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Association of fat-mass and obesity-associated gene FTO rs9939609 polymorphism with the risk of obesity among children and adolescents: a meta-analysis.
Quan, LL, Wang, H, Tian, Y, Mu, X, Zhang, Y, Tao, K
European review for medical and pharmacological sciences. 2015;(4):614-23
Abstract
OBJECTIVE To elucidate the association of fat-mass and obesity-associated gene (FTO) rs9939609 polymorphism with obesity among children and adolescents. METHODS A literature search was conducted in PubMed, MEDLINE, Springer, and Google scholar to identify eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used for four models: co-dominant model (AA vs. TT, AT vs. TT), dominant model (AA + AT vs. TT), recessive model (AA vs. AT + TT), and allelic model (A vs. T). Subgroup analyses stratified by ethnicity (Caucasian, others) and participants (children, children and adolescents) were assessed under allelic model. The heterogeneity and publication bias were examined. RESULTS This meta-analysis included 12 eligible studies consisting 5,000 cases and 9,853 controls. The results revealed that FTO rs9939609 polymorphism was significantly associated with the increased risk of obesity in co-dominant model (AA vs. TT: OR = 1.91, 95% CI: 1.47-2.48, p < 0.01; AT vs. TT: OR = 1.18, 95% CI: 1.02-1.38, p = 0.03), dominant model (AA + AT vs. TT: OR = 1.47, 95% CI: 1.35-1.59, p < 0.01), recessive model (AA vs. AT + TT: OR = 1.79, 95% CI: 1.47-2.17, p < 0.01), and allelic model (A vs. T: OR = 1.39, 95% CI: 1.22-1.58, p < 0.01). Similar results were obtained for the subgroup analyses stratified by ethnicity and participants under allelic model. CONCLUSIONS FTO rs9939609 polymorphism is associated with the increased risk of obesity among children and adolescents, especially the homozygous carriers.
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Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.
Zimmermann, E, Ängquist, LH, Mirza, SS, Zhao, JH, Chasman, DI, Fischer, K, Qi, Q, Smith, AV, Thinggaard, M, Jarczok, MN, et al
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2015;(4):327-340
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Abstract
Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.
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FTO genetic variants and risk of obesity and type 2 diabetes: a meta-analysis of 28,394 Indians.
Vasan, SK, Karpe, F, Gu, HF, Brismar, K, Fall, CH, Ingelsson, E, Fall, T
Obesity (Silver Spring, Md.). 2014;(3):964-70
Abstract
OBJECTIVE To investigate the magnitude of association of FTO variants with obesity, type 2 diabetes (T2DM), and related traits among Asian Indians. METHODS Random-effect meta-analysis was performed on pooled data from eight studies (n = 28,394) for obesity and related traits and six studies (n = 24,987) for assessment of T2DM risk in Indians where FTO variants were reported. RESULTS The minor A-allele of the FTO variant rs9939609 was associated with increased risk of obesity (OR 1.15, 95% CI 1.08-1.21, p = 2.14 × 10(-) (5) ), BMI (β = 0.30 kg/m2, 95% CI 0.21-0.38, p = 4.78 × 10(-) (11) ) and other regional adiposity measurements [waist (β = 0.74 cm, 95% CI 0.49-0.99), HC (β = 0.52, 95% CI 0.26-0.78), and waist-hip ratio (WHR) (β = 0.002, 95% CI 0.001-0.004)] in Indians (p ≤ 0.001). An increased risk for T2DM (OR 1.11; 95% CI 1.04-1.19, p = 0.002) was observed, which attenuated when adjusted for age, gender, and BMI (OR 1.09; 95%CI 1.02-1.16, p = 0.01). CONCLUSIONS Our study provides evidence of association between common FTO variant and obesity risk among Indians with comparable effect sizes as in Caucasians. The attenuation of FTO-T2DM risk on BMI adjustment reinforces that BMI does not fully account for the adiposity effects among Asian Indians who are more centrally obese.
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Association between fat mass- and obesity-associated (FTO) gene polymorphism and polycystic ovary syndrome: a meta-analysis.
Cai, X, Liu, C, Mou, S
PloS one. 2014;(1):e86972
Abstract
AIMS: Many studies have investigated the relationship between FTO gene polymorphism and polycystic ovary syndrome (PCOS) susceptibility but revealed mixed results. In this study, we aimed to perform a meta-analysis to clarify this association. METHODS Published literature from PubMed, Embase and CNKI was retrieved. Meta-analysis was performed to calculate pooled odds ratio (OR) with 95% confidence interval (CI) using the random- or fix- effects model. RESULTS A total of 5 studies (4778 cases and 4272 controls) were included in our meta-analysis. The results suggested that FTO rs9939609 polymorphism (or its proxy) was marginally associated with PCOS risk after adjustment for body mass index (BMI) (OR = 1.26; 95%CI: 1.02-1.55). However, the marginal association was not stable after sensitivity analysis. In the subgroup analysis by ethnicity, the association was significant in East Asians (OR = 1.43, 95%CI = 1.30-1.59) but not in Caucasians (OR = 1.04, 95%CI = 0.85-1.29). CONCLUSIONS Our present meta-analysis indicated that FTO rs9939609 polymorphism (or its proxy) might not be associated with risk of PCOS in overall population. However, in East Asians, there might be a direct association between FTO variant and PCOS risk, which is independent of BMI (adiposity).
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Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.
Holliday, EG, Smith, AV, Cornes, BK, Buitendijk, GH, Jensen, RA, Sim, X, Aspelund, T, Aung, T, Baird, PN, Boerwinkle, E, et al
PloS one. 2013;(1):e53830
Abstract
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
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The FTO gene rs9939609 polymorphism predicts risk of cardiovascular disease: a systematic review and meta-analysis.
Liu, C, Mou, S, Pan, C
PloS one. 2013;(8):e71901
Abstract
OBJECTIVE Genome-wide association studies have shown that variance in the fat mass- and obesity- associated gene (FTO) is associated with risk of obesity in Europeans and Asians. Since obesity is associated with an increased risk of cardiovascular disease (CVD), several studies have investigated the association between variant in the FTO gene and CVD risk, with inconsistent results. In this study, we performed a meta-analysis to clarify the association of rs9939609 variant (or its proxies [r (2)>0.90]) in the FTO gene with CVD risk. METHODS Published literature from PubMed and Embase was retrieved. Pooled odds ratios with 95% confidence intervals were calculated using the fixed- or random- effects model. RESULTS A total of 10 studies (comprising 19,153 CVD cases and 103,720 controls) were included in the meta-analysis. The results indicated that the rs9939609 variant was significantly associated with CVD risk (odds ratio = 1.18, 95% confidence interval = 1.07-1.30, p = 0.001 [Z test], I (2) = 80.6%, p<0.001 [heterogeneity]), and there was an insignificant change after adjustment for body mass index (BMI) and other conventional CVD risk factors (odds ratio = 1.16, 95% confidence interval = 1.05-1.27, p = 0.003 [Z test], I (2) = 75.4%, p<0.001 [heterogeneity]). CONCLUSIONS The present meta-analysis confirmed the significant association of the rs9939609 variant in the FTO gene with CVD risk, which was independent of BMI and other conventional CVD risk factors.
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FTO gene variant and risk of overweight and obesity among children and adolescents: a systematic review and meta-analysis.
Liu, C, Mou, S, Cai, Y
PloS one. 2013;(11):e82133
Abstract
OBJECTIVE The fat mass and obesity associated gene (FTO) polymorphisms have been implicated in the susceptibility of overweight/obesity in children and adolescents. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of FTO gene polymorphisms with overweight/obesity risk among children and adolescents. METHODS PubMed and Embase were used to search for eligible published literatures. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models. RESULTS A total of 21 articles containing 23 studies (11208cases and 35015controls) were included in our analysis. The results indicated that variant in FTO gene was significantly associated with increased risk of overweight/obesity in children and adolescents (OR=1.35; 95%CI: 1.27-1.44; P<0.001). The overall pooled ORs for risk obesity and overweight were 1.34 (95%CI: 1.21-1.48) and 1.35 (95%CI: 1.25-1.47), respectively. Subgroup analyses also showed similar trends in most subgroups of adjustment for covariates and unadjustment, different ethnicities (Caucasians, Asians, and Amerindians), and each of three investigated polymorphisms (rs9939609, rs1421085, and rs1558902). CONCLUSIONS The present meta-analysis suggested a positive association between FTO gene polymorphism and overweight/obesity risk among children and adolescents. Further prospective studies should be recommended to confirm the observed association, and underlying mechanism should be investigated to clarify the association of FTO gene polymorphism with overweight/obesity.
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Genetic variant in fat mass and obesity-associated gene associated with type 2 diabetes risk in Han Chinese.
Qian, Y, Liu, S, Lu, F, Li, H, Dong, M, Lin, Y, Du, J, Lin, Y, Gong, J, Jin, G, et al
BMC genetics. 2013;:86
Abstract
BACKGROUND Genome-wide association study (GWAS) has identified that rs8050136 C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case-control study with 2,925 T2D patients and 3,281 controls in Han Chinese. RESULTS Logistic regression revealed that the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians (OR = 1.13, 95% CI = 1.07-1.19). CONCLUSIONS Our findings indicate that the genetic variant in FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility.
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Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis.
Wojciechowski, P, Lipowska, A, Rys, P, Ewens, KG, Franks, S, Tan, S, Lerchbaum, E, Vcelak, J, Attaoua, R, Straczkowski, M, et al
Diabetologia. 2012;(10):2636-2645
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Abstract
AIMS/HYPOTHESIS FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS. METHODS A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis. RESULTS A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10(-11)) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10(-10)). This translated into an approximately 3.3 kg/m(2) increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations. CONCLUSIONS/INTERPRETATION The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.
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Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.
Fox, CS, Liu, Y, White, CC, Feitosa, M, Smith, AV, Heard-Costa, N, Lohman, K, , , , , , , et al
PLoS genetics. 2012;(5):e1002695
Abstract
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.