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2.
Bull Environ Contam Toxicol ; 106(1): 153-159, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33392685

RESUMO

Soil properties largely control the fate of mercury (Hg), including the synthesis of neurovirulent methylmercury (MeHg). Here, the freshwater snail (Cipangopaludina cahayensis), a snail species commonly bred in flooded farmland, was used in a test of biotoxicity exposure to explore the effects of soil components on Hg bioavailability. The results show that snails incubated on the surface of slightly Hg-polluted flooded soil (2.0 mg/kg) have MeHg concentrations of 7.9 ± 1.5 mg/kg, which greatly exceed the limit of contaminants in food in China (0.5 mg/kg). The addition of ferrous disulfide can significantly increase the MeHg concentrations in soils while reducing the concentrations of total Hg (THg) and MeHg levels in snails by 59.1% and 64.3%, respectively. Peat-derived fulvic acid has the capacity to reduce the MeHg concentrations in soils and snails by 23.8% and 33.2%, respectively, whereas it increases the dissolved Hg levels in overlying water by 104.3%. Moreover, Fe-Mn oxides and humic acid can consistently reduce THg and MeHg concentrations in snails. Overall, freshwater snails bred in Hg-polluted areas may suffer from a high risk of Hg exposure, and importantly, some soil components such as ferrous disulfide and humic acid have strong inhibitory effects on Hg bioaccumulation in snails.


Assuntos
Mercúrio , Compostos de Metilmercúrio , Animais , Bioacumulação , China , Monitoramento Ambiental , Água Doce , Mercúrio/análise , Caramujos , Solo
3.
Mol Genet Genomics ; 296(1): 55-65, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32970232

RESUMO

Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10-8): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10-8, replication p = 1.03 × 10-4), 16q12.2 (rs1421085, discovery p = 2.04 × 10-9, replication p = 6.47 × 10-14) and 18q21.32 (rs11152213, discovery p = 3.47 × 10-8, replication p = 6.69 × 10-6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.


Assuntos
Colo do Fêmur/metabolismo , Loci Gênicos , Pleiotropia Genética , Predisposição Genética para Doença , Osteoporose/genética , Sarcopenia/genética , Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Asiático , Índice de Massa Corporal , Densidade Óssea , Grupo com Ancestrais do Continente Europeu , Feminino , Colo do Fêmur/patologia , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etnologia , Osteoporose/metabolismo , Osteoporose/patologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/etnologia , Sarcopenia/metabolismo , Sarcopenia/patologia , Magreza/genética , Magreza/metabolismo
4.
Int J Obes (Lond) ; 44(10): 2113-2123, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32719433

RESUMO

BACKGROUND: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated. METHODS: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097). RESULTS: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10-8) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, pdiscovery = 3.32 × 10-8, preplication = 4.07 × 10-13), 5q13.1 (rs4976033, pdiscovery = 1.93 × 10-9, preplication = 6.35 × 10-7), 12q24.31 (rs4765528, pdiscovery = 7.19 × 10-12, preplication = 1.88 × 10-11) and 18q21.32 (rs371326986, pdiscovery = 9.04 × 10-9, preplication = 2.35 × 10-95). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development. CONCLUSIONS: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.

5.
Mol Genet Genomic Med ; 8(8): e1267, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32478482

RESUMO

Sarcopenia is a complex polygenic disease, and its molecular mechanism is still unclear. Whole lean body mass (WLBM) is a heritable trait predicting sarcopenia. To identify genomic loci underlying, we performed a whole-exome sequencing (WES) of WLBM variation with high sequencing depth (more than 40*) in 101 Chinese subjects. We then replicated in the major findings in the large-scale UK Biobank (UKB) cohort (N = 217,822) for WLBM. The results of four single-nucleotide polymorphisms (SNPs) were significant both in the discovery stage and replication stage: SNP rs740681 (discovery p = 1.66 × 10-6 , replication p = .05), rs2272303 (discovery p = 3.20 × 10-4 , replication p = 3.10 × 10-4 ), rs11170413 (discovery p = 3.99 × 10-4 , replication p = 2.90 × 10-4 ), and rs2272302 (discovery p = 9.13 × 10-4 , replication p = 3.10 × 10-4 ). We combined p values of the significant SNPs. Functional annotations highlighted two candidate genes, including FZR1 and SOAT2, that may exert pleiotropic effects to the development of body mass. Our findings provide useful insights that further enhance our understanding of genetic interplay in sarcopenia.


Assuntos
Proteínas Cdh1/genética , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Esterol O-Aciltransferase/genética , Adulto , Índice de Massa Corporal , China , Exoma , Feminino , Pleiotropia Genética , Humanos , Masculino
6.
Sci Rep ; 10(1): 4293, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152362

RESUMO

Whole body lean mass (WBLM) is a heritable trait predicting sarcopenia. To identify genomic locus underlying WBLM, we performed a genome-wide association study of fat-adjusted WBLM in the Framingham Heart Study (FHS, N = 6,004), and replicated in the Kansas City Osteoporosis Study (KCOS, N = 2,207). We identified a novel locus 3p27.1 that was associated with WBLM (lead SNP rs3732593 P = 7.19 × 10-8) in the discovery FHS sample, and the lead SNP was successfully replicated in the KCOS sample (one-sided P = 0.04). Bioinformatics analysis found that this SNP and its adjacent SNPs had the function of regulating enhancer activity in skeletal muscle myoblasts cells, further confirming the regulation of WBLM by this locus. Our finding provides new insight into the genetics of WBLM and enhance our understanding of sarcopenia.


Assuntos
Composição Corporal , Cromossomos Humanos Par 3/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Sarcopenia/patologia , Magreza/genética , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
7.
Sci Rep ; 10(1): 5057, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193455

RESUMO

Sarcopenia is characterized by low skeletal muscle, a complex trait with high heritability. With the dramatically increasing prevalence of obesity, obesity and sarcopenia occur simultaneously, a condition known as sarcopenic obesity. Fat mass and obesity-associated (FTO) gene is a candidate gene of obesity. To identify associations between lean mass and FTO gene, we performed a genome-wide association study (GWAS) of lean mass index (LMI) in 2207 unrelated Caucasian subjects and replicated major findings in two replication samples including 6,004 unrelated Caucasian and 38,292 unrelated Caucasian. We found 29 single nucleotide polymorphisms (SNPs) in FTO significantly associated with sarcopenia (combined p-values ranging from 5.92 × 10-12 to 1.69 × 10-9). Potential biological functions of SNPs were analyzed by HaploReg v4.1, RegulomeDB, GTEx, IMPC and STRING. Our results provide suggestive evidence that FTO gene is associated with lean mass.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/fisiologia , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Magreza/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Sarcopenia/genética
8.
Environ Sci Pollut Res Int ; 27(8): 8596-8610, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31907806

RESUMO

Zooplankton play an important role in the transfer of mercury (Hg) from the lower to upper trophic positions in the food chain. In this study, total mercury (THg) and methylmercury (MeHg) levels were measured in three size fractions of zooplankton collected from three reservoirs (Hongfeng, Baihua, and Aha Reservoir) and one wetland in karst areas to understand mercury accumulation in zooplankton from alkaline environments. The results showed that the alkaline waters had lower zooplankton MeHg levels (0.1 to 66.8 ng g-1) than most of the acidic waters reported. However, the zooplankton THg levels (6.3 to 494.9 ng g-1) were comparable. The macro-zooplankton (> 500 µm) had significantly higher THg and MeHg levels than meso-zooplankton (116 to 500 µm) in the three reservoirs at all seasons, which showed biomagnification of mercury in the food chain. The correlation between Hg in water and zooplankton and Hg in zooplankton of different sizes indicated that THg bioaccumulation in zooplankton was related to the THg levels in water; however, MeHg bioaccumulation in zooplankton was controlled by many other factors, such as their feeding and living habits. In the three reservoirs, the THg and MeHg concentrations in zooplankton decreased with increasing eutrophication. However, compared with the three reservoirs, Caohai Wetland, with large amounts of aquatic plants, had a much lower trophic level and higher MeHg content in water but much lower zooplankton MeHg levels and bioaccumulation factors (BAFs). The large amounts of plant residue might dilute mercury in the food chain, revealing that high primary production could result in lower Hg bioaccumulation, rather than only being influenced by nutrient levels.


Assuntos
Mercúrio , Compostos de Metilmercúrio , Poluentes Químicos da Água , Zooplâncton/química , Animais , Bioacumulação , China , Monitoramento Ambiental , Eutrofização , Cadeia Alimentar , Mercúrio/análise , Mercúrio/química , Compostos de Metilmercúrio/química
9.
Shanghai Kou Qiang Yi Xue ; 28(3): 246-250, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489410

RESUMO

PURPOSE: To compare the antimicrobial effect of different irrigations on Enterococcus faecalis biofilms in extracted teeth and evaluate the antimicrobial activity of irrigating solutions residual against E. faecalis biofilms formation, in order to provide a better strategy for clinician. METHODS: Extracted human premolar teeth with single root canal were clearly autoclaved. These teeth were contaminated with E. faecalis(ATCC33186) and incubated for 60 days. The samples were randomly assigned to 4 experimental groups. During biomechanical instrumentation, the root canal was irrigated with different irrigating agents. The bacteria samples were collected with sterile paper points before and after instrumentation to F2. Then, samples that had been instrumented and autoclaved again were randomly divided into 2 groups treated with normal saline and 1%NaOCl for 30 min. E. faecalis was used to contaminate these root canals. The bacteria samples were collected with sterile paper points after 2, 6, 24, 48 h. SPSS19.0 software package was used for statistical analysis. RESULTS: Group using 1% NaOCI with ultrasound devices was significantly more effective than NS alone groups. 1% NaOCI groups showed a better residual activity than NS group. CONCLUSIONS: NaOCl is still the most important irrigating solutions, and it could be a better choice after biomechanical instrumentation, because of its long time substantivity achieves residual antimicrobial activity. Ultrasound devices is recommended to coordinate with irrigation.


Assuntos
Anti-Infecciosos , Cavidade Pulpar , Enterococcus faecalis , Irrigantes do Canal Radicular , Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Humanos , Irrigantes do Canal Radicular/farmacologia , Hipoclorito de Sódio
10.
Int J Obes (Lond) ; 43(12): 2480-2490, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30944420

RESUMO

OBJECTIVES: Aiming to uncover the genetic basis of abdominal obesity, we performed a genome-wide association study (GWAS) meta-analysis of trunk fat mass adjusted by trunk lean mass (TFMadj) and followed by a series of functional investigations. SUBJECTS: A total of 11,569 subjects from six samples were included into the GWAS meta-analysis. METHODS: Meta-analysis was performed by a weighted fixed-effects model. In silico replication analysis was performed in the UK-Biobank (UKB) sample (N = 331,093) and in the GIANT study (N up to 110,204). Cis-expression QTL (cis-eQTL) analysis, dual-luciferase reporter assay and electrophoresis mobility shift assay (EMSA) were conducted to examine the functional relevance of the identified SNPs. At last, differential gene expression analysis (DGEA) was performed. RESULTS: We identified an independent SNP rs12409479 at 1p21 (MAF = 0.07, p = 7.26 × 10-10), whose association was replicated by the analysis of TFM in the UKB sample (one-sided p = 3.39 × 10-3), and was cross-validated by the analyses of BMI (one-sided p = 0.03) and WHRadj (one-sided p = 0.04) in the GIANT study. Cis-eQTL analysis demonstrated that allele A at rs12409479 was positively associated with PTBP2 expression level in subcutaneous adipose tissue (N = 385, p = 4.15 × 10-3). Dual-luciferase reporter assay showed that the region repressed PTBP2 gene expression by downregulating PTBP2 promoter activity (p < 0.001), and allele A at rs12409479 induced higher luciferase activity than allele G did (p = 4.15 × 10-3). EMSA experiment implied that allele A was more capable of binding to unknown transcription factors than allele G. Lastly, DGEA showed that the level of PTBP2 expression was higher in individuals with obesity than in individuals without obesity (N = 20 and 11, p = 0.04 and 9.22 × 10-3), suggesting a regulatory role in obesity development. CONCLUSIONS: Taken together, we hypothesize a regulating path from rs12409479 to trunk fat mass development through its allelic specific regulation of PTBP2 gene expression, thus providing some novel insight into the genetic basis of abdominal obesity.


Assuntos
Cromossomos Humanos Par 1/genética , Obesidade Abdominal/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Índice de Massa Corporal , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/análise , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo
11.
J Bone Miner Res ; 34(6): 1086-1094, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30690781

RESUMO

Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a meta-analysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (α = 5.0 × 10-8 ), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p = 3.58 × 10-4 ) and coding regions (p = 5.71 × 10-4 ). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations. © 2019 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea/genética , Loci Gênicos , Animais , Linhagem Celular , Cromossomos de Mamíferos/genética , Estudos de Associação Genética , Genoma , Camundongos , Proteínas do Grupo Polycomb/genética , Polimorfismo de Nucleotídeo Único/genética
12.
Shanghai Kou Qiang Yi Xue ; 27(3): 239-243, 2018 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-30411115

RESUMO

PURPOSE: The aim of this study was to determine the influence of fluoride-resistant strains of S. mutans on the bonding strength of dental resin composite. METHODS: Standardized specimens of resin composite (Z350), and self-etch adhesives (Single bond Universal, 3M) were incubated with S. mutans UA159, fluoride-resistant strains of S. mutans UA159 (UA159-FR) or uninoculated culture medium (Control) or PBS for up to 14 days. Resin-dentin bonded disks were subjected to push-out test. Fractured surface analysis of the specimens was performed by scanning electron microscopy(SEM). SPSS18.0 software package was used for statistical analysis. RESULTS: UA159-FR and UA159 were shown to decrease the bond strengths in levels comparable with those found in the control groups (P<0.05). SEM confirmed the increased degradation of all materials with UA159-FR and UA159, compared with control and PBS. CONCLUSIONS: The results suggest that resin-dentin interface can be compromised by oral bacteria that contribute to the progress of secondary caries. Fluoride-resistant strains of S. mutans and its parental strains both decrease bonding strengths in a short time, but no significant difference in the extent of damage.


Assuntos
Colagem Dentária , Adesivos Dentinários , Fluoretos , Streptococcus mutans , Resinas Compostas , Dentina , Fluoretos/farmacologia , Teste de Materiais , Cimentos de Resina , Streptococcus mutans/fisiologia , Propriedades de Superfície , Resistência à Tração
13.
Genome Med ; 9(1): 97, 2017 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-29149916

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10-5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls. RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10-12), SOD1 (p = 8.9 × 10-9) and NEK1 (p = 1.1 × 10-9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10-3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.


Assuntos
Esclerose Amiotrófica Lateral/genética , Quinase 1 Relacionada a NIMA/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Humanos , Risco , Sequenciamento Completo do Exoma
14.
Nat Commun ; 8(1): 611, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28931804

RESUMO

Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.


Assuntos
Esclerose Amiotrófica Lateral/genética , Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Glutationa Peroxidase/genética , Esclerose Amiotrófica Lateral/etnologia , Austrália , China , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Sequência de DNA
15.
Sci Rep ; 7: 45025, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28322352

RESUMO

Lean body mass (LBM) is a complex trait for human health. To identify genomic loci underlying LBM, we performed a gene-based genome-wide association study of lean mass index (LMI) in 1000 unrelated Caucasian subjects, and replicated in 2283 unrelated Caucasians subjects. Gene-based association analyses highlighted the significant associations of three genes UQCR, TCF3 and MBD3 in one single locus 19p13.3 (discovery p = 6.10 × 10-5, 1.65 × 10-4 and 1.10 × 10-4; replication p = 2.21 × 10-3, 1.84 × 10-3 and 6.95 × 10-3; combined p = 2.26 × 10-6, 4.86 × 10-6 and 1.15 × 10-5, respectively). These results, together with the known functional relevance of the three genes to LMI, suggested that the 19p13.3 region containing UQCR, TCF3 and MBD3 genes was a novel locus underlying lean mass variation.


Assuntos
Composição Corporal/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Estudo de Associação Genômica Ampla , Magreza/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
16.
Bone ; 91: 1-10, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27397699

RESUMO

Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p=1.20×10(-8), FHS p=0.05 for trochanter BMD; rs9287237, discovery p=3.55×10(-7), FHS p=9.20×10(-3) for trochanter BMD, GEFOS p=0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p=7.48×10(-7), FHS p=0.10 for inter-trochanter BMD, GEFOS p=0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p=3.09×10(-6), FHS p=8.50×10(-3), GEFOS p=1.23×10(-24) for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p=1.64×10(-6), GEFOS p=1.69×10(-3) for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p=8.79×10(-7), GEFOS p=2.61×10(-7) for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.


Assuntos
Densidade Óssea/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 2/genética , Estudo de Associação Genômica Ampla , Quadril/fisiopatologia , Adulto , Feminino , Redes Reguladoras de Genes , Loci Gênicos , Quadril/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
17.
Hum Genet ; 135(2): 171-84, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26661625

RESUMO

Accurately estimating the distribution and heritability of SNP effects across the genome could help explain the mystery of missing heritability. In this study, we propose a novel statistical method for estimating the distribution and heritability of SNP effects from genome-wide association studies (GWASs), and compare its performance to several existing methods using both simulations and real data. Specifically, we study the full range of GWAS summary results and link observed p values and unobserved effect sizes by (non-central) Chi-square distribution. By modeling the observed full set of association signals using a multinomial distribution, we build a likelihood function of SNP effect sizes using parametric and non-parametric maximum likelihood frameworks. Simulation studies show that the proposed method can accurately estimate effect sizes and the number of associated SNPs. As real applications, we analyze publicly available GWAS summary results for height, body mass index (BMI), and bone mineral density (BMD). Our analyses show that there are over 10,000 SNPs that might be associated with height, and the total heritability attributable to these SNPs exceeds 70 %. The heritabilities for BMI and BMD are ~10 and ~15 %, respectively. The results indicate that the proposed method has the potential to improve the accuracy of estimates of heritability and effect size for common SNPs in large-scale GWAS meta-analyses. These improved estimates may contribute to an enhanced understanding of the genetic basis of complex traits.


Assuntos
Estudos de Associação Genética/métodos , Característica Quantitativa Herdável , Índice de Massa Corporal , Densidade Óssea , Humanos , Funções Verossimilhança , Desequilíbrio de Ligação , Metanálise como Assunto , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
PLoS One ; 9(3): e89776, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24626161

RESUMO

Skeletal muscle is a major component of the human body. Age-related loss of muscle mass and function contributes to some public health problems such as sarcopenia and osteoporosis. Skeletal muscle, mainly composed of appendicular lean mass (ALM), is a heritable trait. Copy number variation (CNV) is a common type of human genome variant which may play an important role in the etiology of many human diseases. In this study, we performed genome-wide association analyses of CNV for ALM in 2,286 Caucasian subjects. We then replicated the major findings in 1,627 Chinese subjects. Two CNVs, CNV1191 and CNV2580, were detected to be associated with ALM (p = 2.26×10(-2) and 3.34×10(-3), respectively). In the Chinese replication sample, the two CNVs achieved p-values of 3.26×10(-2) and 0.107, respectively. CNV1191 covers a gene, GTPase of the immunity-associated protein family (GIMAP1), which is important for skeletal muscle cell survival/death in humans. CNV2580 is located in the Serine hydrolase-like protein (SERHL) gene, which plays an important role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli. In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM.


Assuntos
Índice de Massa Corporal , Variações do Número de Cópias de DNA , Proteínas de Ligação ao GTP/genética , Estudo de Associação Genômica Ampla , Proteínas de Membrana/genética , Músculo Esquelético/fisiologia , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China , Grupo com Ancestrais do Continente Europeu , Feminino , GTP Fosfo-Hidrolases/genética , Dosagem de Genes , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Controle de Qualidade , Reprodutibilidade dos Testes , Software
19.
J Renin Angiotensin Aldosterone Syst ; 15(3): 218-27, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23283823

RESUMO

INTRODUCTION: This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. MATERIALS AND METHODS: Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. RESULTS: Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. CONCLUSION: Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/urina , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/urina , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/patologia , Masculino , Camundongos Endogâmicos DBA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Estreptozocina , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Tíbia/patologia , Microtomografia por Raio-X
20.
Hum Mol Genet ; 23(3): 820-30, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24064335

RESUMO

Obesity is a major public health problem with strong genetic determination. Multiple genetic variants have been implicated for obesity by conducting genome-wide association (GWA) studies, primarily focused on body mass index (BMI). Fat body mass (FBM) is phenotypically more homogeneous than BMI and is more appropriate for obesity research; however, relatively few studies have been conducted on FBM. Aiming to identify variants associated with obesity, we carried out meta-analyses of seven GWA studies for BMI-related traits including FBM, and followed these analyses by de novo replication. The discovery cohorts consisted of 21 969 individuals from diverse ethnic populations and a total of over 4 million genotyped or imputed SNPs. The de novo replication cohorts consisted of 6663 subjects from two independent samples. To complement individual SNP-based association analyses, we also carried out gene-based GWA analyses in which all variations within a gene were considered jointly. Individual SNP-based association analyses identified a novel locus 1q21 [rs2230061, CTSS (Cathepsin S)] that was associated with FBM after the adjustment of lean body mass (LBM) (P = 3.57 × 10(-8)) at the genome-wide significance level. Gene-based association analyses identified a novel gene NLK (nemo-like kinase) in 17q11 that was significantly associated with FBM adjusted by LBM. In addition, we confirmed three previously reported obesity susceptibility loci: 16q12 [rs62033400, P = 1.97 × 10(-14), FTO (fat mass and obesity associated)], 18q22 [rs6567160, P = 8.09 × 10(-19), MC4R (melanocortin 4 receptor)] and 2p25 [rs939583, P = 1.07 × 10(-7), TMEM18 (transmembrane protein 18)]. We also found that rs6567160 may exert pleiotropic effects to both FBM and LBM. Our results provide additional insights into the molecular genetic basis of obesity and may provide future targets for effective prevention and therapeutic intervention.


Assuntos
Predisposição Genética para Doença , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Tecido Adiposo/fisiologia , Catepsinas/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Proteínas Serina-Treonina Quinases/genética
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