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

Jacobsson, Josefin A.; Danielsson, Pernilla; Svensson, Victoria; Kloviņš, Jānis; Gyllensten, Ulf; Marcus, Claude; Schiöth, Helgi B.; Fredriksson, Robert

doi:10.1016/j.bbrc.2008.01.087

Cited by 109 publications

(115 citation statements)

References 20 publications

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“…20 The degree of skewing of allelic FTO expression is remarkably similar in our subjects, suggesting that most of the variation in FTO expression is due to cis-regulatory variation in intron 1 of this gene. As the determination of allelic expression with intronic SNPs gives very similar estimates with those obtained with exonic SNPs, 18 we can assume that allelic mRNA levels are also skewed.…”

Section: Discussionsupporting

confidence: 57%

The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels

2010

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As shown by genome-wide association studies single-nucleotide polymorphisms (SNPs) within intron 1 of the FTO gene are associated with the body mass index and type II diabetes, although the functional significance of these SNPs has remained unclear. Using primer extension assays, we have determined the ratio of allelic FTO transcript levels in unspliced heterogeneous nuclear RNA preparations from blood of individuals heterozygous for SNP rs9939609. Allelic expression ratios of the neighboring RPGRIP1L gene were investigated in individuals who were heterozygous for SNP rs4784319 and heterozygous or homozygous for rs9939609. In each of five individuals, the FTO transcripts containing the A (risk) allele of rs9939609 were more abundant than those with T allele (mean 1.38; 95% confidence interval 1.31-1.44). Similar results were obtained in a fibroblast sample. We also observed skewed allelic expression of the RPGRIP1L gene in blood, but skewing was independent of the FTO genotype. Our data suggest that increased expression of FTO is associated with increased body mass. (Figure 1). Using bioinformatics analysis, Gerken et al 3 have proposed that the FTO protein is an Fe(II) and 2-oxoglutarate-dependent oxygenase. 3 Loss-of-function mutation in FTO causes severe growth retardation and multiple malformations in homozygotes, 4 whereas loss of one functional copy of this gene seems to be compatible with both lean and obese phenotype. 5 Leanness, postnatal growth retardation and a higher metabolic rate were observed in Fto knockout mice 7 and in mice with a missense mutation in exon 6. 8 The FTO gene shares a CpG island with the adjacent RPGRIP1L gene, which is transcribed in the opposite direction, suggesting that the two genes are coregulated. The RPGRIP1L protein is located in the cilia and centrosomes. 6 Loss-of-function mutations in RPGRIP1L cause Joubert syndrome type 7 or Meckel syndrome type 5. It can be noted that FTO and RPGRIP1L genes are ubiquitously expressed and show similarity of expression profile both in fetal and adult tissues (data not shown).As the obesity-associated SNPs in the FTO gene are intronic, their functional significance is unclear. It is possible that one of the SNPs is located in a regulatory sequence and that the risk allele increases or decreases the transcription rate, but strong linkage disequilibrium (LD) of these SNPs makes it difficult to identify the functionally relevant SNP. In 2008, Stratigopoulos et al 9 reported that the risk allele (A) of SNP rs8050136 preferentially bound to the transcription factor CUTL1 in human fibroblast DNA and that an siRNA knockdown of

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Section: Discussionsupporting

confidence: 57%

The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels

2010

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“…10 Although the phenotypic characteristics are different for this novel gene variant, the genotype-gender interactions found in the present study further points out that the FTO gene may act differently depending on gender. The best predictor of insulin sensitivity is body fatness, and changes in body composition are known to be gender specific, especially during early puberty, in concert with changes in the hormonal environment.…”

Section: Discussionsupporting

confidence: 50%

“…10 Briefly (1) one group of 450 obese children and adolescents (232 girls and 218 boys, age 6-21 years) enrolled at National Childhood Obesity Centre at Karolinska University Hospital, Huddinge, Sweden and (2) a group of 512 normal weight Swedish adolescents (268 girls and 244 boys, age 15-20 years) recruited from 17 upper secondary schools around Stockholm to match the obese group with respect to ethnicity and socioeconomic status. Subjects with overweight/obesity or chronic diseases were excluded from the group of normal weight adolescents, and subjects with type 2 diabetes were excluded from the obese group.…”

Section: Subjectsmentioning

confidence: 99%

Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents

et al. 2008

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Background:The global prevalence of obesity and overweight is increasing rapidly among adults as well as among children and adolescents. Recent genome-wide association studies have provided strong support for association between variants in the FTO gene and obesity. We sequenced regions of the FTO gene to identify novel variants that are associated with obesity and related metabolic traits. Results: We screened exons 3 and 4 including exon-intron boundaries in FTO in 48 obese children and adolescents and identified three novel single nucleotide polymorphism in the fourth intronic region, (c.896 þ 37A4G, c.896 þ 117C4G and c.896 þ 223A4G). We further genotyped c.896 þ 223A4G in 962 subjects, 450 well-characterized obese children and adolescents and 512 adolescents with normal weight. Evidence for differences in genotype frequencies were not detected for the c.896 þ 223A4G variant between extremely obese children and adolescents and normal weight adolescents (P ¼ 0.406, OR ¼ 1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P ¼ 0.017) and increased degree of insulin resistance (P ¼ 0.025). There were in addition no differences in body mass index (BMI) or BMI standard deviation score (SDS) levels among the obese subjects according to genotype and the associations with insulin levels and insulin resistance remained significant when adjusting for BMI SDS. Conclusion: These findings suggest that this novel variant in FTO is affecting metabolic phenotypes such as insulin resistance, which are not mediated through differences in BMI levels.

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“…Moreover, different SNPs have different effects on the genders. Jacobsson et al 45 first proposed that the association between common variants in the FTO gene with obesity was only found among girls in a Swedish population. However, a study of African populations was inconsistent with this view.…”

Section: Discussionmentioning

confidence: 99%

Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty

et al. 2011

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OBJECTIVE: Genome-wide association studies (GWAS) have identified some common variants associated with obesity risk in European descents. However, their influences on obesity-related indices for the Chinese children at puberty are not widely clear yet. To address this question, we conducted a study that aims to examine effects of eight previously reported GWAS singlenucleotide polymorphisms (SNPs) on four obesity-related indices in a sample of Chinese children aged 10 --12 years. METHODS: Anthropometric indices were measured in 1688 children (10.8 ± 0.4 years, boys ¼ 877, girls ¼ 811) from Shanghai Children's Sleep Project. Eight SNPs within the NEGR1, TMEM18, GNPDA2, MTCH2, SH2B1, FTO, MC4R and KCTD15 genes were genotyped using matrix-assisted laser desorption/ionization --time of flight mass spectrometry. Linear regression and genetic additive model were used to test for the association betweens SNPs and obesity-related indices (weight, body mass index (BMI), waist-to-height ratio and body fat). RESULTS: Only two SNPs, rs6548238 (TMEM18) and rs9939609 (FTO), were associated with all obesity-related indices with Po0.05. After adjusting for multiple tests, rs9939609 is the only one significantly associated with the indices. SNPs, rs6548238 and rs9939609 explained 0.28% (P ¼ 0.03) and 0.54% (P ¼ 0.002) variance of BMI, respectively, that are almost two-fold of the previously GWAS-reported effects. In addition, rs6548238 was associated with four indices in boys, but not in girls. In contrast, rs9939609 showed a strong association only in girls. Six other SNPs, rs2815752 (NEGR1), rs10938397 (GNPDA2), rs10838738 (MTCH2), rs7498665 (SH2B1), rs17782313 (MC4R) and rs11084753 (KCTD15), were not associated with obesity (P40.05). CONCLUSIONS: Variants of TMEM18 and FTO are associated with obesity indices during puberty in Chinese children, but candidate SNPs of NEGR1, GNPDA2, MTCH2, SH2B1, MC4R and KCTD15 have no significant effects on obesity indices. The findings also suggest that obesity susceptibility genes may exert more obvious effects during children's puberty. In addition, gender differences may exist in various obesity-related genes.

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

Cited by 109 publications

References 20 publications

The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels

The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels

Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents

Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty

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