we analyzed a functionally suggestive FTO variant (rs1421085) in a separate cohort, examining its impact on (i) alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), (ii) subjective well-being based on the WHO (Ten) Well-Being Index, and (iii) neuroticism based on Schafer’s Five Factor Model or the Karolinska Scales of Personality. Our results confirmed a direct association between rs1421085 and neuroticism that was independent of age, sex, alcohol use, body mass index (BMI), and childhood adversities. Interestingly, while no direct association with alcohol intake was observed, both cross-sectional and lagged longitudinal mediation analyses uncovered indirect relationships between rs1421085 and problematic alcohol use (AUDIT-P), with increased neuroticism acting as the intermediary. Mediation analyses also supported an indirect effect of rs1421085 on lower well-being through the pathways of increased neuroticism and BMI. Our study is the first to validate a direct association between FTO and neuroticism. However, additional studies are warranted to affirm the causal pathways linking FTO to well-being and alcohol use through neuroticism.

Role of FTO (Fat Mass and Obesity-Associated) and IRX3 (Iroquois Homeobox 3) gene variants on obesity in Quetta

Obesity has become globally prevalent. The novel studies about long-range interaction between promoter-enhancer sequences of FTO and IRX3 genes SNPs, affects the conversion of adipocytes maturation and hence obesity. This can be implemented in pharmaceutical field. The study was established to investigate the association of FTO and IRX3 SNP and its impact on Quetta subjects. Blood Samples taken from 250 individuals (150 obese and 100 non-obese) after informed consent along with demographic information. Organic method of DNA extraction and ARMS-PCR for genotyping was performed. Data analysis was done by liner regression at 95%confidence interval. Both genes’ SNPs were strongly associated with obesity. The AA genotype of FTO SNP rs8050136 showed 3.48-fold (95% CI: 1.45–8.37, P = 0.013) increased risk and allele A 1.76-fold (95%CI: 1.21–2.57, P = 0.004) comparing with allele C. Similarly, compared with TT or GT genotype the GG genotype of IRX3 SNP rs3751723 displayed 3.22-fold (95%CI: 1.40–7.39, P = 0.018) increased onset of obesity, with the frequency of G allele 1.67-fold (95%CI: 1.15–2.41, P = 0.007). Gender and Social statuses were not significantly associated, the different genotypes affect both male and female; AA = 1.21(95%CI: 0.57–2.55, P = 0.41) and AC = 1.14(95%CI: 0.65–1.98, P = 0.65) respectively. Moreover, only Baloch ethnic group in GG genotype of IRX3 variant display 3.16-times (95%CI: 0.86–11.5, P = 0.08) increase obesity risk. Our study suggested that studied polymorphism of both genes are strongly associated with obesity in Quetta population. Moreover, lack of knowledge about obesity genetics is one of the major hurdles in its management at individual level in Pakistan.

Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Māori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

The role of FTO variant rs1421085 in the relationship with obesity: a systematic review and meta-analysis.

Fat mass and obesity-associated (FTO) is considered the first locus associated with adiposity, a concerning health problem worldwide. Many studies have evaluated the relationship between the FTO variants and obesity susceptibility. While the strong association of FTO rs1421085 with the risk of obesity across populations was reported in different studies, some researchers found a lack of association of this variant with adiposity. This systematic review and meta-analysis aimed to assess the association between obesity and rs1421085 polymorphism. We systematically searched PubMed, Scopus, and Google Scholar up to June 2022 to find pertinent studies. To further assess this issue, we surveyed the probable association of rs1421085 with obesity development among Iranian adults using the logistic regression analysis, and the obtained results were used for doing meta-analysis. After selection, nine eligible studies were included in the meta-analysis through the random- and fixed-effect models to determine the combined odds ratios (OR) and 95% confidence intervals (CI). According to our meta-analysis conducted on 5169 obese and 7772 non-obese individuals using different genetic models, including recessive, dominant, over-dominant, and additive, rs1421085 could positively increase the risk of obesity under all tested genetic models. Also, we detected a high to moderate level of heterogeneity among different studies under various genetic models. This meta-analysis further verified the positive association of FTO rs1421085 with the risk of developing obesity. This study is registered as PROSPERO CRD42021220092. Level I, systematic reviews and meta-analyses.

Differential Effect of Fat Intake on Blood Pressure in Healthy Japanese Women with and without the Variant of Fat Mass and Obesity-Associated Gene.

A high-fat diet is believed to be a risk factor for hypertension through inducing obesity. It has been reported that variants of the fat mass and obesity-associated (FTO) and beta-3 adrenergic receptor (B3AR) genes are associated with obesity and blood pressure. The purpose of this study was to investigate the effect of dietary fat on blood pressure with or without the variant of the FTO and B3AR genes. A total of 227 healthy Japanese women aged 18 to 64 years were recruited for measurement of nutrient intake and blood pressure. The single nucleotide polymorphism rs9939609 of the FTO gene and rs4994 of the B3AR gene were genotyped. Spearman's rank correlation coefficient was applied to investigate the relationship between fat intake and blood pressure. A hierarchical multiple regression analysis was performed to determine whether the genotype interacts with fat intake to affect blood pressure. No significant correlations were found between fat intake and either systolic or diastolic blood pressure. A significant negative correlation was found between fat intake and both blood pressures in the FTO-gene-variant group, but not in the normal-FTO-gene group. In hierarchical multiple regression analysis, the interaction of fat intake and the gene variant showed significance, and the change in coefficient of determination (R 2) was significantly increased with increases of the interaction variable. These results indicate that the effect of fat intake on blood pressure may be modified by the variant of the FTO gene such that a high-fat diet intake may be associated with a decrease of systolic and diastolic blood pressure in healthy Japanese women with the FTO variant. Our results did not support the hypothesis that a high-fat diet increases blood pressure.

The association of Fat Mass and Obesity-Associated (FTO) gene polymorphism (rs9939609) with metabolic disturbances and response to sofosbuvir, ribavirin and interferon triple therapy in patients with viral hepatitis C

ObjectivesChronic hepatitis C virus (HCV) infection is a major health problem in Egypt. The Fat mass and obesity associated (FTO) gene has metabolic regulatory roles. HCV affects the signaling cascade of insulin. This study aimed to assess the relation of FTO rs9939609 polymorphisms with treatment outcomes and metabolic disturbance in HCV Egyptian patients. Subjects and methodsThe study included 200 HCV genotype 4 patients treated with triple therapy (sofosbuvir, ribavirin and interferon) for 12 weeks. The principal efficiency endpoint was sustained viral response at 12 weeks (HCV RNA < 12 IU/mL) and FTO rs9939609 gene was analyzed by real-time PCR. Fasting serum insulin and alpha-feto protein (AFP) and were measured by ELISA. ResultsPatients response to HCV triple therapy was 93%. Stepwise logistic regression showed that the chance of non-response increases by 7.9% with every unit increase of the AFP value (OR = 1.079, 95% CI = 1.036; 1.124, P < 0.001). There was no correlation between the FTO variant and treatment outcome. There was a significant increase in HOMA-IR in non-responders compared with responder patients. ConclusionFTO rs9939609 variant is not associated with treatment outcome of HCV patients on triple therapy. However, insulin resistance and AFP levels were associated with achievement of successful virological response.

Effects of FTO and PPARγ variants on intrauterine growth restriction in a Brazilian birth cohort.

Intrauterine growth restriction (IUGR) is related to a higher risk of neonatal mortality, minor cognitive deficit, metabolic syndrome, and cardiovascular disease in adulthood. In previous studies, genetic variants in the FTO (fat mass and obesity-associated) and PPARγ (peroxisome proliferator-activated receptor-gamma) genes have been associated with metabolic disease, body mass index, and obesity among other outcomes. We studied the association of selected FTO (rs1421085, rs55682395, rs17817449, rs8043757, rs9926289, and rs9939609) and PPARγ (rs10865710, rs17036263, rs35206526, rs1801282, rs28763894, rs41516544, rs62243567, rs3856806, and rs1805151) single-nucleotide polymorphisms (SNPs) with IUGR, through a case-control study in a cohort of live births that occurred from June 1978 to May 1979 in a Brazilian city. We selected 280 IUGR cases and 256 controls for analysis. Logistic regression was used to jointly analyze the SNPs as well as factors such as maternal smoking, age, and schooling. We found that the PPARγ rs41516544 increased the risk of IUGR for male offspring (OR 27.83, 95%CI 3.65-212.32) as well as for female offspring (OR=8.94, 95%CI: 1.96-40.88). The FTO rs9939609 TA genotype resulted in a reduced susceptibility to IUGR for male offspring only (OR=0.47, 95%CI: 0.26-0.86). In conclusion, we demonstrated that PPARγ SNP had a positive effect and FTO SNP had a negative effect on IUGR occurrence, and these effects were gender-specific.

Association among Body Mass Index, Genetic Variants of FTO, and Thyroid Cancer Risk: A Hospital-Based Case-Control Study of the Cancer Screenee Cohort in Korea.

PurposeObesity has been determined to be associated with fat mass and obesity-associated (FTO) gene and thyroid cancer risk. However, the effect of combined interactions between obesity and the FTO gene on thyroid cancer needs further investigation. This study aimed to examine whether interactions between body mass index (BMI) and the FTO gene are associated with an increased risk of thyroid cancer.Materials and MethodsA total of 705 thyroid cancer cases and 705 sex- and age-matched normal controls were selected from the Cancer Screenee Cohort in National Cancer Center, Korea. A conditional logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the measure of associations and the combined effect of BMI and FTO gene on thyroid cancer.ResultsBMI was associated with an increased risk of thyroid cancer in subclasses of overweight (23–24.9 kg/m2; adjusted OR, 1.50; 95% CI, 1.12 to 2.00) and obese (≥ 25 kg/m2) (adjusted OR, 1.62; 95% CI, 1.23 to 2.14). There were positive associations between the FTO genetic variants rs8047395 and rs8044769 and an increased risk of thyroid cancer. Additionally, the combination of BMI subclasses and FTO gene variants was significantly associated with thyroid cancer risk in the codominant (rs17817288), dominant (rs9937053, rs12149832, rs1861867, and rs7195539), and recessive (rs17817288 and rs8044769) models.ConclusionFindings from this study identified the effects of BMI on thyroid cancer risk among individuals carrying rs17817288, rs9937053, rs12149832, rs1861867, rs7195539, and rs8044769, whereas the effects of BMI may be modified according to individual characteristics of other FTO variants.

FTO variants are associated with ANGPTL4 abundances and correlated with body weight reduction after bariatric surgery

BackgroundThe FTO (fat mass- and obesity-associated) gene variant is an established obesity-susceptibility locus. FTO protein is a nucleic acid demethylase and FTO genetic variants form long-range functional connections with IRX3, which regulates fat mass and metabolism in humans. From our previous results, we found FTO regulates the metabolism of triglyceride in adipocytes through demethylating Angptl4 (angiopoietin-like protein 4) mRNA in mice. We hypothesized that the FTO genetic variants regulate ANGPTL4 abundances in human adipose tissues and affect the outcome after bariatric surgery. Methods and resultsWe recruited 188 obesity subjects with body mass indices (BMI)>35kg/m2 and 102 non-obese subjects with BMI<30kg/m2 from the OCEAN registry between 2011 and 2014. The distribution of FTO variants rs9939609 among participates was 73.79% TT, 23.79% AT, and 2.41% AA. The subjects with FTO variants AA or AT were correlated with higher BMI than those with FTO variants TT. The serum ANGPTL4 levels were significantly higher in obese subjects and positively correlated with the presence of FTO AA or AT haplotype. Of these participates, 84 obese subjects underwent bariatric surgery and adipose Angptl4 expressions were analyzed. The adipose Angptl4 mRNA levels and protein abundances were correlated with FTO AA or AT haplotype. The magnitude of excess body weight reduction 2 years after bariatric surgery was correlated with the adipose ANGPTL4 protein levels. ConclusionAdipose ANGPTL4 abundances were affected by the presence of FTO obesity risk haplotype and correlated with excess weight loss percentage after bariatric surgery. These data signify the critical role of FTO variants and adipose ANGPTL4 in fatty acid metabolism and bariatric outcomes in humans.

FTO Variant rs1421085 Associates With Increased Body Weight, Soft Lean Mass, and Total Body Water Through Interaction With Ghrelin and Apolipoproteins in Arab Population.

Association studies have implicated single nucleotide polymorphisms (SNPs), particularly rs1421085, from the fat mass and obesity-associated (FTO) gene with body composition phenotypes, obesity, dietary intake, and physical activity in European, East Asian, and African populations. However, the impact of the rs1421085 variant has not been sufficiently tested in ethnic populations (such as Arabs) with high levels of obesity. Further, there is a lack of studies identifying biomarkers that interact with FTO. Therefore, we investigated the association of rs1421085 with obesity and body composition traits and metabolic biomarkers in Arab population. We genotyped rs1421085 SNP in 278 Arab individuals, where multiple biomarkers relating to obesity, inflammation, and other metabolic pathways were quantified. We performed genetic association tests under additive mode of inheritance using linear regression models and found association of rs1421085_C allele with higher levels of body weight, soft lean mass (SLM), and total body water. Examination (using linear regression models under dominant mode of inheritance) of correlation among biomarkers and interaction with genotypes at the variant revealed that measures of these three body composition traits were found mediated by interaction between carrier genotypes (TC+CC) and measures of ghrelin, ApoA1, and ApoB48. Lean body mass (LBM), to which SLM contributes, is an important determinant of physical strength and is a focal point in studies on sarcopenia. Low LBM is known to be associated with higher risk of cardiometabolic disorders. Thus, the finding on the FTO variant as a genetic determinant of SLM via interaction with ghrelin, ApoA1, and ApoB48 is important.

Genetic variants in the fat mass and obesity-associated (FTO) gene confer risk for extreme obesity and modulate adiposity in a Brazilian population.

Obesity is a major public health problem worldwide. It has a complex etiology, influenced by environmental and genetic factors. FTO has been recognized as an important genetic factor for obesity development. This study evaluated the contribution of FTO polymorphisms (rs9939609 and rs17817449) for extreme obesity in terms of the period of obesity onset, anthropometric, and biochemical parameters. The haplotype and the combined effects of FTO risk alleles on obesity susceptibility were evaluated. We investigated 169 normal-weight subjects (body mass index, BMI: 22.8 [21.0; 24.0] kg/m2) and 123 extremely obese individuals (BMI: 47.6 [44.1; 53.1] kg/m2). Genotyping was performed by real time PCR. Our results showed a strong association between FTO variants and extreme obesity. Carriers of the AT haplotype had an increased risk for extreme obesity. Gene scores suggested that the risk of developing extreme obesity was increased 1.37-fold per risk allele added. Both polymorphisms also influenced BMI and body weight. Additionally, rs17817449 influenced triglyceride levels. No effect of FTO variants on the period of obesity onset was found. In conclusion, the FTO polymorphisms showed a strong association with development of extreme phenotype of obesity and adiposity modulation in a Brazilian population.

PHYSICAL ACTIVITY ATTENUATES THE EFFECT OF THE FTO T/A POLYMORPHISM ON OBESITY-RELATED PHENOTYPES IN ADULT RUSSIAN MALES

Introduction. Although the effect of the fat mass and obesity-associated (FTO) gene on adiposity is well established, there is a lack of evidence whether physical activity (PA) modifies the effect of FTO variants on obesity in Russians. Therefore, the purpose of this study was to examine PA influences and interactive effects between FTO variants and PA on measures of adiposity in Russians. Materials and methods. 110 Russian males aged 22–52 years old were examined. Anthropometry: height and weight, waist and hip circumferences were taken. The whole-body impedance was measured on the right-hand side of the body using the bio­impedance meter ABC-01 ‘Medas’ (SRC Medas, Russia) according to a conventional tetrapolar scheme at a frequency of 50 kHz. For each subject participating in the study, the genotype was determined by the polymorphic systems of the T/A (rs9939609) polymorphism of the FTO gene (Lytekh, Moscow). Results. Participants who did not engage in regular PA exhibited higher BMI, fat mass, HC, and WC with statistical significance (P ≤ 0.01). Although significant asso­ciations between the three FTO genotypes and adiposity measures were found in the sedentary group. There were no significant associations between FTO genotypes and obesity-related phenotypes in the PA group. Conclusion. Comparison of morphological parameters in carriers of alternative genotypes in two subgroups with different lifestyles makes it possible to conclude that the A allele determines a greater tendency to accumulate fat in cases where there is no regular physical activity.

FRIED FOOD AND POSSIBLE HEALTH HAZARDS

FRIED FOOD AND POSSIBLE HEALTH HAZARDS

Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population.

IntroductionSeveral studies indicate that polygenic obesity is linked to fat‐mass and obesity‐associated (FTO) genetic variants. Nevertheless, the link between variants in FTO and mental disorders has been barely explored. The present work aims to determine whether FTO genetic variants are associated with bipolar disorder and obesity, and to perform an in silico prediction of variant‐dependent functional impact on the developing brain transcriptome.MethodsFour hundred and forty‐six Mexican mestizos were included in a genetic association analysis. SNP‐sequence kernel association test and linear mixed models were implemented for genetic association assessment. For functional impact prediction, we analyzed the mapping of regulatory elements, the modification of binding sites of transcription factors and the expression of transcription factors in the brain developing transcriptome, searching on different databases.ResultsIn the set‐based analysis, we found different associated regions to BD (bipolar disorder) and obesity. The promoter flanking region of FTO intron 1 was associated with differential effects on BMI, while intron 2 of RPGRIP1L and FTO upstream regions were associated with BD. The prediction analysis showed that FTO BD‐associated variants disturb binding sites of SP1 and SP2; obesity‐associated variants, on the other hand, disturb binding sites of FOXP1, which are transcription factors highly expressed during prenatal development stages of the brain.ConclusionOur results suggest a possible effect of FTO variants on neurodevelopment in obesity and bipolar disorder, which gives new insights into the molecular mechanism underlying this association.

Fat mass and obesity-associated (FTO) and leptin receptor (LEPR) gene polymorphisms in Egyptian obese subjects

Background Several studies addressed the contribution of fat mass and obesity-associated (FTO) and leptin receptor (LEPR) polymorphisms for the susceptibility to obesity among different ethnic subjects. The main purpose of this work is to evaluate the association of these polymorph\\isms with obesity among Egyptian subjects. Subjects and methods This case-control study was carried out on 110 unrelated obese Egyptian subjects who were compared with 122 controls. Their genomic DNA was genotyped using the PCR technique. Results The allelic frequencies of FTO rs9939609 (A) and LEPR rs1137101 (223R) were significantly higher in obese subjects compared with non-obese controls (p < .001). Comparing different phenotype frequencies including clinical, anthropometric, and biochemical parameters in obese subjects revealed no significant difference in relation to their genotype frequencies (p> .05). Conclusions This study designates a strong association for FTO and LEPR variants with the risk of obesity among Egyptian subjects.

FTO variant is not associated with osteoarthritis in the Chinese Han population: replication study for a genome-wide association study identified risk loci

BackgroundOsteoarthritis is the most prevalent form of arthritis worldwide and is the major cause of pain and loss of function in elderly people. A signal of the fat mass and obesity-associated (FTO) gene had been reported in a genome-wide association study of osteoarthritis. The FTO polymorphism (rs8044769) might exert its effect on osteoarthritis through obesity, because it was reported as a body mass index-associated single-nucleotide polymorphism. And replication studies showed inconsistent results for this association. Our present study is to check the association of rs8044769 with osteoarthritis and body mass index in Chinese Han population.MethodsA case-control association study was conducted by using 890 osteoarthritis cases and 844 controls in Chinese Han population. rs8044769 was genotyped in all subjects. Allelic and genotypic frequencies were compared between osteoarthritis cases and control subjects. Associations between rs8044769 and body mass index, and body mass index and osteoarthritis were also assessed.ResultsNo significant difference was detected in genotype or allele distribution between osteoarthritis cases and controls (P > 0.05). Stratification by gender and body mass index revealed negative association between rs8044769 and osteoarthritis. We did not find any solid association between rs8044769 and higher body mass index. Meanwhile, we demonstrated that higher body mass index (body mass index ≥ 25) was associated with osteoarthritis.ConclusionOur present study suggested that rs8044769 was not associated with osteoarthritis susceptibility or higher body mass index, and higher body mass index was a risk factor for osteoarthritis in the Chinese Han population. We also proposed that stratification by clinical parameters was crucial to reduce false-positive result in OA association studies.

The role of FTO variants in the susceptibility of polycystic ovary syndrome and in vitro fertilization outcomes in Chinese women

We investigated the association between single nucleotide polymorphisms (SNPs) in the fat mass and obesity associated (FTO) gene (rs9926289 A/G, rs79206939 A/G, rs9930506 A/G, rs8050136 A/C, and rs1588413 C/T) and polycystic ovary syndrome (PCOS), as well as outcomes of in vitro fertilization (IVF). A case-control study consisting of 147 PCOS patients and 120 healthy controls was conducted. FTO SNPs were genotyped by PCR to determine allelic frequencies, and IVF outcomes were analyzed. The results showed that FTO rs8050136 (p = .025) and rs1588413 (p = .042) were significantly associated with PCOS susceptibility, and women with risk alleles were often found to be obese (p < .05). For SNP rs8050136, women with AA + AC genotypes had higher body mass indexes (BMIs), oral glucose tolerance test/2 h (OGTT) levels and implantation rates but lower follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) day progesterone levels and ovulation numbers (all p < .05) than those with the CC genotype. For SNP rs1588413, women carrying risk alleles exhibited higher BMIs, implantation rate, and levels of luteinizing hormone (LH), estradiol, and OGTT/2 h (all p < .05) compared with those with non-risk genotypes. Therefore, these findings suggest that rs8050136 and rs1588413 are associated with PCOS susceptibility, and that women with risk alleles have less ovulation numbers but higher implantation rates than those with other genotypes.

FTO genotype impacts food intake and corticolimbic activation

Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with "high-risk" FTO genotypes exhibit preference for high-fat foods, reduced satiety responsiveness, and greater food intake consistent with impaired satiety. We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype. We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal. Higher-risk participants reported less subjective fullness (χ2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ2 = 3.92, P < 0.05), and consumed ∼350 more kilocalories than lower-risk participants (β = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by "fattening" food images (compared with objects) in the medial orbital frontal cortex (β = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (β = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (β = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (β = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01). The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.

Association of FTO rs9939609 with Obesity in the Kuwaiti Population: A Public Health Concern?

Objective: To investigate the effect of the common fat mass and obesity-associated (FTO) gene polymorphism rs9939609 on body mass index (BMI) in one of the most obese populations worldwide. Subjects and Methods: Genotypic data for FTO rs9939609 were available for 1,034 unrelated Kuwaiti adults obtained from Kuwait’s Dasman Diabetes Institute and Kuwait University. The association between the FTO polymorphism with BMI as continuous and categorical (normal BMI [< 25] vs. overweight/obese [> 25]) variables was analyzed using both linear and logistic regression models, respectively, with the assumption of both dominant and additive genetic models performed using the SNPassoc package from R statistics. Results: The A allele was associated with increased BMI (β = 1.21; 95% CI = 0.16–2.26; p = 0.023). In concordance, the categorical BMI (normal vs. overweight/obese) also showed a significant association between the A allele and overweight/obesity (OR = 1.47; 95% CI = 1.01–2.12; p = 0.041). However, no association between the FTO variant was observed with cardiometabolic traits. Conclusion: We observed an association between the common FTO rs9939609 polymorphism and increased BMI (overweight/obesity) in Kuwaiti adults, which is consistent with previous research in other populations. Our findings encourage further investigation of genetic variants to elucidate the mechanisms involved in the development of obesity in such an obesogenic population.

Is FTO gene variant related to cancer risk independently of adiposity? An updated meta-analysis of 129,467 cases and 290,633 controls.

Previous studies have examined the association between the fat mass and obesity-associated (FTO) gene variant and risk of cancer in diverse populations. However, the results have been inconsistent. PubMed and Embase databases were searched for the eligible publications in English language by July, 2016. The associations of FTO variants with cancer risk were estimated by calculating the pooled odds ratios and 95% confidence intervals by meta-analyses. A total of 27 publications (129,467 cancer cases and 290,633 normal controls) were included in our meta-analysis. Overall, FTO rs9939609 variant (or its proxy) was not associated with cancer risk without adjustment for body mass index, as well as additional adjustment for body mss index. However, FTO rs9939609 variant was associated with some types of cancer in the subgroup analysis. In addition, overall, there was no significant association between FTO rs1477196 variant and cancer risk regardless of adjustment for body mass index. However, FTO rs11075995 variant risk allele was associated with breast cancer risk without adjustment for body mass index, but the association disappeared with further adjustment for body mass index. This study overall does not support that the FTO variant is associated with cancer risk independently of the adiposity.