ABSTRACT
Despite the high contagion and mortality rates that have accompanied the coronavirus disease-19 (COVID-19) pandemic, the clinical presentation of the syndrome varies greatly from one individual to another. Potential host factors that accompany greater risk from COVID-19 have been sought and schizophrenia (SCZ) patients seem to present more severe COVID-19 than control counterparts, with certain gene expression similarities between psychiatric and COVID-19 patients reported. We used summary statistics from the last SCZ, bipolar disorder (BD), and depression (DEP) meta-analyses available on the Psychiatric Genomics Consortium webpage to calculate polygenic risk scores (PRSs) for a target sample of 11,977 COVID-19 cases and 5943 subjects with unknown COVID-19 status. Linkage disequilibrium score (LDSC) regression analysis was performed when positive associations were obtained from the PRS analysis. The SCZ PRS was a significant predictor in the case/control, symptomatic/asymptomatic, and hospitalization/no hospitalization analyses in the total and female samples; and of symptomatic/asymptomatic status in men. No significant associations were found for the BD or DEP PRS or in the LDSC regression analysis. SNP-based genetic risk for SCZ, but not for BD or DEP, may be associated with higher risk of SARS-CoV-2 infection and COVID-19 severity, especially among women; however, predictive accuracy barely exceeded chance level. We believe that the inclusion of sexual loci and rare variations in the analysis of genomic overlap between SCZ and COVID-19 will help to elucidate the genetic commonalities between these conditions.
Subject(s)
Bipolar Disorder , COVID-19 , Schizophrenia , Male , Humans , Female , Schizophrenia/genetics , Schizophrenia/metabolism , Genetic Predisposition to Disease , COVID-19/genetics , SARS-CoV-2/genetics , Bipolar Disorder/metabolism , Multifactorial Inheritance , Genome-Wide Association StudyABSTRACT
Introducción La obesidad es considerada un factor de riesgo en casos graves de la COVID-19, habiendo sido analizada mediante el índice de masa corporal (IMC), estimador que no correlaciona adecuadamente con el porcentaje de grasa corporal (GC). El objetivo de este estudio ha sido analizar la fracción atribuible poblacional a la GC en formas graves de COVID-19 atendiendo al IMC y al CUN-BAE. Material y métodos Estudio multicéntrico observacional de prevalencia. Se recogió información sociodemográfica, antecedentes personales, IMC y CUN-BAE, de casos positivos SARS-CoV-2, de las provincias de León y La Rioja. Mediante modelos de regresión logística se calcularon odds ratio con sus respectivos intervalos de confianza del 95% ajustando por edad y antecedentes personales, así como la fracción atribuible poblacional a la GC. Resultados Participaron 785 pacientes, 123 (15,7%) fueron graves. Se detectaron como factores de riesgo la edad, la obesidad (tanto por IMC como por CUN-BAE) y los antecedentes personales. Un 51,6% de casos graves podrían ser atribuidos a un exceso de IMC y un 61,4% a exceso de GC estimada según CUN-BAE, observándose una mayor infraestimación del riesgo en mujeres. Conclusiones El exceso de GC es un factor de riesgo para formas graves de la COVID-19 junto con la edad avanzada y la presencia de enfermedades cardiovasculares, respiratorias crónicas u oncohematológicas. El IMC infraestima el riesgo, especialmente en mujeres, siendo el CUN-BAE el predictor seleccionado por su mejor estimación del porcentaje de GC (AU)
Introduction Obesity is considered a risk factor in severe cases of COVID-19, which has been analysed using body mass index (BMI), an estimator that does not correlate adequately with body fat (BF) percentage. The aim of this study was to analyse the population attributable fraction to BF in severe forms of COVID-19 based on BMI and CUN-BAE. Material and methods Multicentre observational prevalence study. Sociodemographic information, personal history, BMI and CUN-BAE were collected in SARS-CoV-2 positive cases from the provinces of León and La Rioja. Logistic regression models were used to calculate odds ratios with their respective 95% confidence intervals adjusting for age and personal history, as well as the population attributable fraction to BF. Results Seven hundred eighty-five patients participated, 123 (15.7%) were severe. Age, obesity (both by BMI and CUN-BAE) and personal history were detected as risk factors. 51.6% of severe cases could be attributed to excess BMI and 61.4% to excess BF estimated according to CUN-BAE, with a higher underestimation of risk in women. Conclusions Excess BF is a risk factor for severe forms of COVID-19 together with advanced age and the presence of cardiovascular, chronic respiratory or oncohematological diseases. BMI underestimates the risk especially in women, being CUN-BAE the predictor selected for its better estimation of the percentage of BF (AU)
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Obesity/complications , Coronavirus Infections , Pneumonia, Viral , Pandemics , Body Mass Index , Severity of Illness Index , Risk Factors , PrevalenceABSTRACT
INTRODUCTION: Obesity is considered a risk factor in severe cases of COVID-19, which has been analysed using body mass index (BMI), an estimator that does not correlate adequately with body fat (BF) percentage. The aim of this study was to analyse the population attributable fraction to BF in severe forms of COVID-19 based on BMI and CUN-BAE. MATERIAL AND METHODS: Multicentre observational prevalence study. Sociodemographic information, personal history, BMI and CUN-BAE were collected in SARS-CoV-2 positive cases from the provinces of León and La Rioja. Logistic regression models were used to calculate odds ratios with their respective 95% confidence intervals adjusting for age and personal history, as well as the population attributable fraction to BF. RESULTS: Seven hundred eighty-five patients participated, 123 (15.7%) were severe. Age, obesity (both by BMI and CUN-BAE) and personal history were detected as risk factors. 51.6% of severe cases could be attributed to excess BMI and 61.4% to excess BF estimated according to CUN-BAE, with a higher underestimation of risk in women. CONCLUSIONS: Excess BF is a risk factor for severe forms of COVID-19 together with advanced age and the presence of cardiovascular, chronic respiratory or oncohematological diseases. BMI underestimates the risk especially in women, being CUN-BAE the predictor selected for its better estimation of the percentage of BF.
Subject(s)
COVID-19 , Humans , Female , Body Mass Index , COVID-19/complications , SARS-CoV-2 , Obesity/complications , Obesity/epidemiology , Risk FactorsABSTRACT
Esta versión actualizada de las guías de osteoporosis de la Sociedad Española de Investigación en Osteoporosis y Metabolismo Mineral (SEIOMM) incorpora la información más relevante publicada en los últimos 7años, desde las guías de 2015, con estudios de imagen, como la valoración de la fractura vertebral y el análisis del índice trabecular óseo. Además, los avances terapéuticos incluyen los nuevos fármacos anabólicos, los estudios comparativos de la eficacia de los fármacos y la terapia secuencial y combinada. Por ello se actualizan también las recomendaciones de los tratamientos (AU)
This updated version of the Spanish Society for Research in Osteoporosis and Mineral Metabolism (SEIOMM) osteoporosis guides incorporate the most relevant information published in the last 7years, since the 2015 guides, with imaging studies, such as vertebral fracture assessment and bone trabecular score analysis. In addition, therapeutic advances include new anabolic agents, comparative studies of drug efficacy, and sequential and combined therapy. Therefore, therapeutic algorithms are also updated (AU)
Subject(s)
Humans , Osteoporosis/drug therapy , Osteoporotic Fractures , Bone Density , Osteoporosis, Postmenopausal/drug therapy , Risk Factors , Societies, Medical , SpainABSTRACT
This updated version of the Spanish Society for Research in Osteoporosis and Mineral Metabolism (SEIOMM) osteoporosis guides incorporate the most relevant information published in the last 7 years, since the 2015 guides, with imaging studies, such as vertebral fracture assessment and bone trabecular score analysis. In addition, therapeutic advances include new anabolic agents, comparative studies of drug efficacy, and sequential and combined therapy. Therefore, therapeutic algorithms are also updated.
Subject(s)
Bone Density , Osteoporosis , Bone and Bones , Humans , Male , Minerals/therapeutic use , Osteoporosis/drug therapy , PostmenopauseABSTRACT
Esta versión actualizada de la Guía de osteoporosis de la SEIOMM (Sociedad Española de Investigación en Osteoporosis y Metabolismo Mineral) incorpora la información más relevante publicada en los últimos 7 años, desde la Guía de 2015, con estudios de imagen, como la valoración de la fractura vertebral y el análisis del índice trabecular óseo. Además, los avances terapéuticos incluyen los nuevos fármacos anabólicos, los estudios comparativos de la eficacia de los fármacos y la terapia secuencial y combinada. Por ello se actualizan también las recomendaciones de los tratamientos. (AU)
Subject(s)
Humans , Osteoporosis , Fractures, Bone , Densitometry , Medicine , Alendronate , Risedronic Acid , Zoledronic Acid , Ibandronic Acid , Diagnosis , PatientsABSTRACT
Esta actualización de las Guías incorpora la información más relevante aparecida durante los 7 años trascurridos desde la publicación de la versión anterior, especialmente en cuanto a procedimientos diagnósticos y opciones terapéuticas. Entre los primeros, merece la pena destacar la incorporación del TBS y la detección de fracturas vertebrales por densitometría. Entre los tratamientos, se consideran los nuevos fármacos anabólicos, los estudios comparativos de eficacia en osteoporosis grave, las pautas de actuación tras la suspensión de los antirresortivos y otros esquemas de tratamiento secuencial y combinado. Teniendo en cuenta todo ello, se actualizan los esquemas de tratamiento recomendados. (AU)
Subject(s)
Humans , Osteoporosis , Fractures, Bone , Densitometry , Pharmaceutical Preparations , Patients , TherapeuticsABSTRACT
The clinical spectrum of hypophosphatasia (HPP) is broad and variable within families. Along severe infantile forms, adult forms with mild manifestations may be incidentally discovered by the presence of low alkaline phosphatase (ALP) activity in serum. However, it is still unclear whether individuals with persistently low levels of ALP, in the absence of overt manifestations of HPP, have subclinical abnormalities of bone remodeling or bone mass. The aim of this study was to obtain a better understanding of the skeletal phenotype of adults with low ALP by analyzing bone mineral density (BMD), bone microarchitecture (trabecular bone score, TBS), and bone turnover markers (P1NP and ß-crosslaps). We studied 42 individuals with persistently low serum ALP. They showed lower levels of P1NP (31.4 ± 13.7 versus 48.9 ± 24.4 ng/ml; p = 0.0002) and ß-crosslaps (0.21 ± 0.17 versus 0.34 ± 0.22 ng/ml, p = 0.0015) than individuals in the control group. There were no significant differences in BMD, bone mineral content, or TBS. These data suggest that individuals with hypophosphatasemia have an overall reduction of bone turnover, even in the absence of overt manifestations of HPP or low BMD. We evaluated bone mineral density (BMD), bone microarchitecture, and bone turnover markers in patients with low serum levels of alkaline phosphatase. Our results show that these patients have low bone remodeling even in the absence of BMD abnormalities, thus supporting the recommendation of avoiding antiresorptives such as bisphosphonates in these subjects.
Subject(s)
Alkaline Phosphatase/deficiency , Bone Remodeling/physiology , Hypophosphatasia/physiopathology , Adult , Aged , Alkaline Phosphatase/blood , Biomarkers/blood , Bone Density/physiology , Cancellous Bone/physiopathology , Case-Control Studies , Collagen/blood , Female , Humans , Hypophosphatasia/blood , Hypophosphatasia/enzymology , Male , Middle Aged , Peptide Fragments/blood , Procollagen/bloodABSTRACT
Population with Down syndrome (DS) has lower areal BMD, in association with their smaller skeletal size. However, volumetric BMD and other indices of bone microarchitecture, such as trabecular bone score (TBS) and calcaneal ultrasound (QUS), were normal. INTRODUCTION: Patients with DS have a number of risk factors that could predispose them to osteoporosis. Several studies reported that people with DS also have lower areal bone mineral density, but differences in the skeletal size could bias the analysis. METHODS: Seventy-five patients with DS and 76 controls without intellectual disability were recruited. Controls were matched for age and sex. Bone mineral density (BMD) was measure by Dual-energy X-ray Absorptiometry (DXA), and volumetric bone mineral density (vBMD) was calculated by published formulas. Body composition was also measured by DXA. Microarchitecture was measured by TBS and QUS. Serum 25-hidroxyvitamin D (25OHD), parathyroid hormone (PTH), aminoterminal propeptide of type collagen (P1NP), and C-terminal telopeptide of type I collagen (CTX) were also determined. Physical activity was assessed by the International Physical Activity Questionnaires (IPAQ-short form). To evaluate nutritional intake, we recorded three consecutive days of food. RESULTS: DS individuals had lower height (151 ± 11 vs. 169 ± 9 cm). BMD was higher in the controls (lumbar spine (LS) 0.903 ± 0.124 g/cm2 in patients and 0.997 ± 0.115 g/cm2 in the controls; femoral neck (FN) 0.761 ± .126 g/cm2 and 0.838 ± 0.115 g/cm2, respectively). vBMD was similar in the DS group (LS 0.244 ± 0.124 g/cm3; FN 0.325 ± .0.073 g/cm3) and the controls (LS 0.255 ± 0.033 g/cm3; FN 0.309 ± 0.043 g/cm3). Microarchitecture measured by QUS was slightly better in DS, and TBS measures were similar in both groups. 25OHD, PTH, and CTX were similar in both groups. P1NP was higher in the DS group. Time spent on exercise was similar in both groups, but intensity was higher in the control group. Population with DS has correct nutrition. CONCLUSIONS: Areal BMD is reduced in DS, but it seems to be related to the smaller body and skeletal size. In fact, the estimated volumetric BMD is similar in patients with DS and in control individuals. Furthermore, people with DS have normal bone microarchitecture.
Subject(s)
Bone Density/physiology , Down Syndrome/physiopathology , Absorptiometry, Photon/methods , Adult , Anthropometry/methods , Body Composition/physiology , Bone and Bones/metabolism , Calcaneus/diagnostic imaging , Case-Control Studies , Diet/statistics & numerical data , Down Syndrome/diagnostic imaging , Exercise/physiology , Female , Humans , Life Style , Male , Reference Values , Ultrasonography , Young AdultABSTRACT
In order to detect chimerism after allogeneic hematopoietic SCT (HSCT), several methods have been developed. In this study we describe the use of a set of insertion/deletion (Indel) polymorphic loci to determine the level of donor cell engraftment. We analyzed 50 DNA samples from patients who had undergone HSCT, and also several artificial chimeric samples created by mixing different DNA specimens from non-transplanted donors in various proportions. A specific set of 38 autosomic Indel polymorphisms were analyzed. For comparison purposes, a set of 15 short tandem repeats (STRs) were analyzed using the Identifiler Plus Amplification Kit. Our results suggest that Indel-based and STR-based procedures behave similarly in most cases. However, Indel analysis may provide additional information in some cases with a small minor chimeric component or when the presence of stutter bands complicates chimerism estimation.
Subject(s)
Genetic Loci , Hematopoietic Stem Cell Transplantation , Polymerase Chain Reaction/methods , Polymorphism, Genetic , Transplantation Chimera/genetics , Allografts , Female , Humans , MaleABSTRACT
NR5A2 is a nuclear receptor which regulates the expression of genes involved in cholesterol metabolism, pluripotency maintenance and cell differentiation. It has been recently shown that DLPC, a NR5A2 ligand, prevents liver steatosis and improves insulin sensitivity in mouse models of insulin resistance, an effect that has been associated with changes in glucose and fatty acids metabolism in liver. Because skeletal muscle is a major tissue in clearing glucose from blood, we studied the effect of the activation of NR5A2 on muscle metabolism by using cultures of C2C12, a mouse-derived cell line widely used as a model of skeletal muscle. Treatment of C2C12 with DLPC resulted in increased levels of expression of GLUT4 and also of several genes related to glycolysis and glycogen metabolism. These changes were accompanied by an increased glucose uptake. In addition, the activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions. Our results suggest that NR5A2, mostly by enhancing glucose uptake, switches muscle cells into a state of glucose preference. The increased use of glucose by muscle might constitute another mechanism by which NR5A2 improves blood glucose levels and restores insulin sensitivity.
Subject(s)
Glucose Transporter Type 4/metabolism , Glucose/metabolism , Muscle Fibers, Skeletal/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Cell Line , Gene Expression Regulation/physiology , Mice , Signal Transduction/physiologyABSTRACT
UNLABELLED: Two missense polymorphisms of WNT16 were associated with hip bone mineral density (BMD), the buckling ratio of the femoral neck, calcaneal ultrasound and hip fractures in individuals under 80 years of age. These results confirm the association of the WNT16 gene with bone mass and osteoporotic fractures. INTRODUCTION: Osteoporosis has a strong genetic component. Wnt ligands stimulate the differentiation of osteoblast precursors and play a major role in skeletal homeostasis. Therefore, the aim of this study was to explore the association of allelic variants of the WNT16 gene with BMD, other structural parameters of bone and osteoporotic hip fractures. METHODS: Six single nucleotide polymorphisms were analysed in 1,083 Caucasian individuals over 49 years of age. RESULTS: Two missense polymorphisms (rs2908004 and rs2707466) were associated with femoral neck BMD, with average differences across genotypes of 35 mg/cm(2) (p = 0.00037 and 0.0015, respectively). Likewise, the polymorphisms were associated with calcaneal quantitative ultrasound parameters (p = 0.00004 and 0.0014, respectively) and the buckling ratio, an index of cortical instability of the femoral neck (p = 0.0007 and 0.0029, respectively). Although there were no significant differences in the genotype frequency distributions between 294 patients with hip fractures and 670 controls, among the subgroup under 80 years of age, TT genotypes were underrepresented in patients with fractures (odds ratio 0.50; CI 0.27-0.94). CONCLUSION: Common missense polymorphisms of the WNT16 gene are associated with BMD at the hip, calcaneal ultrasound and the buckling ratio of the femoral neck, as well as with hip fractures in individuals under 80 years of age. Overall, these results confirm the association of the WNT16 locus with BMD identified in genome-wide association studies and support its role in determining the risk of osteoporotic fractures.
Subject(s)
Hip Fractures/genetics , Mutation, Missense , Osteoporosis/genetics , Osteoporotic Fractures/genetics , Wnt Proteins/genetics , Aged , Aged, 80 and over , Bone Density/genetics , Calcaneus/diagnostic imaging , Female , Femur Neck/physiopathology , Genetic Predisposition to Disease , Genotype , Hip Joint/physiopathology , Humans , Lumbar Vertebrae/physiopathology , Male , Middle Aged , Polymorphism, Single Nucleotide , Stress, Mechanical , UltrasonographyABSTRACT
Forensic-oriented kits analysing short tandem repeat (STR) polymorphisms are widely used to determine the proportions of donor and recipient cells after haematopoietic stem cell transplantation. The sensitivity of this technology is crucial for the early detection of relapse and, in consequence, the adjustment of the treatment to enhance donor-origin haematopoiesis in transplant recipients. The objective of this study was to compare the performance of two recently developed STR multiplex kits, AmpFâSTR(®) Identifiler(®) Plus PCR Amplification Kit (Applied Biosystems) and Investigator™ IDplex(®) (Qiagen), in the analysis of chimerism. Fifteen STR loci were amplified with both kits in 26 peripheral blood samples of transplantated patients showing chimerism. Peak amplitude threshold, detection limit (%DL), per cent donor chimerism and efficacy of each multiplex and STR were determined, and the results with both kits were compared. The %DL and the estimated per cent donor chimerism were similar with both kits. On the other hand, Identifiler(®) Plus kit allowed chimerism identification only in 24 (92%) of the 26 cases with chimerism detected by using the Investigator™ IDplex(®) when only 'type 5' allelic constellations (i.e. without potential interference by stutter peaks) were taken into account. However, IDplex(®) efficacy was somewhat lower than that of Identifiler Plus when only the most informative loci (D2S1338, D21S11, D18S51 and FGA) were considered. Therefore, although each system had some particular advantages and disadvantages, overall both STR multiplexes showed similar performance in qualitative and quantitative chimerism analysis.
Subject(s)
Bone Marrow Transplantation , Hematopoietic Stem Cell Transplantation , Transplantation Chimera/genetics , Chimerism , Humans , Limit of Detection , Microsatellite Repeats , Reagent Kits, Diagnostic , Sensitivity and SpecificityABSTRACT
Farnesyl diphosphate synthase (FDPS) is necessary for osteoclast survival and activity and is considered as a major molecular target of aminobisphosphonates. Our objective was to analyze the influence of FDPS polymorphisms on bone mineral density (BMD) and the response to antiresortive drugs. Three single-nucleotide polymorphisms of FDPS were analyzed in 1186 postmenopausal women. There was only a marginally significant association of baseline hip BMD with rs11264359 alleles (P=0.043). However, among 191 women receiving antiresortive therapy, there was a very significant association between rs2297480 or rs11264359 alleles and the BMD changes after aminobisphosphonate therapy for an average period of 2.5 years (P=0.001). The genotype explained 7.2% of the variance in the BMD response. On the other hand, there was no association between the BMD changes after raloxifene therapy and any of the polymorphisms studied. These results suggest that common polymorphisms of the FDPS gene influence the response to aminobisphosphonates.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Diphosphonates/therapeutic use , Geranyltranstransferase/genetics , Osteoporosis/drug therapy , Osteoporosis/genetics , Polymorphism, Single Nucleotide , Absorptiometry, Photon , Adult , Aged , Aged, 80 and over , Analysis of Variance , Bone Density/drug effects , Bone Density/genetics , Bone Resorption/drug therapy , Bone Resorption/enzymology , Bone Resorption/genetics , Female , Gene Frequency , Geranyltranstransferase/metabolism , Haplotypes , Humans , Linear Models , Linkage Disequilibrium , Middle Aged , Osteoporosis/diagnostic imaging , Osteoporosis/enzymology , Phenotype , Risk Assessment , Risk Factors , Spain , Time Factors , Treatment OutcomeABSTRACT
BACKGROUNDS: The analysis of chimerism after bone marrow transplantation by STR-PCR is frequently carried out with commercial kits designed for forensic purposes and including too many non informative STR. Furthermore, in routine clinical practice it is not uncommon to lack the pre-transplant genotype of the recipient or the donor, thus making it difficult to identify both components in the post-transplant genotype. The objective of this paper is to overcome these drawbacks by analyzing the informativity of STR markers from a perspective which can be applied whether the pretransplant genotypes are available or not, and selecting a minimum STR panel that allows an effective direct detection of chimerism. METHODS: DNA extraction, STR-PCR and fragment analysis of 15 STR in 90 donor-recipient pairs, 60 of which were part of the discovery set and 30 in a validation set. Loci were considered as informative when there were 3 or 4 different alleles in the combined genotypes of the recipient and the donor. RESULTS: The informativity varied between 41.6 and 76.6. The 4 most informative loci were D2S1338, D21S11, D18S51 and FGA. We could select a minimum set of 8 markers (D2S1338, D21S11, D18S51, FGA, VWA, D19S433, TH01 and D3S1358) that provided at least 3 informative loci in 95% of cases. CONCLUSION: This minimum STR panel may be an efficient way to detect and quantitate donor-recipient chimerism after transplantation.
Subject(s)
Microsatellite Repeats/genetics , Transplantation Chimera/genetics , Genotype , Humans , Polymerase Chain Reaction , SoftwareABSTRACT
Acetyl-CoA carboxylase beta, encoded by the ACAB gene, plays an important role in the oxidation of fatty acids. The aim of this study was to check the hypothesis that allelic variants of ACACB influence the risk of obesity and type 2 diabetes mellitus. Twenty five tagging single nucleotide polymorphisms (SNPs) capturing common variants of the ACACB gene were selected and analyzed in two cohorts including 1695 postmenopausal women of the general population and in 161 women with severe obesity (BMI>35). In vitro binding of transcription factors was explored by electrophoretic mobility shift assays (EMSA). T alleles at the rs2268388 locus were overrepresented in women with severe obesity (18% vs. 10% in controls; OR 1.74 [95% confidence interval 1.30-2.47]), which was statistically significant after multiple-test adjustment (p=0.0004). Likewise, T alleles at the rs2268388 locus and C alleles at the rs2239607 locus were associated with diabetes, in the discovery as well as in the replication cohorts, even after women with severe obesity were excluded (OR 3.6 and 2.8, for TT and CC homozygotes, respectively). Allelic differences in the binding affinity for nuclear proteins were revealed in vitro by EMSA and competition experiments were consistent with the binding of glucorticoid receptor and serum response factor. In conclusion, common polymorphisms of ACACB gene are associated with obesity and, independently, with type 2 diabetes in postmenopausal women, suggesting that the activity of acetyl-CoA carboxylase beta plays an important role in these disorders related to energy metabolism.
Subject(s)
Acetyl-CoA Carboxylase/genetics , Diabetes Mellitus, Type 2/genetics , Obesity/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Cohort Studies , Female , Genetic Association Studies , Haplotypes , Humans , Linkage Disequilibrium , Middle Aged , PostmenopauseABSTRACT
OBJECTIVE: Several lines of evidence suggest that estrogens influence the development of osteoarthritis (OA). The aim of this study was to explore the association of two common polymorphisms within the aromatase (CYP19A1) and estrogen receptor (ER) alpha (ESR1) genes with severe OA of the lower limbs. METHODS: The rs1062033 (CYP19A1) and rs2234693 (ESR1) single nucleotide polymorphisms were genotyped in 5528 individuals (3147 patients with severe hip or knee OA, and 2381 controls) from four centres in Spain and the United Kingdom. Gene expression was measured in femoral bone samples from a group of patients. RESULTS: In the global analysis, both polymorphisms were associated with OA, but there was a significant sex interaction. The GG genotype at rs1062033 was associated with an increased risk of knee OA in women [odds ratio (OR) 1.23; P=0.04]. The CC genotype at rs2234693 tended to be associated with reduced OA risk in women (OR 0.76, P=0.028, for knee OA; OR=0.84, P=0.076 for hip OA), but with increased risk of hip OA in men (OR 1.28; P=0.029). Women with unfavourable genotypes at both loci had an OR of 1.61 for knee OA (P=0.006). The rs1062033 genotype associated with higher OA risk was also associated with reduced expression of the aromatase gene in bone. CONCLUSIONS: Common genetic variations of the aromatase and ER genes are associated with the risk of severe OA of the large joints of the lower limb in a sex-specific manner. These results are consistent with the hypothesis that estrogen activity may influence the development of large-joint OA.
Subject(s)
Aromatase/genetics , Estrogen Receptor alpha/genetics , Osteoarthritis/genetics , Polymorphism, Genetic , Aged , Aged, 80 and over , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Joints , Male , Middle Aged , Risk FactorsABSTRACT
UNLABELLED: In comparison with hip fractures, increased expression of genes in the Wnt pathway and increased Wnt activity were found in bone samples and osteoblast cultures from patients with osteoarthritis, suggesting the involvement of this pathway in subchondral bone changes. No consistent differences were found in the genetic association study. INTRODUCTION: This study aims to explore the allelic variations and expression of Wnt pathway genes in patients with osteoporosis and osteoarthritis. METHODS: The expression of 86 genes was studied in bone samples and osteoblast primary cultures from patients with hip fractures and hip or knee osteoarthritis. The Wnt-related activity was assessed by measuring AXIN2 and in transfection experiments. Fifty-five SNPs of the LRP5, LRP6, FRZB, and SOST genes were analyzed in 1,128 patients. RESULTS: Several genes were differentially expressed in bone tissue, with the lowest values usually found in hip fracture and the highest in knee osteoarthritis. Overall, seven genes were consistently upregulated both in tissue samples and in cell cultures from patients with knee osteoarthritis (BCL9, FZD5, DVL2, EP300, FRZB, LRP5, and TCF7L1). The increased expression of AXIN2 and experiments of transient transfection of osteoblasts with the TOP-Flash construct confirmed the activation of Wnt signaling. Three SNPs of the LRP5 gene and one in the LRP6 gene showed marginally significant differences in allelic frequencies across the patient groups, but they did not resist multiple-test adjustment. CONCLUSIONS: Genes in the Wnt pathway are upregulated in the osteoarthritic bone, suggesting their involvement not only in cartilage distortion but also in subchondral bone changes.
Subject(s)
Osteoarthritis/genetics , Osteoporosis/genetics , Wnt Proteins/genetics , Aged , Aged, 80 and over , Cells, Cultured , Female , Gene Frequency , Genetic Association Studies/methods , Genetic Predisposition to Disease , Genotype , Hip Fractures/genetics , Hip Fractures/metabolism , Humans , Male , Osteoarthritis/metabolism , Osteoarthritis, Hip/genetics , Osteoarthritis, Hip/metabolism , Osteoarthritis, Knee/genetics , Osteoarthritis, Knee/metabolism , Osteoblasts/metabolism , Osteoporosis/metabolism , Polymorphism, Single Nucleotide , Signal Transduction/genetics , Up-Regulation , Wnt Proteins/metabolismABSTRACT
The aim of the study was to investigate the distribution of 163 A/G osteoprotegerin gene promoter and 1181 G/C osteoprotegerin exon 1 polymorphisms in a group of women with different hormonal status and to analyze their relationship with BMD. Osteoprotegerin polymorphisms and BMD were analyzed in 332 women (69 premenopausal and 263 postmenopausal). BMD was quantified at the lumbar spine (L 2-4), femoral neck, and total hip. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman ((R)) SNP Genotyping assays. There were not significant differences in BMD according to 163 A/G genotype. However, significant differences in lumbar spine BMD were found according to 1181 G/C alleles. Thus, women with CC genotype had significant higher BMD at the lumbar spine than those with GC or GG genotype. No differences were found in femoral neck and total hip BMD. In age-adjusted models, the 1181 G/C OPG polymorphism explained 2.2% of BMD variance at the spine, 0.3% at the femoral neck, and 0.9% at the total hip in the whole group. In the subgroup of premenopausal women, the polymorphism was strongly related to spine BMD, and explained 11.5% of the variance, whereas body weight explained 7.9%. The 1181 G/C polymorphism was associated with lumbar spine BMD in Spanish women. Premenopausal women with the CC genotype had a higher BMD.
Subject(s)
Bone Density/genetics , Osteoporosis/genetics , Osteoprotegerin/genetics , Polymorphism, Single Nucleotide/genetics , Absorptiometry, Photon , Adult , Aged , Aged, 80 and over , DNA Primers , Female , Genotype , Humans , Lumbar Vertebrae/physiology , Middle Aged , Postmenopause , Promoter Regions, Genetic , Spain/epidemiology , Spine/physiologyABSTRACT
BACKGROUND: Down syndrome (DS) is a frequent cause of intellectual disability. With the increasing life expectancy of these patients, concerns have been raised about the risk of osteoporosis. In fact, several investigators have reported a reduced bone mass in DS. However, the results may be confounded by comorbid diseases, and differences in lifestyle habits and body size. Therefore, we planned to determine anthropometric and lifestyle factors influencing bone mineral density (BMD) in young adults with DS. METHODS: Thirty-nine patients with DS (mean age 26 years) and 78 controls were studied. Areal BMD was measured by dual x-ray densitometry (DXA); volumetric BMD at the lumbar spine and femoral neck was estimated with published formulae. RESULTS: DS patients had lower areal BMD than controls at all regions (spine, hip and total body). Height and projected bone area were also lower. There were no differences between both groups regarding estimated volumetric BMD at the femoral neck. However, spine volumetric BMD was also lower in DS than controls. In multivariate analysis, DS, male sex, little physical activity and low sunlight exposure were associated with lower spine volumetric BMD; on the other hand, fat mass and sunlight exposure were associated with femoral neck volumetric BMD. CONCLUSION: This study shows that patients with DS had a reduced areal BMD, but it is in part a consequence of the reduced body size, particularly at the femoral neck. Physical activity and sunlight exposure are associated to volumetric BMD and should be stimulated in order to maintain an adequate bone mass in these patients.
