Jacobsson J A, Klovins J, Kapa I, Danielsson P, Svensson V, Ridderstråle M, Gyllensten U, Marcus C, Fredriksson R, Schiöth H B
Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
Int J Obes (Lond). 2008 Nov;32(11):1730-5. doi: 10.1038/ijo.2008.168. Epub 2008 Sep 16.
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.
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+37A>G, c.896+117C>G and c.896+223A>G). We further genotyped c.896+223A>G 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+223A>G variant between extremely obese children and adolescents and normal weight adolescents (P=0.406, OR=1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P=0.017) and increased degree of insulin resistance (P=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.
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.
肥胖和超重的全球患病率在成年人以及儿童和青少年中都在迅速上升。最近的全基因组关联研究为FTO基因变异与肥胖之间的关联提供了有力支持。我们对FTO基因区域进行测序，以鉴定与肥胖及相关代谢特征相关的新变异。
我们对48名肥胖儿童和青少年的FTO基因外显子3和4（包括外显子-内含子边界）进行了筛查，在第四个内含子区域鉴定出三个新的单核苷酸多态性（c.896+37A>G、c.896+117C>G和c.896+223A>G）。我们进一步对962名受试者（450名特征明确的肥胖儿童和青少年以及512名体重正常的青少年）进行了c.896+223A>G基因分型。在极度肥胖儿童和青少年与体重正常的青少年之间，未检测到c.896+223A>G变异的基因型频率存在差异（P=0.406，OR=1.154（0.768-1.736））。然而，具有GG基因型的肥胖受试者空腹血清胰岛素水平升高了30%（P=0.017），胰岛素抵抗程度增加（P=0.025）。此外，根据基因型，肥胖受试者之间的体重指数（BMI）或BMI标准差评分（SDS）水平没有差异，在调整BMI SDS后，与胰岛素水平和胰岛素抵抗的关联仍然显著。
这些发现表明，FTO基因中的这种新变异正在影响诸如胰岛素抵抗等代谢表型，而这种影响并非通过BMI水平的差异介导。
