Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genome wide analysis reveals association of a FTO gene variant with epigenetic changes of several genes in human blood

ABSTRACT: FTO gene variants show the strongest association to obesity so far, but the role of the gene in obesity remains unclear. The FTO protein is a demethylation enzyme, which suggests that the link to obesity could be mediated through epigenetic changes. Herein, we determine the genome wide DNA methylation profile in blood from 47 female preadolescents and detect changes in five methylated regions, corresponding to six genes, associated with the FTO risk allele (rs9939609). In addition, we identify 20 differentially methylated regions associated with obesity. Our findings indicate that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, the identified regions might prove valuable biomarkers for the diagnosis and prognosis of obesity and comorbidites, such as cardiovascular disease. Bisulphite converted DNA from 47 girls were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2. Half of the subjects are carriers of the FTO obesity risk allele (AA) and half of the normal allele (TT). In addition, both obese and normal-weigh indiviudals were included.

ORGANISM(S): Homo sapiens

SUBMITTER: Markus Sällman Almén

PROVIDER: E-GEOD-27860 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome wide analysis reveals association of a FTO gene variant with epigenetic changes.

Almén Markus Sällman MS Jacobsson Josefin A JA Moschonis George G Benedict Christian C Chrousos George P GP Fredriksson Robert R Schiöth Helgi B HB

Genomics 20120102 3

Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1, STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Ou ...[more]

PMID: 22234326

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Project description:A female patient with a partial trisomy 16q was described previously. Her clinical characteristics included obesity, severe anisomastia, moderate to severe mental retardation, dysmorphic facies, and contractions of the small joints. In this paper, we describe a more detailed analysis of the genetic anomaly in this patient. We were particularly interested in the involvement of the fat mass and obesity associated gene (FTO) in her duplication. Single nucleotide polymorphisms in FTO have recently been associated with obesity. We have precisely mapped the breakpoints of the duplication using high resolution oligonucleotide array comparative genome hybridization (CGH). We found that the duplication spans 11.45 Mb on 16q11.2 to 16q13 and it includes FTO. The increased copy number of FTO was confirmed with a qPCR on genomic DNA of the patient and healthy controls. We investigated the influence of the increased FTO copy number on FTO gene expression in immortalized lymphocytes from the using qPCR. We found no evidence of increased FTO expression in the patient. This observation could be explained by maternal imprinting. We found evidence supporting this hypothesis in a database of imprinted genes. In addition, our results generated new candidate genes for the mental retardation, dysmorphic facies, small joints contractions, small teeth, and anisomastia of the patient. We used a high density oligonucleotide microarray to delineate the borders of the duplication with high resolution. This analysis enabled us to confirm the inclusion of FTO in the duplication. This was confirmed with quantitative real-time PCR (qPCR) at the level of genomic DNA. To further investigate the role of FTO in the obese phenotype of the patient, we used qPCR to study the expression of FTO in immortalized lymphocytes of the patient. Remarkably, the increased FTO copy number in the patient’s genomic DNA did not give rise to an increased copy number of FTO mRNA molecules. We think this may be the result of maternal imprinting of the gene. The CGH results also allowed us to generate new hypotheses regarding the etiology of the other clinical problems of the patient. We propose candidate genes for her mental retardation, dysmorphic facies, joint contractures, small teeth, and anisomastia.

Dataset Information

Genome wide analysis reveals association of a FTO gene variant with epigenetic changes of several genes in human blood

Publications

Genome wide analysis reveals association of a FTO gene variant with epigenetic changes.

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