FTO (rs1121980 / rs9930506)

Obesity is a multifactorial disease caused by environmental and genetic factors. In human obesity the genetic contribution in most cases is due to a multigenic defect. The advent of the method GWA (Genome Wide Association) in the study of the genetic basis of BMI (body mass index) has led to new knowledge about the factors predisposing to obesity. FTO (fat mass-And Obesity-Associated Gene) is the gene which in recent years has received much attention in research because it seems to have a direct genetic correlation with obesity. Its gene expression is elevated in the hypothalamic and level of this expression is regulated by the intake of calories.

FTO thus appears to be the first gene unequivocally associated with the BMI, intervening in the circuits hormonal active in the brain in the control of appetite and feelings of satiety. Considering the strong link between FTO and obesity, it is not surprising the presence of a correlation between the gene itself and diabetes mellitus, knowing that there is a strong link between obesity and diabetes mellitus. It follows therefore that the FTO gene affects two out of four of the factors underlying the diagnosis of metabolic syndrome. The genetic variant rs1121980, in which you have a replacement at the level of intron 1 of the gene for a C (cytosine, allele maior) with T (thymine, minor allele) was associated with a predisposition to obesity with an odds ratio for heterozygotes (C/T) equal to 1.67 and an odds ratio of 2.75 for homozygotes Subjects TT, homozygous for the gene variant, have indeed altered circulating levels of the hormone ghrelin, a central element of the neuroendocrine control of energy homeostasis. Further confirmation came from examination of brain activity through MRI.

Compared with those in possession of the common variant of the FTO gene CC, TT genetic condition corresponded, in fact, a kind of activation in different brain areas to the processing of feelings of satisfaction in response to the sight of images depicting food. Similarly happens with the genetic variant rs9930506 in which there is a substitution at the level of intron 1 of the gene of an A (adenine, allele maior) with a G (guanine, minor allele), and has been associated with a predisposition to obesity with a increase of about 1.3 units of BMI in GG Subjects GG, homozygous for the variant gene, have also altered circulating levels of the hormone ghrelin and compared to those in possession of the common AA variant of the FTO gene, the genetic condition GG produced the same result as already described for the condition of rs1121980 TT . The link between the FTO gene and obesity seems to be pretty clear by now, therefore, as revealed by the impact of some of its genetic variants on the hormonal control of feeding behavior and energy metabolism.

 MC4R

The gene for the melanocortin 4 receptor (MC4R) is involved in energy homeostasis and in the central regulation of body weight. The first mutations in the gene have been identified in severely obese subjects and more than 34 variants have been identified in cases of obesity. All mutations associated with obesity are characterized by a loss of function of the receptor and would be present in 3-6% of severely obese subjects. The variant V103I (rs 2229616), present in 3% of the Caucasian population, which implies a change in the amino acid position 103 (valine-isoleucine), instead brings a gain of receptor function and would be protective against obesity with a reduction about 0:48 kg / m2 BMI (body mass index). At the nucleotide level, the most common allele is the allele G that within the GTC triplet coding for the amino acid valine, while the rare allele A leads to the ATC triplet coding for the amino acid isoleucine. The rare allele A was associated with a significant reduction in hip circumference, to a decrease in glycated hemoglobin, and an increase in The risk for the metabolic syndrome is reduced in carriers of the rare A and while these individuals are slightly leaner than the homozygous GG.