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1.
Circ Res ; 125(8): 773-782, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31476962

RESUMO

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

2.
J Bone Miner Res ; 34(7): 1284-1296, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30888730

RESUMO

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30503163

RESUMO

BACKGROUND: Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. METHODS: We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. FINDINGS: 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. INTERPRETATION: HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. FUNDING: National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.

4.
Arch Osteoporos ; 13(1): 123, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30421154

RESUMO

The distribution of bone tissue within the vertebra can modulate vertebral strength independently of average density and may change with age and disc degeneration. Our results show that the age-associated decrease in bone density is spatially non-uniform and associated with disc health, suggesting a mechanistic interplay between disc and vertebra. PURPOSE: While the decline of bone mineral density (BMD) in the aging spine is well established, the extent to which age influences BMD distribution within the vertebra is less clear. Measures of regional BMD (rBMD) may improve predictions of vertebral strength and suggest how vertebrae might adapt with intervertebral disc degeneration. Thus, we aimed to assess how rBMD values were associated with age, sex, and disc height loss (DHL). METHODS: We measured rBMD in the L3 vertebra of 377 participants from the Framingham Heart Study (41-83 years, 181 M/196 F). Integral (Int.BMD) and trabecular BMD (Tb.BMD) were measured from QCT images. rBMD ratios (anterior/posterior, superior/mid-transverse, inferior/mid-transverse, and central/outer) were calculated from the centrum. A radiologist assigned a DHL severity score to adjacent intervertebral discs (L2-L3 and L3-L4). RESULTS: Int.BMD and Tb.BMD were both associated with age, though the decrease across age was greater in women (Int.BMD, - 2.6 mg/cm3 per year; Tb.BMD, - 2.6 mg/cm3 per year) than men (Int.BMD, - 0.5 mg/cm3 per year; Tb.BMD, - 1.2 mg/cm3 per year). The central/outer (- 0.027/decade) and superior/mid-transverse (- 0.018/decade) rBMD ratios were negatively associated with age, with similar trends in men and women. Higher Int.BMD or Tb.BMD was associated with increased odds of DHL after adjusting for age and sex. Low central/outer ratio and high anterior/poster and superior/mid-transverse ratios were also associated with increased odds of DHL. CONCLUSIONS: Our results indicate that the distribution of bone within the L3 vertebra is different across age, but not between sexes, and is associated with disc degeneration.

5.
Sci Rep ; 8(1): 13756, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30213970

RESUMO

Transcriptomic analysis showed that the central circadian pathway genes had significantly altered expression in fracture calluses from mice fed a low phosphate diet. This led us to hypothesize that phosphate deficiency altered the circadian cycle in peripheral tissues. Analysis of the expression of the central clock genes over a 24-36 hour period in multiple peripheral tissues including fracture callus, proximal tibia growth plate and cardiac tissues after 12 days on a low phosphate diet showed higher levels of gene expression in the hypophosphatemia groups (p < 0.001) and a 3 to 6 hour elongation of the circadian cycle. A comparative analysis of the callus tissue transcriptome genes that were differentially regulated by hypophosphatemia with published data for the genes in bone that are diurnally regulated identified 1879 genes with overlapping differential regulation, which were shown by ontology assessment to be associated with oxidative metabolism and apoptosis. Network analysis of the central circadian pathway genes linked their expression to the up regulated expression of the histone methyltransferase gene EZH2, a gene that when mutated in both humans and mice controls overall skeletal growth. These data suggest that phosphate is an essential metabolite that controls circadian function in both skeletal and non skeletal peripheral tissues and associates its levels with the overall oxidative metabolism and skeletal growth of animals.

6.
Bioinformatics ; 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30101356

RESUMO

Motivation: Clustering algorithms like K-Means and standard Gaussian mixture models (GMM) fail to account for the structure of variability of replicated data or repeated measures over time. Additionally, a priori cluster number assumptions add an additional complexity to the process. Current methods to optimize cluster labels and number can be inaccurate or computationally intensive for temporal gene expression data with this additional variability. Results: An extension to a model-based clustering algorithm is proposed using mixtures of mixed effects polynomial regression models and the EM algorithm with an entropy penalized log-likelihood function (EPEM). The EPEM is used to cluster temporal gene expression data with this additional variability. The addition of random effects in our model decreased the misclassification error when compared to mixtures of fixed effects models or other methods such as K-Means and GMM. Applying our method to microarray data from a fracture healing study revealed distinct temporal patterns of gene expression. Supplementary information: Supplementary text are available at Bioinformatics online.

7.
J Bone Miner Res ; 33(4): 621-626, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29115684

RESUMO

We tested whether cortical bone tissue properties assessed by in vivo impact microindentation would distinguish postmenopausal women with recent distal radius (DRF) or hip fracture (HF) from nonfracture controls (CONT). We enrolled postmenopausal women with recent DRF (n = 57), HF (n = 41), or CONT (n = 93), and used impact microindentation to assess bone material strength index (BMSi) at the anterior surface of the mid-tibia diaphysis. Areal bone mineral density (aBMD) (g/cm2 ) of the femoral neck (FN), total hip (TH), and lumbar spine (LS) were measured by dual-energy X-ray absorptiometry (DXA). HF and DRF subjects had significantly lower BMD than CONT at all sites (-5.6% to -8.2%, p < 0.001 for all). BMSi was 4% lower in DRF compared to CONT (74.36 ± 8.77 versus 77.41 ± 8.79, p = 0.04). BMSi was similarly lower in HF versus CONT, but the difference did not reach statistical significance (74.62 ± 8.47 versus 77.41 ± 8.79, p = 0.09). Lower BMSi was associated with increased risk of DRF (unadjusted OR, 1.43; 95% CI, 1.02 to 2.00, per SD decrease, p = 0.04), and remained statistically significant after adjustment for age, age and BMI, and age, BMI, and FN BMD (OR = 1.48 to 1.55). Lower BMSi tended to be associated with HF, but only reached borderline significance (unadjusted OR = 1.39; 95% CI, 0.96 to 2.01, p = 0.08). These results provide strong rationale for future investigations aimed at assessing whether BMSi can predict fracture in prospective studies and improve identification of women at risk for fragility fractures. © 2017 American Society for Bone and Mineral Research.

8.
J Bone Miner Res ; 33(1): 54-62, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28929525

RESUMO

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non-T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR-pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non-T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR-pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross-sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non-T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non-T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non-T2D, but only among those who did not have a prior fracture. Findings from this large, community-based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.

10.
J Bone Miner Res ; 32(11): 2151-2156, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28722129

RESUMO

Genetic factors contribute to the risk of bone fractures, partly because of effects on bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) estimates bone strength using micro-finite element analysis (µFEA). The goal of this study was to investigate if the bone failure load estimated by HR-pQCT-based µFEA is heritable and to what extent it shares genetic regulation with areal bone mineral density (aBMD). Bone microarchitecture was measured by HR-pQCT at the ultradistal tibia and ultradistal radius in adults from the Framingham Heart Study (n = 1087, mean age 72 years; 57% women). Radial and tibial failure load in compression were estimated by µFEA. Femoral neck (FN) and ultradistal forearm (UD) aBMD were measured by dual-energy X-ray absorptiometry (DXA). Heritability (h2 ) of failure load and aBMD and genetic correlations between them was estimated adjusting for covariates (age and sex). Failure load values at the non-weight-bearing ultradistal radius and at the weight-bearing ultradistal tibia were highly correlated (r = 0.906; p < 0.001). Estimates of h2 adjusted for covariates were 0.522 for the radius and 0.497 for the tibia. Additional adjustment for height did not impact on the h2 results, but adjustment for aBMD at the UD and FN somewhat decreased h2 point estimates: 0.222 and 0.380 for radius and tibia, respectively. In bivariate analysis, there was a high phenotypic and genetic correlation between covariate-adjusted failure load at the radius and UD aBMD (ρP = 0.826, ρG = 0.954, respectively), whereas environmental correlations were lower (ρE = 0.696), all highly significant (p < 0.001). Similar correlations were observed between tibial failure load and femoral neck aBMD (ρP = 0.577, ρG = 0.703, both p < 0.001; ρE = 0.432, p < 0.05). These data from adult members of families from a population-based cohort suggest that bone strength of distal extremities estimated by micro-finite element analysis is heritable and shares some genetic composition with areal BMD, regardless of the skeletal site. © 2017 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea/genética , Osso e Ossos/fisiologia , Análise de Elementos Finitos , Predisposição Genética para Doença , Padrões de Herança/genética , Absorciometria de Fóton , Idoso , Osso e Ossos/anatomia & histologia , Feminino , Humanos , Masculino , Fenótipo , Suporte de Carga
11.
Nat Commun ; 8(1): 80, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28724990

RESUMO

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.


Assuntos
Estudo de Associação Genômica Ampla , Magreza/genética , 17-Hidroxiesteroide Desidrogenases/genética , Proteínas ADAMTS/genética , Aldeído Oxirredutases/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Composição Corporal , Proteínas da Matriz Extracelular/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Elementos Reguladores de Transcrição , Versicanas/genética
12.
Nat Commun ; 8(1): 121, 2017 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-28743860

RESUMO

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.


Assuntos
Proteínas de Transporte/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Desenvolvimento Musculoesquelético/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Peso Corporal , Densidade Óssea , Criança , Feminino , Expressão Gênica , Humanos , Masculino , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
13.
Circ Cardiovasc Genet ; 10(1)2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28213390

RESUMO

BACKGROUND: Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. METHODS AND RESULTS: To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P<1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P=8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P=0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (PTC=0.004, PHDL-C=0.008 and Ptriglycerides=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. CONCLUSIONS: We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.


Assuntos
Doença das Coronárias/genética , Metilação de DNA , Dislipidemias/genética , Epigênese Genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Locos de Características Quantitativas , Idoso , Biomarcadores/sangue , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Ilhas de CpG , Estudos Transversais , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Epigenômica/métodos , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
14.
J Bone Miner Res ; 32(1): 106-114, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27419666

RESUMO

High-resolution peripheral quantitative computed tomography (HR-pQCT) measures bone microarchitecture and volumetric bone mineral density (vBMD), important risk factors for osteoporotic fractures. We estimated the heritability (h2 ) of bone microstructure indices and vBMD, measured by HR-pQCT, and genetic correlations (ρG ) among them and between them and regional aBMD measured by dual-energy X-ray absorptiometry (DXA), in adult relatives from the Framingham Heart Study. Cortical (Ct) and trabecular (Tb) traits were measured at the distal radius and tibia in up to 1047 participants, and ultradistal radius (UD) aBMD was obtained by DXA. Heritability estimates, adjusted for age, sex, and estrogenic status (in women), ranged from 19.3% (trabecular number) to 82.8% (p < 0.01, Ct.vBMD) in the radius and from 51.9% (trabecular thickness) to 98.3% (cortical cross-sectional area fraction) in the tibia. Additional adjustments for height, weight, and radial aBMD had no major effect on h2 estimates. In bivariate analyses, moderate to high genetic correlations were found between radial total vBMD and microarchitecture traits (ρG from 0.227 to 0.913), except for cortical porosity. At the tibia, a similar pattern of genetic correlations was observed (ρG from 0.274 to 0.948), except for cortical porosity. Environmental correlations between the microarchitecture traits were also substantial. There were high genetic correlations between UD aBMD and multivariable-adjusted total and trabecular vBMD at the radius (ρG = 0.811 and 0.917, respectively). In summary, in related men and women from a population-based cohort, cortical and trabecular microarchitecture and vBMD at the radius and tibia were heritable and shared some h2 with regional aBMD measured by DXA. These findings of high heritability of HR-pQCT traits, with a slight attenuation when adjusting for aBMD, supports further work to identify the specific variants underlying volumetric bone density and fine structure of long bones. Knowledge that some of these traits are genetically correlated can serve to reduce the number of traits for genetic association studies. © 2016 American Society for Bone and Mineral Research.


Assuntos
Osso e Ossos/anatomia & histologia , Padrões de Herança/genética , Absorciometria de Fóton , Idoso , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Família , Feminino , Humanos , Masculino , Característica Quantitativa Herdável , Tomografia Computadorizada por Raios X
15.
Hum Mol Genet ; 25(23): 5234-5243, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27616567

RESUMO

Background: Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis. Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study ( n = 925) and Cardiovascular Health Study ( n = 366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF <1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find protein-coding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS , ARHGAP1 , and 5' of MEF2C ( P- values < 8x10 - 5 ; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements. Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.


Assuntos
Densidade Óssea/genética , Doenças Cardiovasculares/genética , Proteínas Ativadoras de GTPase/genética , Envelhecimento/genética , Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Estudos de Coortes , Estudos Epidemiológicos , Feminino , Colo do Fêmur/metabolismo , Colo do Fêmur/patologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fatores de Transcrição MEF2/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
J Bone Miner Res ; 31(12): 2077-2084, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27455046

RESUMO

Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co-occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T4 -T12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (ρˆG , -0.46; 95% CI, -0.67 to -0.26), vertebral fracture (ρˆG , 0.39; 95% CI, 0.18 to 0.61), vBMD (ρˆG , -0.23; 95% CI, -0.41 to -0.04), and paraspinal muscle density (ρˆG , -0.22; 95% CI, -0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (ρˆG , 0.17; 95% CI, -0.05 to 0.38) and facet joint OA (ρˆG , 0.05; 95% CI, -0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density. © 2016 American Society for Bone and Mineral Research.


Assuntos
Padrões de Herança/genética , Curvaturas da Coluna Vertebral/genética , Vértebras Torácicas/patologia , Distribuição por Idade , Idoso , Algoritmos , Feminino , Humanos , Cifose/diagnóstico por imagem , Cifose/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Curvaturas da Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
17.
PLoS Genet ; 12(5): e1006034, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27149122

RESUMO

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Metilação de DNA/genética , Insuficiência Cardíaca/genética , Receptores de Citocinas/genética , Afro-Americanos/genética , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Cromossomos Humanos Par 5/genética , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Células HEK293 , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Citocinas/sangue
18.
J Med Genet ; 53(7): 441-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27036123

RESUMO

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.


Assuntos
Angiopoietinas/genética , Éxons/genética , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína 4 Semelhante a Angiopoietina , Jejum/fisiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
19.
PLoS One ; 11(3): e0144997, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26950853

RESUMO

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.


Assuntos
Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Infarto do Miocárdio/genética , Idoso , Estudos de Coortes , Comportamento Cooperativo , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
20.
PLoS One ; 10(10): e0140496, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26516778

RESUMO

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.


Assuntos
Afro-Americanos/genética , Anti-Hipertensivos/farmacologia , Doenças Cardiovasculares/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Hipertensão/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Idoso , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Incidência , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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