RESUMO
1. This study on long-life layers, covering the period 20-100 weeks of age, investigated longitudinal effects on mortality, layer integument, and skeletal properties in Bovans White (BoW) and Lohmann Selected Leghorn Classic (LSL), with or without supplementation with dietary organic zinc (Zn).2. Two experiments, using 1440 layers in furnished small group cages (FC) and 1836 layers in a traditional floor housing system (Floor), were run in parallel. Each replicate consisted of five adjacent cages containing eight hens in each FC, or a pen with 102 layers in the Floor group.3. Mortality was recorded daily. Integument and keel bone condition were scored at 35, 55, 85, and 100 weeks of age on 20% of the layers. Tibial strength was recorded from 933 layers at 100 weeks. Statistical analyses were performed on replicate means, with four to five and nine replicates per combination of hybrid and diet in Floor and FC groups, respectively.4. Cumulative mortality was 9.6% and 16.3% in FC and Floor, respectively, and increased in the latter part of the production cycle, particularly in the Floor group.5. In FC, LSL had inferior feather cover, less keel bone deviation, and shorter claws than BoW. In Floor, LSL had superior feather cover, less severe vent wounds, more bumble foot, and cleaner plumage than BoW. In both production systems, claws grew longer and keel bone deviation became more severe with age.6. In FC, layers fed organic Zn had lower body weight and less keel bone deviation at 100 weeks of age.7. In conclusion, keel bone integrity, claw length, and mortality rate are potential threats to welfare in long-life layers. Feather pecking is a problem that needs addressing at an early stage in the production period. On the whole, organic Zn did not improve welfare conditions in long-life layers.
Assuntos
Galinhas , Abrigo para Animais , Criação de Animais Domésticos , Bem-Estar do Animal , Animais , Galinhas/genética , Galinhas/lesões , Feminino , Genótipo , ZincoRESUMO
The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.
Assuntos
Acidentes por Quedas , Força da Mão , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Idoso , Idoso de 80 Anos ou mais , Exercício Físico , Humanos , Masculino , Estudos Prospectivos , Suécia , CaminhadaRESUMO
BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, mainly caused by mutations in the collagen type I genes (COL1A1 and COL1A2). Tooth agenesis is a common feature of OI. We investigated the association between tooth agenesis and collagen type I mutations in individuals with OI. SUBJECTS AND METHODS: In this cohort study, 128 unrelated individuals with OI were included. Panoramic radiographs were analyzed regarding dentinogenesis imperfecta (DGI) and congenitally missing teeth. The collagen I genes were sequenced in all individuals, and in 25, multiplex ligation-dependent probe amplification was performed. RESULTS: Mutations in the COL1A1 and COL1A2 genes were found in 104 of 128 individuals. Tooth agenesis was diagnosed in 17% (hypodontia 11%, oligodontia 6%) and was more frequent in those with DGI (P = 0.016), and in those with OI type III, 47%, compared to those with OI types I, 12% (P = 0.003), and IV, 13% (P = 0.017). Seventy-five percent of the individuals with oligodontia (≥6 missing teeth) had qualitative mutations, but there was no association with OI type, gender, or presence of DGI. CONCLUSION: The prevalence of tooth agenesis is high (17%) in individuals with OI, and OI caused by a qualitative collagen I mutation is associated with oligodontia.
Assuntos
Anodontia/genética , Colágeno Tipo I/genética , Osteogênese Imperfeita/genética , Anodontia/diagnóstico por imagem , Criança , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação/genética , Osteogênese Imperfeita/diagnóstico por imagem , Radiografia PanorâmicaRESUMO
BACKGROUND: Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe OI; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated. MATERIALS AND METHODS: COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n=33, type III n=25 and type IV n=21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non-vertebral and vertebral fractures were collected prior to, and at several time points during treatment. RESULTS: An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to Δ LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p<0.0003, <0.0001 and 0.0003 for all OI types I, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4yrs Pamidronate. Twice as many boys as girls with OI type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p=0.0236). Greater Δ LS BMD, but smaller Δ fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11years of age at treatment initiation (p<0.0001). CONCLUSION: Pamidronate treatment in children with all types of OI increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.
Assuntos
Densidade Óssea , Difosfonatos/uso terapêutico , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Farmacogenética , Estatura/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Colágeno Tipo I/genética , Análise Mutacional de DNA , Difosfonatos/farmacologia , Feminino , Fraturas Ósseas/complicações , Fraturas Ósseas/fisiopatologia , Fraturas por Compressão/tratamento farmacológico , Fraturas por Compressão/genética , Glicina/genética , Humanos , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/fisiopatologia , Masculino , Mutação/genética , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/fisiopatologia , Pamidronato , Suécia/epidemiologiaRESUMO
Onset of sexual maturation is a trait of extreme importance both evolutionarily and economically. Unsurprisingly therefore, domestication has acted to reduce the time to sexual maturation in a variety of animals, including the chicken. In comparison with wild progenitor chickens [the Red Junglefowl (RJF)], domestic layer hens attain maturity approximately 20% earlier. In addition, domestic layers also possess larger combs (a sexual ornament), produce more eggs and have denser bones. A large quantitative trait loci (QTL) analysis (n=377) was performed using an F(2) intercross between a White Leghorn layer breed and a RJF population, with onset of sexual maturity measured and mapped to three separate loci. This cross has already been analysed for comb mass, egg production and bone allocation. Onset of sexual maturity significantly correlated with comb mass, whilst the genetic architecture for sexual maturity and comb mass overlapped at all three loci. For two of these loci, the QTL for sexual maturity and comb mass were statistically indistinguishable from pleiotropy, suggesting that the alleles that increase comb mass also decrease onset of sexual maturity.
Assuntos
Galinhas/genética , Galinhas/fisiologia , Crista e Barbelas , Fertilidade/genética , Maturidade Sexual/genética , Maturidade Sexual/fisiologia , Animais , Feminino , Genótipo , Masculino , Locos de Características QuantitativasRESUMO
The extent of pleiotropy and epistasis in quantitative traits remains equivocal. In the case of pleiotropy, multiple quantitative trait loci are often taken to be pleiotropic if their confidence intervals overlap, without formal statistical tests being used to ascertain if these overlapping loci are statistically significantly pleiotropic. Additionally, the degree to which the genetic correlations between phenotypic traits are reflected in these pleiotropic quantitative trait loci is often variable, especially in the case of antagonistic pleiotropy. Similarly, the extent of epistasis in various morphological, behavioural and life-history traits is also debated, with a general problem being the sample sizes required to detect such effects. Domestication involves a large number of trade-offs, which are reflected in numerous behavioural, morphological and life-history traits which have evolved as a consequence of adaptation to selective pressures exerted by humans and captivity. The comparison between wild and domestic animals allows the genetic analysis of the traits that differ between these population types, as well as being a general model of evolution. Using a large F(2) intercross between wild and domesticated chickens, in combination with a dense SNP and microsatellite marker map, both pleiotropy and epistasis were analysed. The majority of traits were found to segregate in 11 tight 'blocks' and reflected the trade-offs associated with domestication. These blocks were shown to have a pleiotropic 'core' surrounded by more loosely linked loci. In contrast, epistatic interactions were almost entirely absent, with only six pairs identified over all traits analysed. These results give insights both into the extent of such blocks in evolution and the development of domestication itself.
Assuntos
Galinhas/genética , Ligação Genética , Pleiotropia Genética , Locos de Características Quantitativas , Animais , Cruzamentos Genéticos , Epistasia Genética , Evolução Molecular , Genótipo , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.
Assuntos
Alanina Transaminase/sangue , Anticoagulantes/efeitos adversos , Azetidinas/efeitos adversos , Benzilaminas/efeitos adversos , Fígado/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Estudos RetrospectivosRESUMO
Given the strong genetic contribution to blood pressure and left ventricular hypertrophy (LVH), and the influence of estrogen on these parameters, we hypothesized that polymorphisms in the estrogen receptor alpha (ERalpha) promoter may influence LVH. Three novel polymorphisms were identified upstream of the ERalpha alternatively spliced exon 1E, within sequence which demonstrated significant promoter activity in vitro. Demonstration of ERalpha E isoform expression in human ventricle by RT-PCR supported a possible functional role for the 1E novel polymorphisms in estrogen signaling in the heart. Indeed, G>A (-721 E) was significantly associated with LVH after controlling for systolic blood pressure and sex in a healthy population (n=74), contributing to 23% of interventricular septum (IVS) width variance (p<0.001) and 9.4% of left ventricular mass index (LVMI) variance (p=0.035). In a separate hypertensive cohort, male carriers of the A allele (n=8) had a 17% increase in IVS (95% CI: 6-28%) and a 19% increase in LVMI (3-34%) compared to GG homozygotes (n=84). We conclude that a novel polymorphism in the promoter of a cardiac mRNA splice isoform of ERalpha is associated with LVH.
Assuntos
Receptor alfa de Estrogênio/genética , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Adolescente , Adulto , Processamento Alternativo , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Feather pecking (FP) is a detrimental behaviour in chickens, which is performed by only some individuals in a flock. FP was studied in 54 red junglefowl (ancestor of domestic chickens), 36 White Leghorn laying hens, and 762 birds from an F(2)-intercross between these two lines. From all F(2)-birds, growth and feed consumption were measured. Age at sexual maturity and egg production in females, and corticosterone levels in males were also measured. From 333 F(2)-birds of both sexes, and 20 parental birds, body composition with respect to bone mineral content, muscle and fat was obtained by post-mortem examinations using Dual X-Ray Absorptiometry (DXA). In femurs of the same birds, the bone density and structure were analysed using DXA and Peripheral Quantitative Computerized Tomography (pQCT), and a biomechanical analysis of bone strength was performed. Furthermore, plumage condition was determined in all birds as a measure of being exposed to feather pecking. Using 105 DNA-markers in all F(2)-birds, a genome-wide scan for Quantitative Trait Loci (QTL), associated with the behaviour in the F(2)-generation was performed. FP was at least as frequent in the red junglefowl as in the White Leghorn strain studied here, and significantly more common among females both in the parental strains and in the F(2)-generation. In the F(2)-birds, FP was phenotypically linked to early sexual maturation, fast growth, weak bones, and, in males, also high fat accumulation, indicating that feather peckers have a different resource allocation pattern. Behaviourally, F(2) feather peckers were more active in an open field test, in a novel food/novel object test, and in a restraint test, indicating that feather pecking might be genetically linked to a proactive coping strategy. Only one suggestive QTL with a low explanatory value was found on chromosome 3, showing that many genes, each with a small effect, are probably involved in the causation of feather pecking. There were significant effects of sire and dam on the risk of being a victim of feather pecking, and victims grew faster pre- and post-hatching, had lower corticosterone levels and were less active in a restraint test. Hence, a wide array of behavioural and developmental traits were genetically linked to FP.
Assuntos
Agressão/fisiologia , Comportamento Animal/fisiologia , Galinhas/fisiologia , Plumas , Locos de Características Quantitativas/genética , Animais , Composição Corporal/genética , Densidade Óssea , Cruzamento , Galinhas/genética , Corticosterona/sangue , Feminino , Genótipo , Abrigo para Animais , Masculino , Fenótipo , Comportamento Social , Especificidade da Espécie , Estresse Fisiológico/genética , Estresse Fisiológico/veterináriaRESUMO
Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture, and the trait is under genetic control by a large number of genes. It is recognized that estrogen plays an important role in the maintenance of bone mass by binding to estrogen receptor alpha (ERalpha). RIZ1 has previously been shown to be a specific ERalpha coactivator and strongly enhances its function both in vivo and in vitro. We performed in vitro studies comparing the abilities of RIZ1 P704 polymorphic variants (homozygous presence, P704+; absence, P704-; heterozygosity P704(+/-) of a proline at position 704) to coactivate the ERalpha and also examined the polymorphism associated to BMD of 343 Swedish women, aged 20-39 yr. The expression vector containing P704- RIZ1 showed an impaired response in coactivating ERalpha in a ligand- and dose-dependent manner compared with P704+ RIZ (P < 0.0001). The genotype frequencies were 19% (P704+), 32% (P704-), and 49% (P704(+/-)) and were in Hardy-Weinberg equilibrium. BMD at the heel was higher in the P704+ genotype group than in the P704(+/-) group (P = 0.02), which was evident also after corrections for fat and lean mass (P = 0.03). We conclude that RIZ1 may be a new candidate gene for involvement in the variation seen in BMD.
Assuntos
Densidade Óssea/genética , Proteínas de Ligação a DNA/genética , Receptor alfa de Estrogênio/metabolismo , Deleção de Genes , Proteínas Nucleares/genética , Polimorfismo Genético , Fatores de Transcrição/genética , Adulto , Estudos de Coortes , Feminino , Genótipo , Histona-Lisina N-Metiltransferase , Humanos , Distribuição Aleatória , SuéciaRESUMO
Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.
Assuntos
Artérias Carótidas/patologia , Glicoproteínas/genética , Hipertensão/genética , Hipertensão/patologia , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/genética , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Atenolol/uso terapêutico , Feminino , Genótipo , Humanos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Osteoprotegerina , Regiões Promotoras Genéticas , Receptores do Fator de Necrose Tumoral , SuéciaRESUMO
Sex steroids are important physiologic regulators of bone mass, and genes regulating sex steroid production and metabolism are obvious as candidate genes for osteoporosis susceptibility. We present data from a study of 1795 recent postmenopausal women, assigned to either hormone replacement therapy (HRT) or no treatment and followed for 5 years. The association between bone mass measurements and two single nucleotide polymorphisms, a T (A1) to C (A2) transition in the 5'-UTR of the cytochrome P450c17alpha (CYP17) gene and a G (Val) to A (Met) transition in exon 4 of the catechol- O-methyltransferase (COMT) gene, was evaluated. Association with CYP17 genotype was modified by body mass index (BMI). In lean women, individuals homozygous for the CYP17 A2 allele were 1 cm shorter and had lower baseline BMD (bone mineral density), BMC, and CSA (cross sectional area) in the spine and femoral neck than did other women (BMD spine A2A2: 0.975 g/cm2 versus 1.011 g/cm2 in A1A1 + A1A2, P = 0.002). Conversely, an adverse association with A2A2 and bone loss over 5 years seemed present only in overweight women, but differences were small. Response to HRT was not dependent on CYP17 genotype. COMT genotype was not associated with bone mass at baseline, bone loss in untreated women, or response to HRT. In conclusion, the A2 allele of the CYP17 T(27)-C polymorphism is associated with reduced bone mass and bone size in lean perimenopausal women, whereas high BMI protects against this negative association. The COMT G(1947)-A polymorphism is not associated with bone parameters in this study.
Assuntos
Densidade Óssea/genética , Catecol O-Metiltransferase/genética , Terapia de Reposição de Estrogênios , Osteoporose Pós-Menopausa/genética , Polimorfismo de Nucleotídeo Único/genética , Esteroide 17-alfa-Hidroxilase/genética , Regiões 5' não Traduzidas/genética , Índice de Massa Corporal , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Genótipo , Hormônios Esteroides Gonadais/metabolismo , Hormônios Esteroides Gonadais/farmacologia , Hormônios Esteroides Gonadais/uso terapêutico , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/metabolismo , Pós-Menopausa/metabolismo , Estudos Prospectivos , Magreza/complicações , Magreza/genéticaRESUMO
Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis and related fragility fractures. A polymorphism of the binding site for the transcription factor Sp1 of the collagen I alpha 1 gene (COLIA1) has shown an association to bone mass and fracture, but the findings have not been consistent, which may be related to population differences. The Sp1 polymorphism was determined in 1044 women, all 75 years old, participating in the population-based Osteoporosis Prospective Risk Assessment study in Malmö (OPRA). Bone mineral density, heel ultrasound and all previous fractures were registered. BMD was 2.7% lower in the femoral neck in women carrying at least one copy of the "s" allele ( P = 0.027). There was no difference in bone mass at any other site, weight, BMI or age at menopause. Women with a prevalent wrist fracture (n = 181) had an increased presence of the "s" allele. The odds ratio for prevalent wrist fracture was 2.73 (95% CI 1.1-6.8) for the ss homozygotes and 1.4 (95% CI 1.0-2.0) for the Ss heterozygotes when compared with the SS homozygotes. In conclusion, in this large and homogeneous cohort of 75-year-old Swedish women, there was an association among the Sp1 COLIA1 polymorphism, bone mass, and fracture. The presence of at least one copy of the "s" allele was associated with lower femoral neck BMD and previous wrist fracture and in addition, it was related to an increased risk for wrist fracture.
Assuntos
Densidade Óssea/genética , Colágeno Tipo I/genética , Fraturas Ósseas/genética , Predisposição Genética para Doença , Polimorfismo Genético , Fator de Transcrição Sp1/genética , Traumatismos do Punho/genética , Idoso , Sítios de Ligação , Calcâneo/diagnóstico por imagem , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , DNA/análise , Feminino , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/metabolismo , Fraturas Ósseas/metabolismo , Genótipo , Humanos , Radiografia , Distribuição Aleatória , Fator de Transcrição Sp1/metabolismo , Ultrassonografia , Traumatismos do Punho/metabolismoRESUMO
Polymorphisms in the androgen receptor ( AR) gene and genes encoding enzymes involved in synthesis of sex steroids (e.g., the CYP19 gene encoding aromatase) have recently received attention in osteoporosis research. In the Danish Osteoporosis Prevention Study, recent postmenopausal women were allocated to either hormone replacement therapy (HRT) or no treatment. We genotyped 1792 women for the CYP19 (TTTA)(n) repeat [short (TTTA)(n
Assuntos
Aromatase/genética , Densidade Óssea/genética , Terapia de Reposição Hormonal , Osteoporose Pós-Menopausa/genética , Polimorfismo Genético , Receptores Androgênicos/genética , Alelos , Biomarcadores/sangue , Biomarcadores/urina , Densidade Óssea/efeitos dos fármacos , Dinamarca/epidemiologia , Feminino , Frequência do Gene , Humanos , Estudos Longitudinais , Repetições de Microssatélites , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/prevenção & controle , Globulina de Ligação a Hormônio Sexual/genéticaRESUMO
Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50-0.64, C1217T P = 0.51-1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61-0.66, C1217T P = 0.14-0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.
Assuntos
Densidade Óssea/genética , Fraturas Espontâneas/genética , Glicoproteínas/genética , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/genética , Idoso , Calcâneo/diagnóstico por imagem , Estudos de Coortes , Feminino , Fraturas Espontâneas/epidemiologia , Humanos , Incidência , Íntrons , Osteoporose Pós-Menopausa/genética , Osteoprotegerina , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Receptores do Fator de Necrose Tumoral , Suécia/epidemiologia , UltrassonografiaRESUMO
Peak bone mass (PBM) and subsequent bone loss are important risk factors for development of osteoporosis later in life, and twin studies have reported strong genetic influence on PBM. The genetic factor influencing PBM is polygenetic, and many genes most likely exert relatively small effects on bone mass. The poly adenosine (A) microsatellite in the 3' untranslated region (UTR) of the VDR gene has been associated with both prostate and breast cancer risk but little is known about the effect of bone mineral density (BMD). In this report the poly A microsatellite and the linked BsmI SNP have been investigated in a population-based cohort of 343 Swedish women, aged 20-39. BMD was measured by dual x-ray absorptiometry at the spine, proximal femur, total body and heel and by quantitative ultrasound at the heel. Correlations were found between VDR genotypes and BMD at lumbar spine L2-L4, (ss versus LL, P = 0.03 and BB versus bb, P = 0.02, respectively), with a similar pattern concerning total hip (ss versus LL, P = 0.12 and BB versus bb, P = 0.16 respectively). After corrections for age, height, fat and lean mass, the VDR BsmI genotype was still associated to BMD at the lumbar spine (BB versus bb, P = 0.03). The polymorphisms were in linkage disequilibrium (Chi-square = 566, P < 0.0001). In conclusion, genetic variation in the VDR is associated with BMD in premenopausal women, and further studies are needed to evaluate a possible functional role of the VDR 3'UTR poly A repeat, a region that has shown to be of important for mRNA stability.
Assuntos
Adenosina/genética , Densidade Óssea/genética , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Absorciometria de Fóton , Adulto , Composição Corporal/fisiologia , Calcâneo/diagnóstico por imagem , Estudos de Coortes , Análise Mutacional de DNA , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Feminino , Ligação Genética , Genótipo , Humanos , Polímeros , Pré-Menopausa , Suécia , UltrassonografiaAssuntos
Vitamina A/administração & dosagem , Feminino , Humanos , Masculino , Noruega/epidemiologia , Osteoporose/epidemiologia , Osteoporose/etiologia , Guias de Prática Clínica como Assunto , Suécia/epidemiologia , Vitamina A/efeitos adversos , Vitamina D/administração & dosagem , Vitamina D/efeitos adversosRESUMO
Since the estrogen receptor alpha (ER) is an important mediator of hormonal responses such as proliferation in estrogen-sensitive tissues, we hypothesized that polymorphisms in the ER gene could be functional and associated with endometrial cancer risk. We performed a population-based case-control study in Sweden, focusing on restriction fragment length polymorphisms for XbaI and PvuII and an upstream TA repeat polymorphism. In the main analysis, 154 cases and 205 controls who never used hormone replacement therapy took part and we calculated age-adjusted and multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The XbaI X allele appeared to confer a reduced risk for endometrial cancer. The multivariate OR for the XX genotype was 0.52 (95% CI 0.21-1.29) compared to the xx genotype and there were suggestions of decreasing risk with increasing number of X alleles (P for trend = 0.07). The PvuII PP genotype was also associated with a non-significantly decreased risk for endometrial cancer (multivariate OR 0.70, 95% CI 0.34-1.44) compared with the pp genotype (P for trend = 0.43). The multivariate OR for two short TA (<19 repeats) alleles versus two long alleles was 1.54 (95% CI 0. 73-3.27) and there were suggestions of increasing risk with increasing number of short alleles (P for trend = 0.26). We observed the same pattern of results in an expanded group of subjects, which included women who had used hormone replacement (in total 288 cases and 392 controls). Our data suggest that variants of the ER gene may be associated with an altered risk of endometrial cancer.
Assuntos
Neoplasias do Endométrio/etiologia , Polimorfismo Genético , Receptores de Estrogênio/genética , Idoso , Densidade Óssea , Repetições de Dinucleotídeos , Receptor alfa de Estrogênio , Feminino , Humanos , Pessoa de Meia-Idade , RiscoRESUMO
Vitamin D regulates parathyroid cell proliferation and secretion of PTH. Increased prevalence of the polymorphic vitamin D receptor (VDR) alleles b, a, and T has been reported in sporadic primary hyperparathyroidism (PHPT), suggesting that these genetic variants may predispose to the disease. Recently, another polymorphism in the VDR gene was related to bone mineral density, and this VDR-FokI polymorphism causes different lengths of the VDR, implying possible functional consequences. The VDR-FokI polymorphism was studied in 182 postmenopausal women with sporadic PHPT and in matched controls. No significant differences in distribution of the VDR-FokI genotypes could be detected between the groups, although there was a tendency toward overrepresentation of the F allele in the PHPT patients (P = 0.05). There were no significant associations with age, serum calcium, serum PTH, bone mineral density, or parathyroid tumor weight. The VDR genotypes were unrelated to VDR and PTH messenger ribonucleic acid levels in the parathyroid adenomas of 42 PHPT patients. In 23 PHPT patients, the Ca2+-PTH set-points were determined in vivo and were unrelated to the VDR alleles. We suggest that the VDR-FokI polymorphism has at most a minor pathogenic importance in the development of PHPT.
Assuntos
Códon de Iniciação/genética , Hiperparatireoidismo/genética , Glândulas Paratireoides/metabolismo , Polimorfismo Genético , RNA Mensageiro/biossíntese , Receptores de Calcitriol/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cálcio/sangue , Cálcio/metabolismo , Citratos , Desoxirribonucleases de Sítio Específico do Tipo II/biossíntese , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Feminino , Genótipo , Humanos , Hiperparatireoidismo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Glândulas Paratireoides/fisiopatologia , Hormônio Paratireóideo/biossíntese , Hormônio Paratireóideo/genética , Receptores de Calcitriol/biossínteseRESUMO
BACKGROUND: The highest incidence of osteoporotic fractures is found in northern Europe, where dietary intake of vitamin A (retinol) is unusually high. In animals, the most common adverse effect of toxic doses of retinol is spontaneous fracture. OBJECTIVE: To investigate whether excessive dietary intake of vitamin A is associated with decreased bone mineral density and increased risk for hip fracture. DESIGN: A cross-sectional study and a nested case-control study. SETTING: Two counties in central Sweden. PARTICIPANTS: For the cross-sectional study, 175 women 28 to 74 years of age were randomly selected. For the nested case-control study, 247 women who had a first hip fracture within 2 to 64 months after enrollment and 873 age-matched controls were selected from a mammography study cohort of 66,651 women 40 to 76 years of age. MEASUREMENTS: Retinol intake was estimated from dietary records and a food-frequency questionnaire. Bone mineral density was measured with dual-energy x-ray absorptiometry. Hip fracture was identified by using hospital discharge records and was confirmed by record review. RESULTS: In multivariate analysis, retinol intake was negatively associated with bone mineral density. For every 1-mg increase in daily intake of retinol, risk for hip fracture increased by 68% (95% CI, 18% to 140%; P for trend, 0.006). For intake greater than 1.5 mg/d compared with intake less than 0.5 mg/d, bone mineral density was reduced by 10% at the femoral neck (P = 0.05), 14% at the lumbar spine (P = 0.001), and 6% for the total body (P = 0.009) and risk for hip fracture was doubled (odds ratio, 2.1 [CI, 1.1 to 4.0]). CONCLUSION: High dietary intake of retinol seems to be associated with osteoporosis.