Agathocles Tsatsoulis

Association of Polymorphisms of the Estrogen Receptor α Gene With Bone Mineral Density and Fracture Risk in Women: A Meta-Analysis†

The contribution of genetic polymorphisms to bone mineral density (BMD) and fracture risk in women is a controversial topic. We evaluated the effect of the XbaI and PvuII polymorphisms of the estrogen receptor α to BMD and fracture risk in a meta‐analysis, including published data and additional information from investigators. Five thousand eight hundred thirty‐four women from 30 study groups were analyzed with fixed and random effects models. The PvuII polymorphism was not associated with BMD at any skeletal site examined and 95% CIs exclude effects over 0.015 g/cm2 for both the femoral neck and the lumbar spine. Conversely, XX homozygotes (women carrying two copies of the gene variant without an XbaI restriction site) consistently had higher BMD than other subjects. The magnitude of the effect was similar in the femoral neck and lumbar spine (0.014 g/cm2 [95% CI, 0.003–0.025] and 0.015 g/cm2 [95% CI, 0.000–0.030], respectively; no between‐study heterogeneity for either). Total body BMD was also significantly higher in XX homozygotes (by 0.039 g/cm2 and 0.029 g/cm2 compared with Xx and xx, respectively). Available data on fractures suggested a protective effect for XX (odds ratio [OR], 0.66 [95% CI, 0.47–0.93] among 1591 women), but not PP (OR, 0.93 [95% CI, 0.72–1.18] among 2229 women). In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk.

Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in the GNAS exons encoding the G protein alpha subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.

The protective role of exercise on stress system dysregulation and comorbidities.

Abstract:  The human body, when under threat, elicits a set of neuroendocrine responses, including an increased secretion of glucocorticoids (GCs) and catecholamines from the adrenal gland and the activation of the sympathetic nervous system. These hormonal secretions allow a “fight or flight” response by mobilizing endogenous substrate and inducing a state of insulin resistance in the liver and skeletal muscles. Although the stress response was essential in ancient times to survive physical aggression, this threat has disappeared in our industrialized societies. However, in todays environment, the same stress responses can be elicited by emotional stimuli or professional and social stress. Such psychological stress may be protracted and unrelated to an increased metabolic demand. Thus, the energy mobilized is not used but is stored in visceral fat depots by the combined action of hypercortisolism and hyperinsulinemia. In addition, chronic activation of the stress system causes suppression of the gonadal, growth hormone (GH), and thyroid axes. These metabolic disturbances, in concert, lead to the clinical expression of a number of comorbidities including central obesity, hypertension, dyslipidemia, and endothelial dysfunction, all components of the metabolic syndrome and cardiometabolic risk factors. Moreover, chronic stress has deleterious effects on the brain and, in particular, affects hippocampal structure and function leading to cognitive and mood disturbances. Importantly, this stress‐induced clinical phenotype is likely to be exaggerated in the presence of physical inactivity, resulting in a “stress‐induced/exercise deficient” phenotype. Assuming that the stress response is a neuroendocrine mechanism that occurs in anticipation of physical action, then physical activity should be the natural means to prevent the consequences of stress. Indeed, accumulating evidence documents the beneficial effects of regular exercise in preventing or ameliorating the metabolic and psychological comorbidities induced by chronic stress. These benefits are thought to derive from a central effect of exercise to reduce the sensitivity to stress and also peripheral actions influencing metabolic functions and, in particular, insulin sensitivity and the partitioning of fuels toward oxidation rather than storage. It is concluded that chronic psychosocial stress, in the presence of physical inactivity, is likely to contribute to the epidemic of cardiometabolic and emotional disease of our current society. The way to prevent and combat this burden is by regular exercise.

Clinical Phenotype and Mutant TRα1

A father and daughter with a mutation in the nuclear receptor gene for thyroid hormone (THRA) have abnormal levels of thyroid hormone, normal thyrotropin levels, growth retardation, and mildly delayed motor and cognitive development.

High prevalence of autoimmune thyroiditis in schoolchildren after elimination of iodine deficiency in northwestern Greece.

The current iodine status and the impact of silent iodine prophylaxis on the prevalence of autoimmune thyroiditis among schoolchildren in a formerly iodine-deficient community in northwestern Greece, were investigated. The findings were compared to those obtained from a similar survey conducted 7 years previously in the same area. A total of 302 schoolchildren (12-18 years of age) from a mountainous area of northwestern Greece were examined for the presence of goiter, and blood and urine samples were collected for assessment of thyroid function, antithyroid antibodies and urinary iodine excretion. In those children (n = 42) with palpable goiter or positive antibodies and/or a thyrotropin (TSH) level greater than 5 mU/L, thyroid ultrasonography was performed to estimate thyroid gland size and morphology. Median urinary iodine concentration in the children was 20.21 microg/dL, indicating sufficient iodine intake. Thyroid function was normal in all but 7 children, who had subclinical hypothyroidism (2.5%). Antithyroid antibodies (antithyroid peroxidase [TPO] and/or antithyroglobulin [Tg]) were positive in 32 children, including those with subclinical hypothyroidism (10.6%). Twenty-nine of these children (9.6%) also had the characteristic echo pattern of thyroiditis on ultrasound and were diagnosed to have autoimmune thyroiditis. In comparison to data from our previous survey 7 years ago, there has been a threefold increase in the prevalence of autoimmune thyroiditis among schoolchildren. In conclusion, silent iodine prophylaxis has resulted in the elimination of iodine deficiency in Greece, and this has been accompanied by an increase in the prevalence of autoimmune thyroiditis.

Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women

The contribution of genetic polymorphisms to bone mineral density (BMD) and fracture risk in women is a controversial topic. We evaluated the effect of the XbaI and PvuII polymorphisms of the estrogen receptor α to BMD and fracture risk in a meta‐analysis, including published data and additional information from investigators. Five thousand eight hundred thirty‐four women from 30 study groups were analyzed with fixed and random effects models. The PvuII polymorphism was not associated with BMD at any skeletal site examined and 95% CIs exclude effects over 0.015 g/cm2 for both the femoral neck and the lumbar spine. Conversely, XX homozygotes (women carrying two copies of the gene variant without an XbaI restriction site) consistently had higher BMD than other subjects. The magnitude of the effect was similar in the femoral neck and lumbar spine (0.014 g/cm2 [95% CI, 0.003–0.025] and 0.015 g/cm2 [95% CI, 0.000–0.030], respectively; no between‐study heterogeneity for either). Total body BMD was also significantly higher in XX homozygotes (by 0.039 g/cm2 and 0.029 g/cm2 compared with Xx and xx, respectively). Available data on fractures suggested a protective effect for XX (odds ratio [OR], 0.66 [95% CI, 0.47–0.93] among 1591 women), but not PP (OR, 0.93 [95% CI, 0.72–1.18] among 2229 women). In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk.

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.

Association of Collagen Iα 1 Sp1 Polymorphism with the Risk of Prevalent Fractures: A Meta‐Analysis

Several studies have addressed the effect of the Sp1 polymorphism of the collagen Iα 1 (COLIA1) gene on the prevalence of fractures. The results are not in full agreement on whether this polymorphism is associated with fracture risk. To clarify this uncertainty, we performed a meta‐analysis including 13 eligible studies with 3641 subjects. The COLIA1 Sp1 polymorphism showed a dose‐response relationship with the prevalence of fractures. The risk was 1.25‐fold (95% CI, 1.09–1.45) in Ss heterozygotes versus SS homozygotes, 1.68‐fold (95% CI, 1.35–2.10) in ss homozygotes versus SS> homozygotes, and 1.35 (95% CI, 1.04–1.75) for ss homozygotes versus Ss heterozygotes by random effects calculations. There was modest heterogeneity for these three effect estimates (p value for heterogeneity, 0.17, 0.16, and 0.08, respectively). The Sp1 polymorphism effects possibly were larger when the analysis was limited to studies considering only vertebral fractures (pooled risk ratios [RR], 1.30, 2.07, and 1.46, respectively). Conversely, the Sp1 polymorphism effects tended to be smaller in studies with mean patient age ≥65 years than in studies with younger patients on average, but the differences were not formally significant. We estimated the total average attributable fraction (AF) of fractures due to the s allele in European/U.S. populations as 9.4%. The meta‐analysis suggests an important role for the Sp1 polymorphism in the regulation of fracture risk; however, potential heterogeneity across ethnic groups, age groups, and skeletal sites may be important to clarify in future studies. Very large studies or meta‐analyses are required to document subtle genetic differences in fracture risk.

Fetal origins of the metabolic syndrome.

The natural history of metabolic syndrome and polycystic ovary syndrome (PCOS), which shares many components of metabolic syndrome, may originate in intrauterine life. Evidence from epidemiological observations, clinical, and experimental animal studies suggest that the nutritional, hormonal, and metabolic environment afforded by the mother may permanently program differentiating target tissues of the offspring toward the development of metabolic syndrome/PCOS phenotype in adult life. The mechanisms of fetal programming are not well understood. Thus, the altered tissue differentiation may be the result of fetal adaptive responses representing homeostatic adaptations due to alterations in fetal nutrition. Also, tissues under the influence of androgen excess may be directed toward a more masculine phenotype with regard to reproductive, neuroendocrine, and metabolic traits, while the importance of epigenetics in fetal origin of metabolic syndrome/PCOS cannot be overlooked.

Insulin resistance: An adaptive mechanism becomes maladaptive in the current environment — An evolutionary perspective

Human survival has relied upon the ability to withstand starvation through energy storage, the capacity to fight off infection by a proinflammatory immune response, and the ability to cope with physical stressors by an adaptive stress response. Energy storage, mainly as glycogen in liver and triglycerides in adipose tissue, is regulated by the anabolic actions of insulin. On the other hand, mobilization of stored energy during infection, trauma or stress is served by the temporary inhibition of insulin action (insulin resistance) in target tissues by proinflammatory cytokines and stress hormones. In the current environment, high energy intake, low physical activity, and chronic stress favor the storage of surplus fat in adipose tissue depots that far exceeds their storage capacity and liporegulation. Lipid overload in central fat depots initiates an inflammatory response and adipocyte dysfunction with resultant low-grade systemic inflammation and lipid overflow to peripheral tissues. In turn, proinflammatory cytokines and non-oxidized lipid metabolites, accumulated in liver and muscle cells, activate the mechanism of insulin resistance as would occur in the case of infection or stress. The same factors together with the ensuing insulin resistance further contribute to pancreatic β-cell dysfunction and ultimately to type 2 diabetes and cardiovascular disease. The present review supports the hypothesis that insulin resistance evolved as a physiological adaptive mechanism in human survival and that the same mechanism is inappropriately activated on a chronic basis in the current environment, leading to the manifestations of the metabolic syndrome.