Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes

Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P = 0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.     

Association of the FTO gene with BMI

Variants in the FTO gene have been strongly associated with obesity in a very large sample (38,759) of diabetic and control subjects. To replicate these findings, the previously reported SNP in the FTO gene (rs9939609, T/A) was genotyped in 5,607 subjects from five different Utah studies. The studies included a random sample of the Utah population, families selected for aggregation of extreme thinness, families selected for severe obesity, a series of unrelated severe obesity subjects, and families participating in a 25-year longitudinal study of cardiovascular disease and aging. Results show a strong significant increase in the rs9939609 A allele frequency with increasing BMI (P < 0.0001). In the longitudinal study, FTO genotypes were significantly associated with BMI at a baseline exam, a 2(1/2)-year follow-up exam and a 25-year follow-up exam using an additive genetic model. The mean genotype difference in BMI ranged from 1.3 to 2.1 kg/m(2) across exams. The genotype difference in BMI means was established in youth, and at-risk subjects under age 20 at baseline had a significantly larger 25-year BMI increase (10.0 for A/A; 9.7 for A/T, and 8.5 kg/m(2) for T/T, P = 0.05). We conclude that the BMI increases associated with FTO genotypes begin in youth and are maintained throughout adulthood.     

Longitudinal replication studies of GWAS risk SNPs influencing body mass index over the course of childhood and adulthood

Genome-wide association studies (GWAS) have identified multiple common variants associated with body mass index (BMI). In this study, we tested 23 genotyped GWAS-significant SNPs (p-value<5*10-8) for longitudinal associations with BMI during childhood (3-17 years) and adulthood (18-45 years) for 658 subjects. We also proposed a heuristic forward search for the best joint effect model to explain the longitudinal BMI variation. After using false discovery rate (FDR) to adjust for multiple tests, childhood and adulthood BMI were found to be significantly associated with six SNPs each (q-value<0.05), with one SNP associated with both BMI measurements: KCTD15 rs29941 (q-value<7.6*10-4). These 12 SNPs are located at or near genes either expressed in the brain (BDNF, KCTD15, TMEM18, MTCH2, and FTO) or implicated in cell apoptosis and proliferation (FAIM2, MAP2K5, and TFAP2B). The longitudinal effects of FAIM2 rs7138803 on childhood BMI and MAP2K5 rs2241423 on adulthood BMI decreased as age increased (q-value<0.05). The FTO candidate SNPs, rs6499640 at the 5 '-end and rs1121980 and rs8050136 downstream, were associated with childhood and adulthood BMI, respectively, and the risk effects of rs6499640 and rs1121980 increased as birth weight decreased. The best joint effect model for childhood and adulthood BMI contained 14 and 15 SNPs each, with 11 in common, and the percentage of explained variance increased from 0.17% and 9.0*10(-6)% to 2.22% and 2.71%, respectively. In summary, this study evidenced the presence of long-term major effects of genes on obesity development, implicated in pathways related to neural development and cell metabolism, and different sets of genes associated with childhood and adulthood BMI, respectively. The gene effects can vary with age and be modified by prenatal development. The best joint effect model indicated that multiple variants with effects that are weak or absent alone can nevertheless jointly exert a large longitudinal effect on BMI.     

Influences of FTO gene on onset age of adult overweight

FTO affects changes in BMI during both childhood and adulthood. However, its effect on onset age of overweight in adulthood is not known. To address this question, we conducted a study to examine effects of FTO tag SNPs on censored age of overweight in the longitudinal Bogalusa Heart Study (BHS) cohort, which began in 1973–1974. Of participating subjects, 658 whites (308 males and 350 females) with genotype data were selected for the study. The FTO gene was examined by a survival analysis of 30 tag SNPs regarding their association with left, interval and right-censored adult overweight. After adjustment for birth weight and sex, SNP rs9939609 has a small nominal p value of 0.004 for the association with onset age, which has an expected proportion of false positives of 9.6?% after adjusting for multiple tests. It was estimated that genotypes AA, AT and TT have onset age (standard error) of 22.82 (1.07), 28.96 (1.04) and 27.76 (1.04)?years, respectively, for a 50?% cumulative proportion of overweight in the population. Genotypes AA, AT and TT, respectively, have estimated survival probability of 65.8, 78.7 and 76.8?% at the age of 18; and survival probability of 6.5, 11.8 and 10.7?% at the age of 60. The odds ratios of survival beyond age ≥18?years are 0.52 for AA versus AT and 0.58 for AA versus TT. We thus concluded that risk genetic variants at FTO gene can accelerate the onset age and influence the survival odds of overweight in younger adults.     

Genetic variants in <Emphasis Type="Italic">FTO</Emphasis> associated with metabolic syndrome: a meta- and gene-based analysis

The objective of this study was to examine the effect of genetic variants in fat mass and obesity associated (FTO) gene on metabolic syndrome (MetS). A systematic literature search was performed and random-effects meta-analysis was used to evaluate genetic variants in FTO with MetS. A gene-based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in FTO. A total of 18 studies from 13 published papers were included in our analysis. Random-effects meta-analysis yielded an estimated odds ratio of 1.19 (95% CI 1.12–1.27; P = 1.38 × 10⁻⁷) for rs9939609, 1.19 (95% CI 1.05–1.35; P = 0.008) for rs8050136, and 1.89 (95% CI 1.20–2.96; P = 0.006) for rs1421085. The gene-based analysis indicated that FTO is strongly associated with MetS (P < 10⁻⁵). This association remains after excluding rs9939609, a SNP that was frequently reported to have strong association with obesity and MetS. In this study, we concluded that the FTO gene may play a critical role in leading to MetS. Targeting this gene may provide novel therapeutic strategies for the prevention and treatment of metabolic syndrome.     

Association of the FTO rs9939609 polymorphism with obesity in Roma/Gypsy population

The rs9939609 SNP located in the first intron of the fat mass and obesity associated gene (FTO) has been found to be associated with common obesity mainly in populations of European descent. The Roma/Gypsy population as an ethnic minority of Asian Indian origin is well known for its adverse health status with a high prevalence of obesity. The main aim of this study was to examine the contribution of the rs9939609 FTO polymorphism to the high prevalence of obesity in the Roma/Gypsy population. Following a number of anthropometric measurements, the FTO rs9939609 polymorphism was genotyped in 312 Roma/Gypsy individuals. We observed significant differences in body mass index (BMI), waist circumference, and waist-to-hip ratio between different genotypes (P = 0.003, P = 0.012, and P = 0.03, respectively). The waist circumference in the subjects with AA genotype was about 7.1 cm larger than in those with TT genotypes (P = 0.005). However, the strongest association of minor allele A of the rs9939609 FTO polymorphism was found with BMI (odds ratio, 1.55; 95% confidence interval, 1.129-2.128; P = 0.007), even after adjusting for age, sex, and smoking status. This study provides the first report of allele and genotype frequencies for the rs9939609 polymorphism and also the first evidence of the association of the FTO variant with obesity in the Roma/Gypsy population.     

Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects

Neuropeptide Y (NPY) is an appetite hormone that acts centrally to control feeding behavior. The 5' and exon 2 regions of NPY2R, one of five NPY receptor genes, have been weakly and inconsistently implicated with obesity. With the ATG start site of the gene at the beginning of exon 2, single-nucleotide polymorphisms (SNPs) across intron 1 may show stronger associations with obesity than expected. Two 5' SNPs, three intron 1 SNPs, and one synonymous exon 2 SNP were genotyped on 2,985 white Utah subjects. Previously associated FTO, NPY, NPY1R, MC4R, PPARGC1A, OR7D4, and four NPFFR2 SNPs were also genotyped and related to BMI. One NPY2R 5' SNP (rs12649641, P = 0.008), an exon 2 SNP (rs2880415, P = 0.009), and an intron 1 SNP (rs17376826, P = 7 × 10(-6)) were each significantly associated with BMI. All three SNPs, plus FTO (rs9939609, P = 1.5 × 10(-6)) and two NPFFR2 SNPs (rs4129733, P = 3.7 × 10(-13) and rs11940196, 4.2 × 10(-10)) remained significant in a multiple regression additive model. Diplotypes using the estimated haplotypes of NPY2R, NPFFR2, and MC4R were significantly associated with BMI (P = 1.0 × 10(-10), 3.2 × 10(-8), and 1.1 × 10(-4), respectively). Haplotypes of NPY2R, NPFFR2, and MC4R, plus the FTO SNP, explained 9.6% of the BMI variance. SNP effect sizes per allele for the four genes ranged from 0.8 to 3.5 kg/m(2). We conclude that haplotypes containing the rs17376826 SNP in intron 1 of NPY2R have strong associations with BMI, some NPFFR2 haplotypes are strongly protective against or increase risk of obesity, and both NPY2R and NPFFR2 play important roles in obesity predisposition independent of FTO and MC4R.     

Racial Differences in the Tracking of Childhood BMI to Adulthood

Objective: The possibility that there are racial differences in the patterns of BMI (kilograms per meter squared) change throughout life has not been examined. For example, the high prevalence of obesity among black women could result from a higher prevalence of obesity among black girls or because normal‐weight black girls experience larger BMI increases in adolescence or adulthood than do their white counterparts. Therefore, we examined the tracking of childhood BMI into adulthood in a biracial (36% black) sample. Research Methods and Procedures: Five‐ to 14‐year‐old children (2392) were followed for (mean) 17 years. Childhood overweight was defined as BMI ≥ 95th percentile, and adult obesity was defined as BMI ≥ 30 kg/m². Results: The tracking of childhood BMI differed between whites and blacks. Among overweight children, 65% of white girls vs. 84% of black girls became obese adults, and predictive values among boys were 71% (whites) vs. 82% (blacks). These racial differences reflected contrasting patterns in the rate of BMI change. Although the initial BMI of black children was not higher than that of white children, BMI increases with age were larger among black girls and overweight black boys than among their white counterparts. In contrast, relatively thin (BMI < 50th percentile) white boys were more likely to become overweight adults than were their black counterparts. Discussion: These findings emphasize the black/white differences in BMI changes with age. Because of the adult health consequences of childhood‐onset obesity, early prevention should be given additional emphasis.     

Probability of Adult Overweight and Risk Change during the BMI Rebound Period

Objective: To develop a probability chart of adult overweight based on childhood body mass index (BMI) values and to evaluate the BMI change during the BMI rebound period during childhood, in different populations, with the use of risk function curves. Research Methods and Procedures: A longitudinal growth study of 3650 full-term healthy Swedish children followed from birth to 18 years of age. Weight and height values of our subjects were obtained. Results: A probability chart for reaching a BMI > 23 kg/m² at 18 years of age was constructed for boys and girls. For example, a BMI of 18 kg/m² at 4 years of age is associated with 0.70 probability of attaining a BMI > 23 kg/m² at 18 years of age in boys; a BMI of 16 kg/m² at 4 years of age leads to 0.40 probability of having a BMI > 23 kg/m² at 18 years of age in girls. Children with an obvious BMI rebound before 8 years of age have a high risk of being overweight at 18 years of age. There is a clear trend of BMI increase from the 1970s to the 1990s in U.S. children from a parallel dataset, and Hispanic children are at the highest risk of adult overweight. Discussion: The probability chart for adult overweight developed here provides a functional method of defining childhood obesity that is based on the risk of long-term ill health rather than on a certain statistical cut-off point. It will help pediatricians or healthcare workers identify those children who are at a high risk of becoming overweight in adulthood, which will allow clinical intervention at younger ages.     

Risk of obesity and metabolic syndrome associated with FTO gene variants discloses clinically relevant gender difference among Turks

Gene variations in the fat mass- and obesity-associated gene (FTO) have shown controversial associations with obesity and metabolic syndrome (MetS) in several populations. We explored the association of FTO gene with obesity, MetS, and insulin-related parameters separately in men and women. Two SNPs in the FTO, gene rs9939609 and rs1421085, were genotyped by the Taqman System in 1967 adults (mean age of the whole group 50.1 ± 12.0; 48.4 % male). A random sample of the Turkish Adult Risk Factor cohort was cross-sectionally analyzed. Both SNPs exhibited strong linkage disequilibrium (r² = 0.85) and minor alleles were associated with risk of obesity in women and of MetS in men. Carriers of the rs1421085 C-allele exhibited higher body mass index (BMI) in each gender. Adjusted fasting insulin and HOMA index were significantly higher in C-allele carriers in men alone. Logistic regression analysis demonstrated significantly increased likelihood for obesity in female C-risk allele carriers (OR 1.61; 95 % CI 1.19–2.18), after adjustment for age, smoking status, alcohol usage, physical activity grade and presence of diabetes mellitus. Male C-allele carriers were at increased risk for MetS (OR 1.44; 95 % CI 1.07–1.95), adjusted for age, smoking status, alcohol consumption, and physical activity. Further adjustment for BMI attenuated the MetS risk, indicating interaction between C-allele, gender and BMI. The FTO gene in Turkish adults contributes independently to obesity in women and—by interacting with BMI—to MetS and insulin resistance in men.     

Childhood intelligence and adult obesity

Objective: Recent studies conclude childhood intelligence has no direct effect on adult obesity net of education, but evolutionary psychological theories suggest otherwise. Design and Methods: A population (n = 17,419) of British babies has been followed since birth in 1958 in a prospectively longitudinal study. Childhood general intelligence is measured at 7, 11, and 16, and adult BMI and obesity are measured at 51. Results: Childhood general intelligence has a direct effect on adult BMI, obesity, and weight gain, net of education, earnings, mother's BMI, father's BMI, childhood social class, and sex. More intelligent children grow up to eat more healthy foods and exercise more frequently as adults. Conclusion: Childhood intelligence has a direct effect on adult obesity unmediated by education or earnings. General intelligence decreases BMI only in adulthood when individuals have complete control over what they eat.     

Meta‐analysis Added Power to Identify Variants in FTO Associated With Type 2 Diabetes and Obesity in the Asian Population

Several common variants in the intron 1 of FTO (fat mass and associated obesity) gene have been reliably associated with BMI and obesity in European populations. We analyzed two variants (rs9939609 and rs8050136) in 4,189 Chinese Han individuals and conducted a meta‐analysis of published studies in Asian population to investigate whether these variants are associated with type 2 diabetes (T2D) and obesity in Asian population. In this study, both the minor allele A of rs9939609 and the minor allele A of rs805136 were associated with increased risk of T2D, independent of measures of BMI; the odds ratios (ORs) per copy of the risk allele were 1.19 for rs9939609 (95% confidence interval (CI), 1.04–1.37; P = 0.01) and 1.22 for rs8050136 (95% CI, 1.07–1.40; P = 0.004) after adjusting for age, sex, and BMI. Our results also showed association with risk of obesity (rs9939609: OR = 1.39 (95% CI 1.04–1.85), P = 0.02; rs8050136: OR = 1.45 (95% CI 1.09–1.93), P = 0.01) but no association with overweight. These results were consistent with the pooled results from our meta‐analysis study (for diabetes, rs8050136, P = 1.3 × 10^?3; rs9939609, P = 9.8 × 10^?4; for obesity, rs8050136, P = 2.2 × 10^?7; rs9939609, P = 9.0 × 10^?9). Our findings indicate that the two variants (rs9939609 and rs8050136) in the FTO gene contribute to obesity and T2D in the Asian populations.     

FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women

The FTO gene was recently identified as a susceptibility locus for both obesity and type 2 diabetes by whole-genome association analyses of several European populations. We tested for an association between FTO risk alleles and obesity and diabetes in a well-characterized multiethnic cohort of postmenopausal women in the United States. We genotyped two most significantly associated single-nucleotide polymorphisms (SNPs) (rs9939609 and rs8050136) in intron 1 of FTO gene in a nested case-control study of 1,517 diabetes cases and 2,123 controls from the Women's Health Initiative-Observational Study (WHI-OS). The allelic frequencies of either rs9939609 or rs8050136 differed widely across four ethnic groups. The frequency of the rare allele A of rs9939609 among controls was much lower in Asians/Pacific Islanders (17%) than in blacks (45%), whites (40%), and Hispanics (31%). We found significant associations of rs9939609 with BMI and waist circumference in white and Hispanic women, but not among black and Asian/Pacific Islander women. On average, each copy of the risk-allele A at rs9939609 was significantly associated with 0.45 kg/m(2) increase in BMI (95% confidence interval (CI): 0.16-0.74; P = 0.004) and 0.97 cm increase in waist circumference (95% CI: 0.21-0.65; P = 0.0002). Similar results were observed for rs8050136. However, we found no significant genetic associations with diabetes risk, either within the full study sample or in any ethnic group. In conclusion, common genetic variants in the intron 1 of FTO gene may confer a modest susceptibility to obesity in an ethnicity-specific manner, but may be unlikely to contribute to a clinically significant diabetes risk.     

Replication study of novel risk variants in six genes with type 2 diabetes and related quantitative traits in the Han Chinese lean individuals

To replicating the associations of type 2 diabetes (T2D) and six novel reported variants in Han Chinese lean individuals of first episode T2D, a total of six high risk single nucleotide polymorphisms (SNPs) from the BCL11A, DUSP9, IRS1, CENTD2, ADRA2A, and CDKAL1 genes were examined. Candidate six SNPs were genotyped in 761 T2D patients and 433 control subjects, and associations between the six SNPs and Body Mass Index (BMI), Fasting Plasma Glucose (FPG) and Two Hours Oral Glucose Tolerance Test (2hOGTT) were also investigated. CDKAL1 provided the strongest evidence for replication, where rs7754840 was associated with T2D (odds ratio = 1.54, per copy of the risk C allele, P = 8.10 × 10⁻⁷). SNP rs5945326 at DUSP9 showed modest significance (odds ratio = 0.81, per copy of the protective G allele, P = 0.02). After adjusting the confounders of age, gender and BMI, the above results remain significant for both rs7754840 (P < 1.0 × 10⁻⁴) and rs5945326 (P = 0.043) respectively. After correcting for multiple testing, however, only the association between T2D and rs7754840 at CDKAL1 (P < 1×10⁻⁴) remains significant. In addition, the risk C allele of CDKAL1 rs7754840 was significantly associated with increased FPG levels (P = 3.8 × 10⁻⁴). The association between genetic variant in CDKAL1 gene was detected in the Han Chinese lean individuals. The correlation between rs7754840-C allele and increased FPG levels is consistent with the potential function of CDKAL1 gene in pancreatic islets.     

MC4R Variant Is Associated With BMI but Not Response to Resistance Training in Young Females

Recently, a genome‐wide association study (GWAS) that identified eight single‐nucleotide polymorphisms (SNPs) associated with BMI highlighted a possible neuronal influence on the development of obesity. We hypothesized these SNPs would govern the response of BMI and subcutaneous fat to resistance training in young individuals (age = 24 years). We genotyped the eight GWAS‐identified SNPs in the article by Willer et al. in a cohort (n = 796) that undertook a 12‐week resistance‐training program. Females with a copy of the rare allele (C) for rs17782313 (MC4R) had significantly higher BMIs (CC/CT: n = 174; 24.70 ± 0.33 kg/m², TT: n = 278; 23.41 ± 0.26 kg/m², P = 0.002), and the SNP explained 1.9% of overall variation in BMI. Males with a copy of the rare allele (T) for rs6548238 (TMEM18) had lower amounts of subcutaneous fat pretraining (CT/TT: n = 65; 156,534 ± 7,415 mm³, CC: n = 136; 177,825 ± 5,139 mm³, P = 0.019) and males with a copy of the rare allele (A) for rs9939609 (FTO) lost a significant amount of subcutaneous fat with exercise (AT/AA: n = 83; ?798.35 ± 2,624.30 mm³, TT: n = 47; 9,435.23 ± 3,494.44 mm³, P = 0.021). Females with a copy of the G allele for a missense variant in the SH2B1 (rs7498665) was associated with less change of subcutaneous fat volume with exercise (AG/GG: n = 191; 9,813 ± 2,250 mm³ vs. AA: n = 126; 770 ± 2,772 mm³; P = 0.011). These data support the original finding that there is an association between measures of obesity and a variant near the MC4R gene and extends these results to a younger population and implicates FTO, TMEM18, and SH2B1 polymorphisms in subcutaneous fat regulation.     

Obesity‐susceptibility loci and the tails of the pediatric BMI distribution

Objective: To determine whether previously identified adult obesity susceptibility loci were associated uniformly with childhood BMI across the BMI distribution. Design and Methods: Children were recruited through the Children's Hospital of Philadelphia (n = 7,225). Associations between the following loci and BMI were assessed using quantile regression: FTO (rs3751812), MC4R (rs12970134), TMEM18 (rs2867125), BDNF (rs6265), TNNI3K (rs1514175), NRXN3 (rs10146997), SEC16B (rs10913469), and GNPDA2 (rs13130484). BMI z‐score (age and gender adjusted) was modeled as the dependent variable, and genotype risk score (sum of risk alleles carried at the 8 loci) was modeled as the independent variable. Results: Each additional increase in genotype risk score was associated with an increase in BMI z‐score at the 5th, 15th, 25th, 50th, 75th, 85th, and 95th BMI z‐score percentiles by 0.04 (±0.02, P = 0.08), 0.07 (±0.01, P = 9.58 × 10^?7), 0.07 (±0.01, P = 1.10 × 10^?8), 0.09 (±0.01, P = 3.13 × 10^?22), 0.11 (±0.01, P = 1.35 × 10^?25), 0.11 (±0.01, P = 1.98 × 10^?20), and 0.06 (±0.01, P = 2.44 × 10^?6), respectively. Each additional increase in genotype risk score was associated with an increase in mean BMI z‐score by 0.08 (±0.01, P = 4.27 × 10^?20). Conclusion: Obesity risk alleles were more strongly associated with increases in BMI z‐score at the upper tail compared to the lower tail of the distribution.     

The Role of Obesity‐associated Loci Identified in Genome‐wide Association Studies in the Determination of Pediatric BMI

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome‐wide association (GWA) studies. In this study, we examined 25 single‐nucleotide polymorphisms (SNPs) corresponding to 13 previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13, and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z‐score. We conclude that among 13 loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.     

Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP

Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI>or=95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r(2) = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08-1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91-1.21; P = 0.49) and of 1.31 (95% CI 1.050-1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.     

Differences in the heritability of growth and growth velocity during infancy and associations with FTO variants

While the associations of common variants in the FTO gene with obesity have been widely replicated in adults, there is conflicting evidence regarding their effects in infancy. We hypothesize that the genetic influences on growth traits vary during infancy, and that conflicting results may stem from variation in the ages at which FTO associations have been examined. Using longitudinal weight and length data at 0, 1, 3, 6, 9, 12, 18, 24, 30, and 36 months in 917 (444 females, 473 males) family members from the Fels Longitudinal Study, we used a variance components-based approach (SOLAR) to: (i) examine differences in heritability (gene-by-age interaction) in weight, length, relative weight (BMI and ponderal index (PI)) and instantaneous weight and length velocities over the course of infancy, and (ii) test whether a common FTO variant (rs9939609) was associated with infant growth at three ages (maximum trait heritability, birth and 36 months). All heritabilities at birth (of 39-74%) were significant (P < 3.9 × 10(-10)), but changed with age (gene-by-age interaction, P < 0.05). Weight, relative weight, and weight velocity reached maximum heritabilities (of 76-89%) at 6-9 months, while length and length velocity reached maximum heritabilities (of 96-99%) at 18-30 months. We found no association of rs9939609 with growth status or velocity measured at any age (P > 0.11). This study for the first time demonstrates the fluctuation of genetic influences on infant growth, but further work is required to determine which gene variants explain the strong additive genetic effects observed.     

Interactions of anthropometric indices,rs9939609 FTO gene polymorphism and breast cancer: A case-control study

Contradictory results were reported on the effect of fat mass- and obesity-associated (FTO) gene and anthropometric measurements on breast cancer (BC). This study aimed to assess the interactions between rs9939609 polymorphism of FTO gene, anthropometric indices and BC risk in Iranian women. This case-control study was performed on 540 women including 180 women with BC and 360 healthy women in Tehran, Iran. Physical activity and dietary intakes were assessed by validated questionnaires. Data on sociodemographic and pathologic factors of the participants as well as their blood samples were collected. The rs9939609 FTO gene polymorphism was genotyped using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). No significant association was found between BC and risk allele of FTO rs9939609 polymorphism after adjustments for the confounders. However, there was a significant association between rs9939609 polymorphism risk allele and BC risk in females with overweight, even after adjusting for age, family history of BC, abortion, BMI and the number of pregnancies (P < .05). The association was disappeared after further adjustments for lifestyle factors including smoking, alcohol consumption, calorie and macronutrients intake, and physical activity. The FTO gene polymorphism was associated with the risk of BC in overweight individuals. This association was influenced by environmental factors including diet, alcohol consumption and smoking. Future studies are required to confirm the association between the FTO gene and BC in overweight females and to identify the underlying mechanisms.