Influence of the TAS2R38 Gene Single Nucleotide Polymorphisms in Metabolism and Anthropometry in Thyroid Dysfunction.

The gene TAS2R38 single nucleotide polymorphisms (SNPs-P49A, A262V and V296I) can condition bitter tasting by PAV (proline-alanine-valine) and non-bitter-tasting by AVI (alanine-valine-isoleucine) homozygosity. We evaluated this polymorphisms association with thyroid function, metabolism and anthropometry parameters determined by: Endpoint analysis (SNPs); DXA (fat mass-%, total fat mass-kg, lean mass-kg); Standard methods (lipid metabolism parameters, HbA1c-%, glycemia-mg/dL, insulinemia-µIU/mL, HOMA-IR, uricemia-mg/dL, calcemia-mg/dL and BMI-kg/m2); ELISA (leptinemia-ng/mL); Spectrophotometry (Angiotensin Converting Enzyme activity-UI/L). Statistics: SPSS program; OR [IC95%]; p < 0.05. Sample: 114 hypothyroid, 49 hyperthyroid, and 179 controls. An association between A262V-valine-valine and hypothyroidism/hyperthyroidism was verified (OR = 2.841; IC95% [1.726-4.676]), p < 0.001/OR = 8.915; IC95% [4.286-18.543]), p < 0.001). Protector effect from thyroid dysfunction: A262V-alanine-valine (OR = 0.467; IC95% [0.289-0.757], p = 0.002/OR = 0.132; IC95% [0.056-0.309], p < 0.001) and PAV (OR = 0.456; IC95% [0.282-0.737], p = 0.001/OR = 0.101; IC95% [0.041-0.250], p < 0.001). Higher parameter values associated with genotypes were: fat-mass-% (V296I-valine-isoleucine), lean-mass (P49A-proline-proline; PVI), leptin (AVI), HbA1c (A262V-alanine-valine) and lower values in lean-Mass (AVI; PVV), leptin (A262V-alanine-alanine), HbA1c (PVV), uricemia (V296I-valine-isoleucine), glycemia (A262V-alanine-alanine; AAV) and plasma triglycerides (PVV). In conclusion, TAS2R38 influences thyroid function, body composition and metabolism. Bitter taste perception (PAV) and the genotype A262V-alanine-valine can protect from thyroid dysfunction. AVV, PVV and genotype A262V-valine-valine may confer higher predisposition for thyroid dysfunction, particularly PVV for hyperthyroidism.

Genetic Contribution of the Adrenergic, Cholinergic, and Serotonergic Systems to Leiomyoma Development and Treatment.

The link between the autonomic nervous system and tumor biology is being unfold. We aim to study the contribution of genes of the adrenergic (ADBR2 - rs1042713, NM_000024.6:c.46G>A, NP_000015.2:p. Gly16Arg), cholinergic (CHRNA5 - rs16969968, NM_000745.3:c.1192G>A, NP_000736.2:p.Asp398Asn), and serotonergic systems (SLC6A4 - 5-HTTVNTR-intron2, HTR2A - rs6313, NM_000621.5:c.102C>T, NP_ 001365853 .1: p. Ser 34=) to gynecological tumorigenesis and their treatment by embolization. A total of 517 DNA samples from women were analyzed. Samples were genotyped by PCR, PCR-RFLP and EndPoint genotyping. Results show a statistically significant association between the AA genotype of the ADBR2 gene and GG genotype of the CHRNA5 gene with leiomyoma (OR = 2.311; p = 0.003 and OR = 2.165; p = 0.001, respectively), and the epistatic interaction between genotypes increases the risk (OR = 2.458; p= 0.043). The GG genotype (CHRNA5) shows a lower reduction of the volume of the main leiomyoma after treatment (p=0.015). Combination of the genotypes 12/12-AA (SLC6A4 - ADBR2) increases the risk to leiomyoma (OR = 2.540, p= 0.030). TT genotype of HTR2A gene in combination with any of the two risk genotypes (of ADBR2 or CHRNA5) increases substantially the risk (OR = 5.266, p = 0.006; OR = 6.364, p=0.007, respectively). We conclude that ADBR2 and CHRNA5 genes have a relevant role that is enhanced by the epistatic relationship with the genes HTR2A and SLC6A4. CHRNA5 gene may also be a modulator of the success of embolization. We confirm the contribution of the genetics of Autonomous Nervous System to tumor biology.

[Endocrinology in Portugal - Census 2016. Board of the Portuguese College of Endocrinology and Nutrition of the Portuguese Medical Association]. / A Endocrinologia em Portugal - Censo 2016. Direção do Colégio de Endocrinologia e Nutrição da Ordem dos Médicos.

INTRODUCTION: On September 2016, the Board of the College of Endocrinology and Nutrition of the Portuguese Medical Association carried out a national survey, about all Endocrinology, Diabetes and Metabolism Departments of the public hospitals included in the Portuguese National Health Service and a simplified version of this survey was sent to all endocrinologists working in Portugal and registered with the Portuguese Medical Association. MATERIAL AND METHODS: Data related to organizational and human resources were collected, reporting the situation by the end of year 2015. The census registered 107 individuals and 27 Departments. RESULTS: The ratio of endocrinologists-population was 1.4, much lower than in the other European countries (varies between 2 to 4), resulting in alarming shortages of services in some areas of Portugal and in worse quality indicators. DISCUSSION: These data suggest that actions should be taken to increase the number of endocrinologists and departments in the country. CONCLUSION: In recent years, the number of residents has significantly increased, which will make it possible to correct this situation.

Introdução: A Direção do Colégio de Endocrinologia e Nutrição da Ordem dos Médicos realizou um inquérito nacional em setembro de 2016, a todos os serviços de Endocrinologia, Diabetes e Metabolismo dos hospitais do Serviço Nacional de Saúde e uma versão simplificada do mesmo foi enviada a todos os endocrinologistas a trabalhar em Portugal e inscritos no colégio. Material e Métodos: O censo inclui dados organizacionais e de recursos humanos relativos ao fim do ano de 2015. Registou 107 respostas individuais e 27 serviços. Resultados: O ratio de endocrinologistas por 100 000 habitantes era de 1,4, muito inferior a outros países europeus (varia de 2 a 4), que resulta numa carência grave de serviços em algumas zonas do País e em piores indicadores de qualidade. Discussão: Estes dados indicam que devem ser implementadas medidas para aumentar o número de endocrinologistas e serviços em Portugal. Conclusão: Nos últimos anos, o número de internos tem vindo a aumentar, o que vai permitir melhorar esta situação.

Hypogonadotropic hypogonadism in human immunodeficiency virus-infected men: uncommonly low testosterone levels.

Hypogonadotropic hypogonadism (HH) is common and occurs prematurely in HIV-infected men. However, HH with very low testosterone has not been described. Three men with normal pubertal development and HIV1 diagnosis at the ages of 22, 34 and 35 years. All complained of decreased libido, anejaculation and erectile dysfunction thirteen years, six months and one year after HIV diagnosis, respectively. Two had depressive syndrome and two were treated with antiretroviral therapy. Laboratory tests revealed isolated HH in all. Sellar and head CT scans were normal and all had normal CD4 count. They started testosterone replacement therapy, with symptoms improvement. Causes of HH in HIV-infected men include undernutrition, severe illness, drugs, pituitary dysfunction and comorbidities. Despite having none of these conditions (except two that were treated with low-dose psychotropics), our patients had HH with uncommonly low testosterone. This suggests that a different mechanism contributes to severe HH in HIV-infected men. LEARNING POINTS: The pathogenesis of hypogonadotropic hypogonadism in HIV-infected men is multifactorial and androgen deficiency is more often a consequence of secondary hypogonadism than primary hypogonadism.Causes of hypogonadotropic hypogonadism in HIV-infected men include undernutrition, severe illness, drugs (psychotropics, opiates, megestrol acetate or steroids), pituitary dysfunction (tumor, hyperprolactinemia), an AIDS-related lesion (very rarely) and comorbid conditions, such as antibody to hepatitis C virus seropositivity and injection drug use.Highly active antiretroviral therapy (HAART), particularly protease inhibitor therapy has been associated with sexual dysfunction in men, but the causal nature of this relation has not been clearly established.Hypogonadotropic hypogonadism with uncommonly low testosterone levels are not usually associated with the conditions referred and this suggests that a different mechanism could contribute to severe hypogonadotropic hypogonadism in HIV-infected men.Screening for hypogonadism in all HIV-infected men might help to understand its etiology.

The main autoimmune and nonautoimmune etiologies of endogenous hyperthyroidism do not seem to influence the increased prevalence of morphometric vertebral fractures and osteoporosis in Portuguese men.

OBJECTIVES: The purpose of this study was to evaluate the effects of hyperthyroidism and their etiology on bone mineral density (BMD), on body soft tissue composition, on the prevalence of vertebral fractures detected by vertebral fracture assessment (VFA) and on the trabecular bone score (TBS). METHODS: From an initial population of 119 Portuguese men (78 with hyperthyroidism [HT]+ 41 controls [CTs]) admitted to the Endocrinology Department we selected 41 men aged over 50 with clinical hyperthyroidism to participate; each one was matched by age and height with a control person. BMD (g/cm2) at the lumbar spine, hip, radius 33% and whole body and the total body masses (kg) were studied by dual-energy X-ray absorptiometry (DXA). VFA with Genant semiquantitative method was used to detect fractures. The TBS was obtained from lumbar spine DXA images. No patient had been treated previously for hyperthyroidism or osteoporosis. Adequate statistical tests were used. RESULTS: In the hyperthyroidism group, total lean mass (CT 58.16 ± 7.7 vs. HT 52.3 ± 5.7, P = 0.03) and distal radius BMD (CT 0.769 ± 0.05 vs. HT 0.722 ± 0.08, P = 0.005) were lower; there was a significantly higher prevalence of osteoporosis (CT 9.7% vs. HT 29.3%, P = 0.015) and vertebral fractures (CT 2.4% vs. HT 24.4%, P = 0.007). TBS was similar in both groups (CT 1.328 ± 0.11 vs. HT 1.356 ± 0.11, P = not significant). Comparing patients with Graves' disease with patients with toxic goiter, there were no differences regarding BMD, BMD qualification, prevalence of fractures and TBS and just total lean mass was significantly lower in patients with Graves' disease. CONCLUSIONS: These results suggest that in a group of hyperthyroid men aged over 50 there are significant decreases in cortical bone BMD and lean mass and a higher prevalence of osteoporosis and silent vertebral fractures, but the etiology of the hyperthyroidism does not seem to influence it. Besides the antithyroid drugs, some patients may benefit from bone-directed treatments.

A WNK4 gene variant relates to osteoporosis and not to hypertension in the Portuguese population.

Germline mutations in the WNK4 gene originate Gordon syndrome or pseudohypoaldosteronism type II, a familial form of hypertension with hyperkalemia and hypercalciuria. In order to elucidate the contribution of WNK4 genetic variants to hypertension and/or osteoporosis, we analyzed 271 control individuals and a cohort of 448 hypertensive and 372 osteoporosis patients from the Portuguese population. Ten genetic variants were detected in 4.3% of the population under study, none of which revealed any significant association to the hypertension phenotype. In contrast, a rare missense alteration within exon 17 in a highly conserved arginine residue showed a possible tendency for association to the osteoporosis group. Our data suggest that WNK4 polymorphism rs56116165 is a rare allelic variant in a candidate gene with a biological function in renal calcium homeostasis that may contribute to a genetic predisposition to osteoporosis.

Clinical and genetic characterization of Portuguese patients with pseudohypoparathyroidism type Ib.

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) present hypocalcemia and hyperphosphatemia, as a consequence of a resistance to PTH action, through its G-protein-coupled receptor, in the renal tubules. This resistance results from tissue-specific silencing of the G-protein alpha-subunit (G(s)α), due to imprinting disruption of its encoding locus--GNAS. In familial PHP-Ib, maternally inherited deletions at the STX16 gene are associated to a regional GNAS methylation defect. In sporadic PHP-Ib, broad methylation changes at GNAS arise from unknown genetic causes. In this study, we describe the clinical presentation of PHP-Ib in four Portuguese patients (two of whom were siblings), and provide further insight for the management of patients with this disease. The diagnosis of PHP-Ib was made after detection of GNAS imprinting defects in each of the cases. In the siblings, a regional GNAS methylation change resulted from a known 3.0 kb STX16 deletion. In the other two patients, the broad methylation defects at GNAS, which were absent in their relatives, resulted from genetic alterations that remain to be identified. We report the first clinical and genetic study of Portuguese patients with PHP-Ib. The genetic identification of a hereditary form of this rare disease allowed an early diagnosis, and may prevent hypocalcemia-related complications.

ACP1 genotype, glutathione reductase activity, and riboflavin uptake affect cardiovascular risk in the obese.

Erythrocyte acid phosphatase (ACP locus 1), also known as low-molecular-weight protein tyrosine phosphatase, has previously been associated to glycemia, dyslipidemia, and obesity. In this study, ACP1 genotype and activity were tested in 318 women aged 19 to 83 (mean, 51.74 +/- 13.44) years. ACP1 genotype was found to directly correlate to glutathione reductase activity (P < .001) and levels of low-density lipoprotein cholesterol (P = .038). Glutathione reductase activity was in turn found to correlate to a series of cardiovascular risk factors such as systolic arterial pressure (P < .001), total cholesterol levels (P = .018), and low-density lipoprotein cholesterol levels (P = .039). A possible protective effect of ACP1 genotype AA against these cardiovascular risk factors was observed in this study. Furthermore, this work hypothesizes that nutritional riboflavin uptake becomes more crucial as body mass index increases, to counteract oxidative stress and minimize cardiovascular risk. This might be especially true in ACP1 genotypes AC, BC, and CC, which might possibly show the least endogenous protection against oxidative stress.

CYP21A2 mutations in Portuguese patients with congenital adrenal hyperplasia: identification of two novel mutations and characterization of four different partial gene conversions.

More than 90% of congenital adrenal hyperplasia (CAH) cases are caused by 21-hydroxylase deficiency. In this study, the CYP21 gene was genotyped in 56 Portuguese unrelated patients with clinical symptoms of 21-hydroxylase deficiency, in a total of 112 independent alleles. CYP21A2 mutations were identified in 99.1% of the alleles. The most common point mutation was 1688G>T (25.9%). A previously unreported partial gene conversion, extending from exon 1 to 7, was found in 16.1% of the alleles, in most cases associated to the mutation 1688G>T in the other chromosome, and in patients with nonclassical CAH. Other three distinct partial gene conversions were also identified, with lower frequencies: one extends from exon 1 to 3 and the others from exons 3 to 7 and 3 to 8. Two novel mutations were identified in two salt-wasting patients: a putative splicing mutation, IVS2+5G>A, and the transition 2557C>T, that gives rise to the nonsense mutation R445X. Seven point mutations and a partial gene conversion were responsible for 88 of the studied disease causing alleles, and the overall concordance between genotype and phenotype was 92.9%. With this study the molecular basis of CAH was characterized, for the first time, in Portuguese patients, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling.