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The genetic influence in obesity prevalence is well described, but the role of genetic markers related to athletic strength/ endurance performance remains controversial. We investigated associations between obesity and the genetic polymorphisms alpha-actinin-3 (ACTN3) R577X and angiotensin-converting enzyme (ACE) I/D in schoolchildren aged 4-13 years from Southern Brazil. We collected sociodemographic data from parents through a questionnaire and conducted an anthropometric assessment. DNA was extracted from buccal cells and genotyping was performed by PCR. We found that 1.9% of the individuals were classified as low weight-for-age, 57.6% as normal weight and 40.5% as overweight/ obesity. Regarding allelic distribution, we found that 52.5% of individuals were DD, 30.8% ID, and 16.7% II for ACE; and 38.8% of individuals were RR, 40.2% RX and 21.0% XX for ACTN3. When both polymorphisms were combined, we observed a clear association between the composed genetic profile of these alleles and severe obesity in schoolchildren. Our data suggest that the combined analysis of ACTN3 R577X and ACE I/D polymorphisms may serve as a predictor for the risk of severe obesity in children. These data can contribute to a better understanding of the relationship between these polymorphisms and the body weight development of school-age children.

Angiotensin-I-converting enzyme (ACE) is involved in the synthesis and degradation of important bioactive peptides. The ACE gene has a 287-bp insertion/deletion polymorphism that controls ACE expression through a mechanism that remains elusive. In this study, we found that the 287-bp polymorphic element of the ACE gene, a member of the AluYa5 sub-family of Alu elements, codes for an RNA molecule that controls the levels of ACE mRNA. Transient transfection of a plasmid containing a CMV promoter upstream of the ACE polymorphic element resulted in significant expression of an AluYa5 RNA and reduced ACE mRNA expression as well as ACE enzymatic activity in AD 293 cells. The AluYa5 element also independently reduced the expression of other genes, regardless of whether these genes harbored Alu elements within their genomic context. Interestingly, the CMV promoter was not required for the expression of the AluYa5 element in AD 293 cells. The 287-bp sequence was sufficient to produce AluYa5 RNA and led to a significant reduction in ACE gene expression. Moreover, the removal of an 11-bp fragment of the 3' end of the ACE polymorphic sequence, which is specific to this particular AluYa5 element, did not prevent this element from being expressed but did affect its ability to target ACE expression. Thus, the expression of the AluYa5 polymorphic element within the ACE gene could explain why patients carrying the ACE insertion polymorphism have reduced risk of developing several chronic diseases.

We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems.