Eliana Frazzatto

Mutation analysis of the follicle-stimulating hormone receptor gene in girls with gonadotropin-independent precocious puberty resulting from autonomous cystic ovaries.

OBJECTIVE To search for germline activating mutations of the FSH receptor in girls with gonadotropin-independent precocious puberty. DESIGN Molecular studies in human tissue. SETTING Four girls with polycystic ovaries and gonadotropin-independent isosexual precocious puberty without clinical and molecular features of McCune-Albright syndrome. INTERVENTION(S) Peripheral blood was used for DNA extraction. The alpha-subunit of the Gs gene and the entire exon 10 of FSH receptor gene were amplified by polymerase chain reaction (PCR). Gs-alpha mutations characteristic of McCune-Albright syndrome were excluded by denaturating gradient gel electrophoresis (DGGE) and allele-specific PCR. Exon 10 of the FSH receptor gene was analyzed by DGGE and direct sequencing. MAIN OUTCOME MEASURE(S) Results of DGGE and direct sequencing. RESULT(S) No germline activating mutations were detected in exon 10 of our patients. Instead, two previously described polymorphisms were found, leading to the substitution of alanine for threonine at position 307 and of serine for asparagine at position 680 of the FSH receptor molecule. CONCLUSION(S) Germline activating mutations were not found in exon 10 of the FSHR gene in any of our patients. Further studies, preferably in ovarian tissue, will be required to exclude the presence of somatic activating mutations of the FSH receptor in these patients.

Allelic variations in the vitamin D receptor gene, insulin secretion and parents' heights are independently associated with height in obese children and adolescents

Polymorphisms in the VDR gene were reported to be associated with variations in intrauterine and postnatal growth and with adult height, but also with other traits that are strongly correlated such as the BMI, insulin sensitivity, insulin secretion and hyperglycemia. Here, we assessed the impact of VDR polymorphisms on body height and its interactions with obesity- and glucose tolerance-related traits in obese children and adolescents. We studied 173 prepubertal (Tanners stage 1) and 146 pubertal (Tanners stages 2-5) obese children who were referred for a weight-loss program. Three single nucleotide polymorphisms were genotyped: rs1544410 (BsmI), rs7975232 (ApaI) and rs731236 (TaqI). BsmI and TaqI genotypes were significantly associated with height in pubertal children, but the associations did not reach statistical significance in prepubertal children. In stepwise regression analyses, the lean body mass, insulin secretion, BsmI or TaqI genotypes and the fathers and the mothers height were independently and positively associated with height in pubertal children. These covariables accounted for 46% of the trait variance. The height of homozygous carriers of the minor allele of BsmI was 0.65 z-scores (4cm) higher than the height of homozygous carriers of the major allele (P=.0006). Haplotype analyses confirmed the associations of the minor alleles of BsmI and TaqI with increased height. In conclusion, VDR genotypes were significantly associated with height in pubertal obese children. The associations were independent from the effects of confounding traits, such as the body fat mass, insulin secretion, insulin sensitivity and glucose tolerance.

Angiotensin converting enzyme insertion/deletion polymorphism is associated with increased adiposity and blood pressure in obese children and adolescents

BACKGROUND The insertion/deletion polymorphism in the gene encoding the angiotensin-converting enzyme (ACE I/D) was associated with arterial hypertension and obesity in adults, but the data in children are scarce and yielded contrasting results. We assessed the impact of the ACE I/D on blood pressure and obesity related traits in a Brazilian cohort of obese children and adolescents. METHODS AND RESULTS ACE I/D was genotyped in 320 obese children and adolescents (64% of girls) aged 7-16years, referred for a weight-loss program. We observed an association of the D-allele with blood pressure and with pre-hypertension/hypertension in boys (odds ratio 2.44, 95% C.I. 1.34-4.68, p=0.005 for a codominant model). The D-allele, insulin resistance and body fat mass had independent and additive effects and explained 14% of the variance of pre-hypertension/hypertension. The BMI, waist circumference, and body fat mass were significantly higher in DD/ID boys than in II boys (p<0.005). Allelic associations with obesity related traits were independent of the association with blood pressure. No genotype associations were observed in girls. CONCLUSIONS The D-allele of the ACE I/D polymorphism was associated with arterial hypertension and with obesity related traits in boys, but not in girls, in a cohort of obese children and adolescents. These associations were independent of each other, as well as of the effects of other confounding traits such as insulin secretion, insulin sensitivity and glucose tolerance. Our results are in agreement with experimental evidences suggesting that the renin-angiotensin system plays a role in the regulation of visceral adipose tissue accumulation.

Binge eating symptoms, diet composition and metabolic characteristics of obese children and adolescents.

This study aimed to determine the occurrence of symptoms of binge eating (BE) among children and adolescents seeking treatment for their obesity, as well as to evaluate their diet composition and metabolic characteristics. The Binge Eating Scale (BES) was answered by 128 children and adolescents (10.77+/-2.04 years, BMI 29.15+/-4.98 kg/m2, BMI Z score 2.28+/-0.46, 53.91% pubescent), who were classified into two subgroups--binge eaters (score greater than or equal to 18 points) and non-binge eaters (score lower than 18 points). Anthropometric data, body composition and Tanner stages were collected and dietary evaluation conducted. Blood pressure was determined, and glucose, lipid profile and insulin assays were performed. Insulin resistance was determined using HOMA-IR. BE symptoms were present in 39.06% of patients. Carbohydrate intake in diet composition was significantly higher among binge eaters. Children with BE did not demonstrate significant dissimilar metabolic characteristics when compared to their counterparts without BE. Therefore, BE seems to be a prevalent problem among children and adolescents seeking help for their obesity. When associated with obesity, this eating behaviour can influence macronutrient consumption through increased carbohydrate intake. Further research would be valuable to verify the reproducibility of these findings.

Associaçäo entre polimorfismo Gln27Glu do receptor Beta 2-adrenérgico e hipertensäo arterial sistêmica em obesos mórbidos

b2-adrenergic receptors (b2AR) are membrane-bound receptors, which upon binding the endogenous cathecolamines epinephrine and nore-pinephrine signal to the interior of cells via stimulatory guanine nucleotide-binding protein Gs. The sympathetic nervous system activation stimulates energy mobilization and utilization in the adipose tissue that is a favored target for high-energy substrate storage, mobilization and utilization. Adrenergic responsiveness may be altered in obesity and could be an important factor in the pathogenesis and maintenance of obesity state. In the hypertensive state there is physiological and biochemical evidence that b-adrenergic responsiveness is diminished in the face of increased sympathetic tone. Recently, several different polymorphic forms of the human b2AR have been identified in general population, including N-terminal substitutions of glutamine (Gln) for glutamic acid (Glu) at position 27. The aim of this study was to investigate the potential interaction between the b2AR (Gln27Glu) polymorphism and obesity accumulation and hypertension in morbidly obese subjects. The Ita I genotypes of b2AR were established using RFLP methods in 135 individuals with BMI 48 ± 8.02kg/m2. The frequency of Gln/Glu was 31.9% and in the homozygous Glu/Glu was 12.6%. No association was found between BMI, weight gain during the past years and the Ita I genotypes and neither was associated with levels of triglycerides, cholesterol, insulin and glucose. Positive association was found between blood pressure (systolic and diastolic) and presence of polymorphism. The results indicate at the first time that presence of polymorphism 27Glu may provide a mechanism for enhanced vascular reactivity and identify a candidate gene for hypertension in this obesity group.