The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Le fratture dell'estremo prossimale dell'omero: incidenza e classificazioni

Fractures of the proximal humerus are common and their incidence increases with age and, consequently, with the degree of osteoporosis. Over time, many classification systems regarding these fractures have been proposed. The aim of classification is to define a fracture on the basis offixed parameters (morphologic characteristics and fracture pathoanatomy) that can be used for better understanding offracture severity, prognosis and potential surgical options. Most classifications are based on the X-ray appearance of the humeral head fracture on plain films; recently 3D-CT scans have complemented traditional radiograms. Neer developed a classification system based on fracture pathoanatomy and on the presence or absence of displacement of one or more of the four major bony segments (surgical neck, anatomic neck, greater and lesser tuberosity). The AO classification system included the concept ofperfusion of the articular segment. Edelson divided humeral head fractures into five basic types that correspond to some degree to the Neer classification, but dijfer significantly regarding the most complex patterns offracture. Furthermore, an interohserver reliability study indicated the improved usefulness of the 3-D concept in providing a common language among clinicians for classifying these injuries. Finally, Hertel developed a classification system for better understanding the predictors of humeral head ischemia. In conclusion, a fracture must be classified for understanding its severity and guiding the treatment. Radiographics are often not sufficient for establishing the number offragments and the entity of their dislocation. 3D-CT scans allow medial hinge condition and other predictors of humeral head ischemia to be better understood

Lipopolysaccharides from atherosclerosis-associated bacteria antagonize TLR4, induce formation of TLR2/1/CD36 complexes in lipid rafts and trigger TLR2-induced inflammatory responses in human vascular endothelial cells

Infection with bacteria such as Chlamydia pneumonia, Helicobacter pylori, or Porphyromonas gingivalis may be triggering the secretion of inflammatory cytokines that leads to atherogenesis. The mechanisms by which the innate immune recognition of these pathogens could lead to atherosclerosis remain unclear. In this study, using human vascular endothelial cells or HEK293 cells engineered to express pattern-recognition receptors (PRRs), we set out to determine Toll-like receptors (TLRs) and functionally associated PRRs involved in the innate recognition of and response to LPS from H. pylori or P. gingivalis. Using siRNA interference or recombinant expression of cooperating PRRs, we show that H. pylori and P. gingivalis LPS-induced cell activation is mediated through TLR2. Human vascular endothelial cell activation was found to be lipid-raft dependent and to require the formation of heterotypic receptor complexes comprising of TLR2, TLR1, CD36 and CD11b/CD18. In addition, we report that LPS from these bacterial strains are able to antagonise TLR4. This antagonistic activity of H. pylori or P. gingivalis LPS, as well as their TLR2 activation capability may be associated with their ability to contribute to atherosclerosis