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Objectives: The aim of this study was to analyze bone mineral density (BMD) changes throughout aromatase inhibitor (AI) treatment in clinical cases and also consider its association with the CYP11A1 gene and the BMD variation after treatment. Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer, in AI treatment. BMD variation was analyzed during AI treatment, as well as the differences those patients who were treated and not treated previously with tamoxifen (TMX). Three polymorphisms (rs4077581, rs11632698 and rs900798) of the CYP11A1 gene were genotyped for their association with BMD variation. Results: TMX-treated patients presented more rapid BMD loss than those who did not undergo prior TMX treatment (60% less in spine and 46% in femur at 2 years and 70% less in the spine and 63% in the femur at 3 years). However, no significant BMD loss was detected after treatment in either group. The 3 CYP11A1 gene polymorphisms were significantly associated with BMD variation in the femur at the end of the treatment. Conclusions: BMD was reduced more rapidly in patients with prior TMX treatment than in those who only received AI, although no significant differences were detected after treatment. The 3 CYP11A1 gene polymorphisms were associated with BMD variation in response to AI treatment. [ABSTRACT FROM AUTHOR]

Polycaprolactone scaffolds modified with cross-linked hyaluronic acid were prepared in order to establish whether a more hydrophilic and biomimetic microenvironment benefits the progenitor cells arriving from bone marrow in a cell-free tissue-engineering approach. The polycaprolactone and polycaprolactone/hyaluronic acid scaffolds were characterized in terms of morphology and water absorption capacity. The polycaprolactone and polycaprolactone/hyaluronic acid samples were implanted in a chondral defect in rabbits; bleeding of the subchondral bone was provoked to generate a spontaneous healing response. Repair at 1, 4, 12, and 24 weeks was assessed macroscopically using the International Cartilage Repair Society score and the Oswestry Arthroscopy Score and microscopically using immunohistological staining for collagen type I and type II, and for Ki-67. The presence of hyaluronic acid improves scaffold performance, which supports a good repair response without biomaterial pre-seeding. [ABSTRACT FROM AUTHOR]

Objectives: The RANK/RANKL/OPG system is involved in the determination of bone mineral density (BMD) and bone microarchitecture. Our study seeks to evaluate if there are SNPs in the 3'UTR region of the RANK gene associated with osteoporotic phenotypes. Material and methods: Seven genetic variants in 1,098 women from the BARCOS cohort were genotyped, and their association with BMD and osteoporotic fractures evaluated. An interaction with SNP rs9594738 in the RANKL gene which was previously associated with BMD was tested. Results: None of the SNPs were associated significantly with BMD. SNP rs78326403 was associated with wrist/forearm fractures (Log-additive model odds ratio (OR)=3.12 [IC 95%: 1.69 ; 5.75]; p=7.16x10-4), while SNP rs884205 was associated with fractures of the spinal column (OR=4.05 Recessive; [95% CI: 1.59 ; 10.35]; p=8.24x10-3). Lastly, an interaction was detected between SNP rs9594738 from RANKL and rs78326403 from RANK on the presence of fracture (p=0.039). The analysis of the effects of combined genotypes rs9594738 and rs78326403 pointed to an increase in the prevalence of fractures in subjects with a greater number of unfavourable alleles, the ORs being 2.76 [95% CI: 1.30 ; 5.81]; p=0.007) and 5.14 [95% CI: 1.37 ; 15.67]; p=0.007) for 2 and ≥3 unfavourable alleles respectively, in comparison with none/1. Conclusions: Two SNPs in 3'UTR from the RANK gene predispose to site-dependent osteoporotic fracture. An interaction with SNP rs9594738 from RANKL suggests an additive effect of BMD and bone strength. [ABSTRACT FROM AUTHOR]

Introduction: People with HIV (PWH) with poor immune response despite adequate antiretroviral treatment (ART) are susceptible to non-AIDS-related health issues. This study seeks to evaluate bone quality in Immunological Non-Responders (INRs) in comparison to those with proper immune response (IRs) using in vivo microindentation to quantify bone quality, in addition to conventional bone mineral density (BMD) evaluations., Methods: A cross-sectional study was conducted at Hospital del Mar in Barcelona from January 2019 to June 2023. Participants were matched in a 1:2-ratio (INRs:IR) based on age, sex, body mass index (BMI), and ART. Participants underwent bone quality assessment using in vivo microindentation, BMD and analysis of bone turnover and inflammation markers. Statistical analyses involved multivariable regression to adjust for potential confounding variables., Results: A total of 159 PWH were included, 53 INRs and 106 IRs. INRs had worse bone quality, with lower median Bone Material Strength index (BMSi) compared to IRs (79 (76-87) vs. 86 (82-89); p<0.001), and similar BMD. INRs shown increased high-sensitive C-Reactive Protein levels with lower 25-(OH)-Vitamin D3. A significant negative correlation between inflammation and bone quality was found, especially noticeable in INRs. Multivariable linear regression shown that INR status is a major predictor of decreased bone quality, regardless of conventional risk factors., Conclusion: INRs condition is significantly associated with higher inflammatory levels, which may contribute to a deleterious effect on bone quality as measured by in vivo microindentation. Further studies are needed to confirm these results and to focus on non-AIDS comorbidities in this subgroup of PWH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

People living with human immunodeficiency virus (HIV) are the individuals most affected by the current Monkeypox virus outbreak that was first announced in May 2022. Here we report Pan-pox-specific T-cell responses in a cohort of HIV-1-infected individuals after receiving the nonreplicative, attenuated smallpox vaccine JYNNEOS from Bavarian Nordic. Intradermal (i.d.) and subcutaneous (s.c.) vaccination was safe without major side effects. Dose-sparing i.d. vaccination was superior to s.c. vaccination and promoted T-cell polyfunctionality, and the expression of the gut-homing marker α4β7 integrin on lymphocytes. HIV-1-infected individuals with CD4 T-cell counts ≤500/mm 3 blood required at least a booster vaccination to exhibit efficient virus-specific T-cell responses. The magnitude of the Th1 response after this booster directly correlated with the CD4 T-cell count of the vaccinees. Further studies with a larger number of participants are warranted to confirm and expand our observations., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: CD4/CD8 ratio has been used as a quantitative prognostic risk factor in patients with viral infections. This study aims to assess the association between in-hospital mortality and at admission CD4/CD8 ratio among individuals with acute SARS-CoV-2 infection., Methods: This is a longitudinal cohort study with data of all consecutive patients admitted to the COVID-19 unit at Hospital del Mar, Barcelona, Spain for ≥48 h between March to May 2020. The CD4+ CD8+ T-cell subset differentiation was assessed by flow cytometry at admission as well as a complete blood test. Patients were classified according to CD4/CD8 ratio tertiles. The primary outcome was in-hospital mortality and the secondary outcome was acute respiratory distress (ARDS)., Results: A total of 338 patients were included in the cohort. A high CD4/CD8 ratio (third tertile) was associated with a higher in-hospital mortality [adjusted Cox model hazard ratio (HR) 4.68 (95%CI 1.56-14.04, p = 0.006), reference: second tertile HR 1]. Similarly, a high CD4/CD8 ratio (third tertile) was associated with a higher incidence of ARDS [adjusted logistic regression model OR 1.97 (95%CI 1.11-3.55, p = 0.022) reference: second tertile HR 1]. There was a trend of higher in-hospital mortality and incidence of ARDS in patients within the first tertile of CD4/CD8 ratio compared with the second one, but the difference was not significant. No associations were found with total lymphocyte count or inflammatory parameters, including D-dimer., Conclusion: CD4/CD8 ratio is a prognostic factor for the severity of COVID-19, reflecting the negative impact on prognosis of those individuals whose immune response has abnormal CD8+ T-cell expansion during the early response to the infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pascual-Dapena, Chillaron, Llauradó, Arnau-Barres, Flores, Lopez-Montesinos, Sorlí, Luis Martínez-Pérez, Gómez-Zorrilla, Du, García-Giralt and Güerri-Fernández.)

Serum albumin levels have been associated with prognosis in several conditions among older adults. The aim of this study is to assess the prognostic value in mortality of serum albumin in older adults with SARS-CoV-2 infection., Methods: Cohort observational study with consecutive older-adults (≥65 years old), with confirmed SARS-CoV-2 infection admitted to a university hospital between March-May 2020. A logistic regression model was fitted to assess the impact of albumin levels on in-hospital mortality adjusted by potential confounders., Results: Among a total of 840 patients admitted to the hospital, 405 (48%) were older adults with a total of 92 deaths (23%) among them. Those who died were older, had more comorbidities, higher inflammation status and lower levels of serum albumin at admission [3.10 g/dL (0.51) vs. 3.45 g/dL (0.45); p < 0.01. Serum albumin levels at admission were negatively correlated with inflammatory markers such as C-Reactive protein (Pearson Coeff -0.4634; p < 0.001) or IL-6 (Pearson's Coeff -0.244; p = 0.006) at admission but also to other clinical outcomes such time to clinical stability (Pearson's Coeff -0.259; p < 0.001). Severe hypoalbuminemia associated with increased risk of mortality was defined as ≤3 g/dL at admission according to the AUC/ROC analysis (0.72 95% CI 0.63-0.81) In a multivariate logistic regression model adjusting by age, inflammation, comorbidities and severity at admission severe hypoalbuminemia was a strong predictor of in-hospital mortality (OR 2.18 95% CI 1.03-4.62; p = 0.039)., Conclusion: Severe hypoalbuminemia with ≤3 g/dL is an independent risk factor for mortality among older adults with SARS-CoV-2 infection. There is a consistent correlation between albumin levels and inflammatory biomarkers. Further studies are needed to determine whether the supplementation of albumin as coadjuvant treatment will have a positive impact on the prognosis of this infection.

Myocardial involvement during SARS-CoV-2 infection has been reported in many prior publications. We aim to study the prevalence and the clinical implications of acute myocardial injury (MIN) during SARS-CoV-2 infection, particularly in older patients. The method includes a longitudinal observational study with all consecutive adult patients admitted to a COVID-19 unit between March-April 2020. Those aged ≥65 were considered as older adult group. MIN was defined as at least 1 high-sensitive troponin (hs-TnT) concentration above the 99th percentile upper reference limit with different sex-cutoff. Results. Among the 634 patients admitted during the period of observation, 365 (58%) had evidence of MIN, and, of them, 224 (61%) were older adults. Among older adults, MIN was associated with longer time to recovery compared to those without MIN (13 days (IQR 6-21) versus 9 days (IQR 5-17); p < 0.001, respectively. In-hospital mortality was significantly higher in older adults with MIN at admission versus those without it (71 (31%) versus 11 (12%); p < 0.001). In a logistic regression model adjusting by age, sex, severity, and Charlson Comorbidity Index, the OR for in-hospital mortality was 2.1 (95% CI: 1.02-4.42; p = 0.043) among those older adults with MIN at admission. Older adults with acute myocardial injury had greater time to clinical recovery, as well as higher odds of in-hospital mortality.

Background: Zinc is an essential micronutrient that impacts host-pathogen interplay at infection. Zinc balances immune responses, and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with an increased risk for severe severe coronavirus disease 2019 (COVID-19) outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression, and thus might represent a useful biomarker., Methods: We ran an observational cohort study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel, we have studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) replication in the Vero E6 cell line modifying zinc concentrations., Findings: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV-2 infected cells., Interpretation: Low SZC is a risk factor that determines COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.

Background: Bone mineral density (BMD) decreases with ART initiation with a tenofovir disoproxil fumarate-containing regimen, although bone tissue quality increases. The impact of dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC)-based ART initiation on bone health parameters is not clear., Objectives: To study the impact of DTG/ABC/3TC-based therapy on bone health parameters in ART-naive individuals with HIV after 48 weeks of treatment., Methods: An observational, prospective and analytical study of treatment-naive patients with HIV undergoing a DTG/ABC/3TC-based regimen at 48 week follow-up. Changes in bone strength parameters (BMD, bone microarchitecture and bone tissue quality) were assessed with non-parametric methods., Results: Sixteen HIV-infected ART-naive patients starting DTG/ABC/3TC were included. BMD in the lumbar spine showed a significant decrease of -2.25% (P = 0.007) and -4.1% in the femoral neck (P = 0.007). Bone microarchitecture, as measured by trabecular bone score, also decreased significantly by -2.5% (P = 0.03). In contrast, bone quality [bone material strength index (BMi)], as measured by microindentation, significantly increased with respect to baseline after 48 weeks of treatment, showing better bone properties of +6.53% (P < 0.001). No significant changes were found in bone turnover markers. In addition, a positive significant correlation between the CD4/CD8 cell count ratio at baseline and changes in BMSi after 48 weeks of treatment was observed (Spearman's rho = 0.4974; P = 0.04)., Conclusions: After a 48 week treatment with DTG/ABC/3TC-based ART, BMD and trabecular bone score decreased while bone tissue quality, as measured by microindentation, improved significantly. The state of the immune system at ART initiation is related to bone quality recovery. An overarching approach to assess bone toxicity in ART-treated patients is needed., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Monoclonal gammopathy of uncertain significance (MGUS) is highly prevalent in older adults and affects bone structure, with osteoporosis and increased risk of fractures in up to 14% of affected patients. Dual-energy X-ray absorptiometry (DXA), the standard technique for diagnosing osteoporosis, is ineffective to reveal microstructure and bone quality in this disease., Materials and Methods: We conducted a cross-sectional study of patients with MGUS, recruited consecutively from the Hematology and Internal Medicine Departments of Hospital del Mar, Barcelona, between January 2011 and January 2018. Medical records, clinical results and spinal X-ray images were collected. Bone mineral density (BMD) at hip and spine was measured by DXA and Bone Material Strength index (BMSi) by impact microindentation on the tibial mid-shaft., Results: Thirty-nine patients with MGUS and 65 age-matched controls without previous fractures were included. In the MGUS group, 11 (28.2%) patients had prevalent fractures, nearly half of them vertebral (n = 5, 45.45%). Compared to controls, MGUS patients had significantly lower BMSi, a mean (SD) of 70.72 (9.70) vs. 78.29 (8.70), p = 0.001, and lower spinal BMD values (0.900 [0.159] vs. 1.003 [0.168], respectively, p = 0.012), but no significant differences at femoral neck and total hip. No association was observed between BMSi and DXA. Bone remodeling markers (procollagen type-1 N propeptide, bone-alkaline phosphatase and C-terminal telopeptide of type I collagen) did not differ between the two groups., Conclusions: Spinal BMD and mechanical properties of bone tissue, as measured by impact microindentation, were impaired in patients with MGUS. These changes in bone tissue mechanical resistance were independent of DXA levels.

Background Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis. Aims Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters. Patients and methods Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR. Results In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001). Conclusions Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.

Numerous GWAS and candidate gene studies have highlighted the role of the Wnt pathway in bone biology. Our objective has been to study in detail the allelic architecture of three Wnt pathway genes: WNT16, DKK1 and SOST, in the context of osteoporosis. We have resequenced the coding and some regulatory regions of these three genes in two groups with extreme bone mineral density (BMD) (n = ∼50, each) from the BARCOS cohort. No interesting novel variants were identified. Thirteen predicted functional variants have been genotyped in the full cohort (n = 1490), and for ten of them (with MAF > 0.01), the association with BMD has been studied. We have found six variants nominally associated with BMD, of which 2 WNT16 variants predicted to be eQTLs for FAM3C (rs55710688, in the Kozak sequence and rs142005327, within a putative enhancer) withstood multiple-testing correction. In addition, two rare variants in functional regions (rs190011371 in WNT16b 3'UTR and rs570754792 in the SOST TATA box) were found only present in three women each, all with BMD below the mean of the cohort. Our results reinforce the higher importance of regulatory versus coding variants in these Wnt pathway genes and open new ways for functional studies of the relevant variants.

Objecive: Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is used to assess bone health in HIV patients. DXA measures the amount of mineral, but not other key aspects of bone strength such as bone microarchitecture or bone quality. Trabecular bone score (TBS) and in-vivo microindentation directly measure trabecular microarchitecture and bone tissue quality, respectively. The aim of this study is to measure bone strength properties using these techniques., Results: Forty naive HIV patients who were going to start antiretroviral therapy (ART), a single pill treatment with elvitegravir/cobicistat, tenofovir disoproxil fumarate (TDF), emtricitavine (FTC) were included. A significant reduction in BMD at spine (-3.25%, P < 0.001) and in femoral neck (-3.82%, P = 0.016) between baseline and 48 weeks of treatment were found. Bone microarchitecture score at the spine, as measured by TBS, also significantly decreased from 1.357 (0.09) to 1.322 (0.09) (-2.5%, P = 0.011) between baseline to 48 weeks of treatment. Microindentation (BMSi) values were significantly higher than at baseline [89.04 (4.2) versus 86.07 (6.1); 3.49%, P < 0.001] after 48 weeks of TDF-based ART treatment, indicating improved bone material properties CONCLUSION:: A significant decrease in BMD and TBS were observed after 1 year of TDF therapy. However, tissue quality significantly improved after 1 year of treatment, suggesting a recovery of bone material properties following the control of the infection despite the significant reduction of BMD. These techniques provide additional and necessary information to DXA about bone health in treated HIV patients, and because of its convenience and feasibility they could be routinely apply to assess bone in clinical practice.

Objectives: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis., Methods: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies., Results: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10 -9 ) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures., Conclusion: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Atypical femoral fractures (AFF) associated with long-term bisphosphonates (LTB) are a growing concern. Their etiology is unknown, but bone material properties might be deteriorated. In an AFF series, we analyzed the bone material properties by microindentation. Four groups of patients were included: 6 AFF, 38 typical osteoporotic fractures, 6 LTB, and 20 controls without fracture. Neither typical osteoporotic fractures nor controls have received any antiosteoporotic medication. A general laboratory workup, bone densitometry by dual-energy X-ray absorptiometry (DXA), and microindentation testing at the tibia were done in all patients. Total indentation distance (Total ID), indentation distance increase (IDI), and creep indentation distance (Creep ID) were measured (microns). Age-adjusted analysis of covariance (ANCOVA) was used for comparisons. Controls were significantly younger than fracture groups. Bisphosphonate exposure was on average 5.5 years (range 5 to 12 years) for the AFF and 5.4 years (range 5 to 8 years) for the LTB groups. Total ID (microns) showed better material properties (lower Total ID) for controls 36 (± 6; mean ± SD) than for AFF 46 (± 4) and for typical femoral fractures 47 (± 13), respectively. Patients on LTB showed values between controls and fractures, 38 (± 4), although not significantly different from any of the other three groups. IDI values showed a similar pattern 13 (± 2), 16 (± 6), 19 (± 3), and 18 (± 5). After adjusting by age, significant differences were seen between controls and typical (p < 0.001) and atypical fractures (p = 0.03) for Total ID and for IDI (p < 0.001 and p < 0.05, respectively). There were no differences in Creep ID between groups. Our data suggest that patients with AFF have a deep deterioration in bone material properties at a tissue level similar to that for the osteoporotic fracture group. The LTB group shows levels that are in between controls and both type of fractures, although not statistically different. These results suggest that bisphosphonate therapy probably does not put the majority of patients at risk for AFF., (Copyright © 2013 American Society for Bone and Mineral Research.)

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research., (Copyright © 2012 American Society for Bone and Mineral Research.)

Osteoporosis is a common disease with a strong genetic component. We previously described two polymorphic sites in the COL1A1 gene promoter, -1997 G/T and -1663indelT, which have been associated with bone mineral density (BMD), a surrogate trait for osteoporosis. Here, we explore the molecular mechanisms underlying this association by performing transient transfections in MG-63 cells of constructs bearing different COL1A1 promoter regions, containing different alleles or haplotypes of the polymorphic sites. These promoter regions drove the transcription of a luciferase reporter gene. The main differences in transcriptional activity relied on an inhibitory region localized to the -1284 to -254 interval. Regarding the polymorphisms, reproducible differences were observed between the alleles of each of them: the G allele at -1997 showed a higher transcriptional activity than the T allele, as did the 7T allele of -1663 as compared with 8T. Accordingly, the T-8T haplotype was the weakest transcriber. A functional interaction was found between the -1997 and -1663 polymorphisms, in that the difference in transcriptional activity between the 7T and 8T alleles was dependent on the allele at -1997. This different transcriptional activity of the two -1663indelT alleles correlated with different binding capacities of the corresponding oligonucleotides to osteoblast nuclear proteins. Supershift assays allowed us to identify one of these proteins as the architectural transcription factor Nmp4/CIZ, a protein known to be an inhibitor of BMP/Smad signalling.

Background: Factors related to hyperhomocystinemia in the pediatric population of our geographical area with a parental history of premature coronary disease (PCD) are not well known., Objectives: To evaluate the possible association between plasma total homocysteine (tHcy), the B vitamins involved in its metabolism (folate, vitamin B12 and B6), and 677C T polymorphism of methylenetetrahydrofolate reductase (MTHFR) in a group of children with a parental history of PCD., Methods: A cross-sectional analytical study of 80 children (aged 5-18 years old) with a parental history of PCD was performed. Values found in these children were compared with reference values for similar age groups. Plasma tHcy and vitamin B6 were evaluated by high-performance liquid chromatography with fluorometric detection. Folate and vitamin B12 concentrations were determined by radioimmunoassay. Detection of 677C T polymorphism of MTHFR was performed using polymerase chain reaction amplification and Hinfl digestion. Statistical analysis was performed using the SPSS program, version 10.0. Concentrations of tHcy and vitamins were compared using the Mann-Whitney U-test and Spearman's correlation coefficient. The association between phenotype, hyperhomocystinemia and low vitamin concentrations was analyzed using the chi-squared test. ResultsPlasma tHcy values in the children aged more than 10 years with a parental history of PCD were significantly higher (p < 0.001) than the reference values. Vitamin B12 levels were significantly lower (p 0.015), but neither folate nor vitamin B6 levels differed from the reference values. A negative correlation (p < 0.0001) was observed between tHcy and folate (r 0.47) and between tHcy and vitamin B12 levels (r 0.51). Eighty percent of the children with the TT genotype of MTHFR showed hyperhomocystinemia. Suboptimal vitamin B levels were also associated with the TT genotype of MTHFR., Conclusions: Hyperhomocystinemia detected in children with a parental history of PCD is associated with the TT genotype of MTHFR and with low folate levels. Because hyperhomocystinemia can be corrected by vitamin B supplementation, tHcy determination is recommended in the offspring of patients with PCD.