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1.
Artigo em Inglês | MEDLINE | ID: mdl-29263935

RESUMO

Although systemic inflammatory responses attributable to infection may lead to significant lung injury, the precise molecular mechanisms leading to lung damage are poorly understood and therapeutic options remain limited. Here, we show that myeloid monocyte chemotactic protein-inducible protein 1 (MCPIP1) plays a central role in protecting against LPS-induced inflammation and lung injury. Myeloid-specific MCPIP1 knockout mice developed spontaneous inflammatory syndromes, but at a late age compared to global MCPIP1 knockout mice. Moreover, mice with a myeloid-specific deletion of MCPIP1 were extremely sensitive to LPS-induced lung injury due to overproduction of proinflammatory cytokines and chemokines. We identified C/EBPß and C/EBPδ, two critical transcriptional factors that drive cytokine production and lung injury, as targets of MCPIP1 RNase. LPS administration caused MCPIP1 protein degradation in the lungs. Pharmacological inhibition of MALT1, a paracaspase that cleaves MCPIP1, by MI-2 selectively increased the MCPIP1 protein levels in macrophages and in the lungs. Meanwhile, administration of MI-2 protected mice from LPS-induced inflammation, lung injury and death. Collectively, these results indicate that myeloid MCPIP1 is central in controlling LPS-induced inflammation and lung injury. Pharmacological inhibition of MALT1 protease activity may be a good strategy to treat inflammatory diseases by enhancing MCPIP1 expression in myeloid cells.

2.
Gigascience ; 6(8): 1-12, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28873967

RESUMO

The human gut microbiome can modulate metabolic health and affect insulin resistance, and it may play an important role in the etiology of gestational diabetes mellitus (GDM). Here, we compared the gut microbial composition of 43 GDM patients and 81 healthy pregnant women via whole-metagenome shotgun sequencing of their fecal samples, collected at 21-29 weeks, to explore associations between GDM and the composition of microbial taxonomic units and functional genes. A metagenome-wide association study identified 154 837 genes, which clustered into 129 metagenome linkage groups (MLGs) for species description, with significant relative abundance differences between the 2 cohorts. Parabacteroides distasonis, Klebsiella variicola, etc., were enriched in GDM patients, whereas Methanobrevibacter smithii, Alistipes spp., Bifidobacterium spp., and Eubacterium spp. were enriched in controls. The ratios of the gross abundances of GDM-enriched MLGs to control-enriched MLGs were positively correlated with blood glucose levels. A random forest model shows that fecal MLGs have excellent discriminatory power to predict GDM status. Our study discovered novel relationships between the gut microbiome and GDM status and suggests that changes in microbial composition may potentially be used to identify individuals at risk for GDM.


Assuntos
Diabetes Gestacional/etiologia , Microbioma Gastrointestinal , Metagenoma , Metagenômica , Biomarcadores , Glicemia , Análise por Conglomerados , Feminino , Humanos , Metagenômica/métodos , Modelos Biológicos , Gravidez , Curva ROC
3.
J Bone Miner Metab ; 35(6): 649-658, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28012008

RESUMO

Several studies indicated bone mineral density (BMD) and alcohol intake might share common genetic factors. The study aimed to explore potential SNPs/genes related to both phenotypes in US Caucasians at the genome-wide level. A bivariate genome-wide association study (GWAS) was performed in 2069 unrelated participants. Regular drinking was graded as 1, 2, 3, 4, 5, or 6, representing drinking alcohol never, less than once, once or twice, three to six times, seven to ten times, or more than ten times per week respectively. Hip, spine, and whole body BMDs were measured. The bivariate GWAS was conducted on the basis of a bivariate linear regression model. Sex-stratified association analyses were performed in the male and female subgroups. In males, the most significant association signal was detected in SNP rs685395 in DYNC2H1 with bivariate spine BMD and alcohol drinking (P = 1.94 × 10-8). SNP rs685395 and five other SNPs, rs657752, rs614902, rs682851, rs626330, and rs689295, located in the same haplotype block in DYNC2H1 were the top ten most significant SNPs in the bivariate GWAS in males. Additionally, two SNPs in GRIK4 in males and three SNPs in OPRM1 in females were suggestively associated with BMDs (of the hip, spine, and whole body) and alcohol drinking. Nine SNPs in IL1RN were only suggestively associated with female whole body BMD and alcohol drinking. Our study indicated that DYNC2H1 may contribute to the genetic mechanisms of both spine BMD and alcohol drinking in male Caucasians. Moreover, our study suggested potential pleiotropic roles of OPRM1 and IL1RN in females and GRIK4 in males underlying variation of both BMD and alcohol drinking.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Densidade Óssea/genética , Grupo com Ancestrais do Continente Europeu/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Adulto , Feminino , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
4.
Sci Rep ; 6: 38975, 2016 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-27941911

RESUMO

Adiporedoxin (Adrx) is a recently discovered redox regulatory protein that is preferentially expressed in adipose tissue and plays a critical role in the regulation of metabolism via its modulation of adipocyte protein secretion. We here report that Adrx suppresses endothelial cell activation via inhibiting MAPK and NF-kB signaling pathways. Adrx is constitutively expressed in human vascular endothelial cells, and significantly induced by a variety of stimuli such as TNFα, IL-1ß, H2O2 and OxLDL. Overexpression of Adrx significantly attenuated TNFα-induced expression of VCAM-1 and ICAM-1, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knockdown of Adrx increased TNFα-induced expression of adhesion molecules and monocyte adherence to HUVECs. Furthermore, forced expression of Adrx decreased TNFα-induced activation of ERK1/2, JNK, p38 and IKKs in HUVECs. Adrx mutant in the CXXC motif that lost its anti-redox activity is less efficient than the wild-type Adrx, suggesting that Adrx-mediated inhibition of endothelial activation is partially dependent on its antioxidant activity. Finally, Adrx expression was markedly increased in human atheroma compared with normal tissue from the same carotid arteries. These results suggest that Adrx is an endogenous inhibitor of endothelial activation, and might be a therapeutic target for vascular inflammatory diseases.


Assuntos
Células Endoteliais/metabolismo , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Peroxirredoxinas , Artérias/metabolismo , Adesão Celular , Linhagem Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/metabolismo , Placa Aterosclerótica/metabolismo , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Sci Rep ; 6: 36666, 2016 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-27827448

RESUMO

Symbiotic gut microbiota is essential for human health, and its compositional changes have been associated with various complex disorders. However, systematic investigation of the acquisition and development of gut microbial communities during early infancy are relatively rare, particularly for infants from non-Western countries. In this study, we characterize the colonization and development of infant microbiota in healthy Chinese infants and compare the pattern with those from other countries. The fecal microbiota of 2-month-old infants was considerably more diverse than that of neonates, as indicated by higher relative abundances of Veillonella, Clostridium, Bacteroides, Lactobacillus, Collinsella and Prevotella, and reduction of Escherichia and Enterococcus. The fecal microbiota of vaginally delivered infants (both neonates and 2-month-old) had significant enrichment of Bacteroides, Parabacteroides and Megamonas, whereas cesarean delivered infants had enrichment of Prevotella, Streptococcus and Trabulsiella. By global comparison, we identify three different enterotypes, referred as "P-type", "A-type "and "F-type" which were highly abundant in Proteobacteria, Actinobacteria and Firmicutes, respectively. The three enterotypes' compositons vary geographically. All Chinese infants in our study belong to the P-type. These findings may provide novel insights into our understanding of the establishment of infant fecal bacterial communities.


Assuntos
Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Microbioma Gastrointestinal/fisiologia , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
6.
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
7.
Sci Rep ; 6: 26648, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27226242

RESUMO

Sample storage conditions are important for unbiased analysis of microbial communities in metagenomic studies. Specifically, for infant gut microbiota studies, stool specimens are often exposed to room temperature (RT) conditions prior to analysis. This could lead to variations in structural and quantitative assessment of bacterial communities. To estimate such effects of RT storage, we collected feces from 29 healthy infants (0-3 months) and partitioned each sample into 5 portions to be stored for different lengths of time at RT before freezing at -80 °C. Alpha diversity did not differ between samples with storage time from 0 to 2 hours. The UniFrac distances and microbial composition analysis showed significant differences by testing among individuals, but not by testing between different time points at RT. Changes in the relative abundance of some specific (less common, minor) taxa were still found during storage at room temperature. Our results support previous studies in children and adults, and provided useful information for accurate characterization of infant gut microbiomes. In particular, our study furnished a solid foundation and justification for using fecal samples exposed to RT for less than 2 hours for comparative analyses between various medical conditions.


Assuntos
Fezes/microbiologia , Microbioma Gastrointestinal , Manejo de Espécimes/métodos , Temperatura Ambiente , Humanos , Lactente , Recém-Nascido , Masculino
8.
J Bone Miner Res ; 31(2): 358-68, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26256109

RESUMO

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10(-6) (0.05/9593) and 1.00 × 10(-4), respectively. In stage 2, nine stage 1-discovered phosSNPs (based on α = 1.00 × 10(-4)) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10(-3), 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 × 10(-10), p = 5.26 × 10(-10), and p = 3.01 × 10(-10), respectively) and HIP-BMD (p = 3.26 × 10(-6), p = 1.97 × 10(-6), and p = 1.63 × 10(-12), respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants.


Assuntos
Densidade Óssea/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Proteínas Wnt/genética , Estudos de Coortes , Feminino , Colo do Fêmur/metabolismo , Humanos , Vértebras Lombares/metabolismo , Masculino , Fosforilação , Proteínas Wnt/metabolismo
9.
Proteomics ; 16(1): 12-28, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26435169

RESUMO

Menopause is one of the crucial physiological events during the life of a woman. Transition of menopause status is accompanied by increased risks of various health problems such as osteoporosis. Peripheral blood monocytes can differentiate into osteoclasts and produce cytokines important for osteoclast activity. With quantitative proteomics LC-nano-ESI-MS(E) (where MS(E) is elevated-energy MS), we performed protein expression profiling of peripheral blood monocytes in 42 postmenopausal women with discordant bone mineral density (BMD) levels. Traditional comparative analysis showed proteins encoded by four genes (LOC654188, PPIA, TAGLN2, YWHAB) and three genes (LMNB1, ANXA2P2, ANXA2) were significantly down- and upregulated, respectively, in extremely low- versus high-BMD subjects. To study functionally orchestrating groups of detected proteins in the form of networks, we performed weighted gene coexpression network analysis and gene set enrichment analysis. Weighted gene coexpression network analysis showed that the module including the annexin gene family was most significantly correlated with low BMD, and the lipid-binding related GO terms were enriched in this identified module. Gene set enrichment analysis revealed that two significantly enriched gene sets may be involved in postmenopausal BMD variation by regulating pro-inflammatory cytokines activities. To gain more insights into the proteomics data generated, we performed integrative analyses of the datasets available to us at the genome (DNA level), transcriptome (RNA level), and proteome levels jointly.


Assuntos
Redes Reguladoras de Genes , Leucócitos Mononucleares/patologia , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/patologia , Proteínas/genética , Proteômica/métodos , Idoso , Anexinas/genética , Anexinas/metabolismo , Densidade Óssea , Proteína de Capeamento de Actina CapZ/genética , Proteína de Capeamento de Actina CapZ/metabolismo , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/metabolismo , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas , Proteínas/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Transcriptoma , Ubiquitina/genética , Ubiquitina/metabolismo
10.
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
11.
Biochem J ; 472(3): 309-18, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26438880

RESUMO

Macrophages within adipose tissue play a key role in mediating inflammatory responses in adipose tissue that are associated with obesity-related metabolic complications. In an effort to identify novel proteins secreted from adipocytes that may negatively regulate macrophage inflammation, we found that peroxiredoxin (PRX)-like 2 activated in M-CSF stimulated monocytes (PAMM), a CXXC-type PRX-like 2 domain-containing redox regulatory protein, is a novel secreted protein with potent anti-inflammatory properties. PAMM is secreted from mature human adipocytes but not preadipocytes. Overexpression of PAMM significantly attenuated lipopolysaccharide (LPS)-induced macrophage inflammation. Incubation of macrophages with adipocyte-conditional medium treated with anti-PAMM antibody significantly enhanced LPS-induced interleukin-12 (IL-12) expression in Raw264.7 cells. In addition, incubation of Raw264.7 cells with purified PAMM protein had a similar anti-inflammatory effect. Moreover, forced expression of PAMM in Raw264.7 cells resulted in decreased LPS-induced ERK1/2, p38 and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting that PAMM exerted the anti-inflammatory function probably by suppressing the mitogen-activated protein kinase (MAPK) signalling pathway. Mutations in the CXXC motif of PAMM that suppressed its anti-redox activity were still able to suppress production of inflammatory cytokines in LPS-stimulated macrophages, suggesting that PAMM's anti-inflammatory properties may be independent of its antioxidant properties. Finally, PAMM was highly expressed in both white (WAT) and brown adipose tissues (BAT) and further increased in obesity status. Our results suggest that adipocyte-derived PAMM may suppress macrophage activation by inhibiting MAPK signalling pathway.


Assuntos
Adipócitos/metabolismo , Sistema de Sinalização das MAP Quinases , Ativação de Macrófagos , Macrófagos/metabolismo , Peroxirredoxinas/metabolismo , Adipócitos/imunologia , Adipócitos/patologia , Motivos de Aminoácidos , Animais , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , MAP Quinase Quinase 4/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mutação , Peroxirredoxinas/genética , Peroxirredoxinas/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Sci Rep ; 5: 13324, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26314804

RESUMO

Coxsackievirus B3 (CVB3) is a causative agent of viral myocarditis, pancreatitis, and meningitis in humans. Although the susceptibility of CVB3-induced acute pancreatitis is age-dependent, the underlying mechanisms remain unclear. Here we identified the host factor Golgi matrix protein 130 (GM130) as a novel target of CVB3 during CVB3-induced acute pancreatitis. The viral protein VP1 interacted with GM130, disrupted GM130-GRASP65 complexes, and caused GM130 degradation, which may lead to disruption of the Golgi ribbon and development of acute pancreatitis in mice. Interestingly, the expression level of GM130 in mouse pancreas was age-dependent, which was nicely correlated with the age-associated susceptibility of CVB3-induced acute pancreatitis. Furthermore, interference RNA-mediated knockdown of GM130 significantly reduced CVB3 replication in HeLa cells. Taken together, the study identified GM130 as a novel target of CVB3, which may implicate in the pathogenesis of CVB3-induced acute pancreatitis.


Assuntos
Autoantígenos/metabolismo , Enterovirus Humano B/fisiologia , Infecções por Enterovirus/metabolismo , Proteínas de Membrana/metabolismo , Pancreatite/metabolismo , Pancreatite/virologia , Proteínas Virais/metabolismo , Doença Aguda , Animais , Infecções por Enterovirus/complicações , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Complexo de Golgi/metabolismo , Proteínas da Matriz do Complexo de Golgi , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Miocardite/metabolismo , Miocardite/patologia , Miocardite/virologia , Especificidade de Órgãos , Pancreatite/patologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteólise , Replicação Viral
13.
J Clin Endocrinol Metab ; 100(11): E1457-66, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26312577

RESUMO

OBJECTIVE: Age at menarche (AAM) is determined by the overall duration of endocrine-tissue sex hormone exposure levels. Osteoporosis, the most common metabolic bone disease, is characterized primarily by reduced bone mineral density (BMD) and an increased risk of low trauma fractures. Bone was an endocrine organ regulating the synthesis and secretion of sex steroid hormones. The mutual dependence between bone and gonads underscore the importance of genetic approaches to identify novel pleiotropic genetic factors coregulating BMD and AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to explore novel ethnic common loci and/or genes that may influence both AAM and BMD. METHODS: We analyzed genotyping data available for 826 unrelated Chinese subjects using genome-wide human genotyping arrays. After quality control, a total of 702 413 single-nucleotide polymorphisms (SNPs) were tested for association using a bivariate linear regression model. The interesting SNPs were replicated in three independent cohorts including 1728 unrelated Caucasians, 709 African-Americans, and 408 Hispanic-Americans. RESULTS: We found four SNPs (rs10817638, rs7851259, rs10982287, and rs4979427), located upstream of the ATP6V1G1 gene, were bivariately associated with hip BMD-AAM (P = 4.90 × 10(-7), P = 1.07 × 10(-6), P = 1.28 × 10(-5), and P = 5.42 × 10(-5), respectively). These four SNPs were replicated in African-Americans, with corresponding values of P = 1.95 × 10(-2), P = 3.18 × 10(-2), P = 2.57 × 10(-2), and P = 3.64 × 10(-2), respectively. rs10817638 and rs10982287 were further replicated in Caucasians (P = 1.76 × 10(-2) and P = 9.42 × 10(-3), respectively) and Hispanic-Americans (P = 8.37 × 10(-3) and P = 1.52 × 10(-3), respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined values of P = 3.02 × 10(-9) and P = 3.49 × 10(-9), respectively. CONCLUSIONS: Our study implicated ATP6V1G1 as a novel pleiotropic gene underlying variation of both BMD and AAM. The findings enhance our knowledge of genetic associations between BMD and AAM and provide a rationale for subsequent functional studies of these implicated genes in the pathophysiology of diseases/traits, such as osteoporosis and AAM.


Assuntos
Regiões 5' não Traduzidas , Desenvolvimento do Adolescente , Predisposição Genética para Doença , Menarca/genética , Osteoporose/genética , Polimorfismo de Nucleotídeo Único , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Densidade Óssea , China , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Menarca/metabolismo , Pessoa de Meia-Idade , Osteoporose/metabolismo , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo , Estados Unidos , ATPases Vacuolares Próton-Translocadoras/metabolismo , Adulto Jovem
14.
Hum Mol Genet ; 24(16): 4710-27, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25941324

RESUMO

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA target sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)- and femoral neck (FN)-bone mineral density (BMD). In stage I, 41 102 poly-miRTSs were meta-analyzed in seven cohorts with a genome-wide significance (GWS) α = 0.05/41 102 = 1.22 × 10(-6). By applying α = 5 × 10(-5) (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P = 7.67 × 10(-6) and 1.58 × 10(-5)) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P = 5.08 × 10(-3)) at α = 0.10/11 = 9.09 × 10(-3). PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P = 7.55 × 10(-6)) at α = 0.05/2 = 0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P = 8.87 × 10(-12)). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.


Assuntos
Regiões 3' não Traduzidas , Densidade Óssea/genética , Loci Gênicos , MicroRNAs/genética , Polimorfismo Genético , Receptor Tipo 5 de Fator de Crescimento de Fibroblastos/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino
15.
J Bone Metab ; 21(2): 99-116, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25006567

RESUMO

In the past few years, the bone field has witnessed great advances in genome-wide association studies (GWASs) of osteoporosis, with a number of promising genes identified. In particular, meta-analysis of GWASs, aimed at increasing the power of studies by combining the results from different study populations, have led to the identification of novel associations that would not otherwise have been identified in individual GWASs. Recently, the first whole genome sequencing study for osteoporosis and fractures was published, reporting a novel rare nonsense mutation. This review summarizes the important and representative findings published by December 2013. Comments are made on the notable findings and representative studies for their potential influence and implications on our present understanding of the genetics of osteoporosis. Potential limitations of GWASs and their meta-analyses are evaluated, with an emphasis on understanding the reasons for inconsistent results between different studies and clarification of misinterpretation of GWAS meta-analysis results. Implications and challenges of GWAS are also discussed, including the need for multi- and inter-disciplinary studies.

16.
PLoS One ; 9(5): e96149, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24879436

RESUMO

Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10(-7) for BMI, 1.80×10(-6) for FM, and 5.29×10(-4) for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10(-3) to 4.94×10(-2)). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.


Assuntos
Grupos de Populações Continentais/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Obesidade/genética , Humanos , Fenótipo , Reprodutibilidade dos Testes
17.
N Engl J Med ; 370(13): 1220-6, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24670168

RESUMO

The human zona pellucida is composed of four glycoproteins (ZP1, ZP2, ZP3, and ZP4) and has an important role in reproduction. Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members. In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte.


Assuntos
Proteínas do Ovo/genética , Proteínas do Ovo/metabolismo , Genes Recessivos , Infertilidade Feminina/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Óvulo/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Adulto , China , Análise Mutacional de DNA , Proteínas do Ovo/química , Feminino , Mutação da Fase de Leitura , Heterozigoto , Homozigoto , Humanos , Infertilidade Feminina/patologia , Glicoproteínas de Membrana/química , Óvulo/patologia , Linhagem , Receptores de Superfície Celular/química , Glicoproteínas da Zona Pelúcida
18.
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
19.
Hum Genet ; 133(3): 265-79, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24114349

RESUMO

Individual genome-wide association (GWA) studies and their meta-analyses represent two approaches for identifying genetic loci associated with complex diseases/traits. Inconsistent findings and non-replicability between individual GWA studies and meta-analyses are commonly observed, hence posing the critical question as to how to interpret their respective results properly. In this study, we performed a series of simulation studies to investigate and compare the statistical properties of the two approaches. Our results show that (1) as expected, meta-analysis of larger sample size is more powerful than individual GWA studies under the ideal setting of population homogeneity among individual studies; (2) under the realistic setting of heterogeneity among individual studies, detection of heterogeneity is usually difficult and meta-analysis (even with the random-effects model) may introduce elevated false positive and/or negative rates; (3) despite relatively small sample size, well-designed individual GWA study has the capacity to identify novel loci for complex traits; (4) replicability between meta-analysis and independent individual studies or between independent meta-analyses is limited, and thus inconsistent findings are not unexpected.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Teóricos , Frequência do Gene , Loci Gênicos , Genoma Humano , Humanos , Fenótipo , Tamanho da Amostra
20.
J Clin Exp Cardiolog ; 4(3)2013 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-24319627

RESUMO

BACKGROUND: Age-associated altered redox imbalances and dysregulated immune function, contribute to the development of a variety of age associated diseases. Inflammatory markers and lipid profiles are useful prognostic indicators of a variety of age-associated and cardiovascular diseases. We have previously studied the impact of several proteasome inhibitors on several markers of inflammation and lipid profiles in vitro, in vivo, in cell lines, animal models, and in human subjects. The current study represents an extension of this work. Our main hypothesis is that a combination of various naturally-occurring proteasome inhibitors, which inhibits nitric oxide (NO), and C-reactive protein (CRP) mediated inflammation, will have better efficacy in the prevention and treatment of age-associated disorders including cardiovascular disease. METHODS: Two double blind, randomized, placebo-controlled cross-over trials were conducted to determine the impact of a mixture of NS-5 (resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid) on serum NO, CRP, γ-glutamyl-transferase (γ-GT) activity, total antioxidant status (TAS), total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides levels. Healthy seniors (Group-1; n = 32) free-living (A, B; 16/group), and hypercholesterolemic (Group-2; n = 64) subjects on AHA-Step-1-diet were divided into two groups (C, D; 32/group). Baseline levels were established for parameters as mentioned above. Groups A, C were administered 4-capsules/d of NS-5 and groups B, D, placebo (starch) for 6-weeks. Groups were crossed-over, followed by a 2-week wash-out period. Groups A, C were given 4-capsules/d of placebo and groups B, D, 4-capsules/d of NS-5 for 6-weeks. Groups C, D were continued on AHA-Step-1-diet. RESULTS: All the subjects completed each phase in both studies without any complaints. There were significant ( P < 0.01 - 0.05) decreases in the serum levels of NO (30%, 26%), CRP (29%, 21%), γ-GT activity (14%, 17%), and blood pressure (systolic/diastolic, 3/6%, 3/3%) of Groups A and B, respectively, of free-living healthy seniors without affecting the total, HDL-, LDL-cholesterol or triglycerides compared to their respective baseline values. However, serum levels of NO (36%, 43%), CRP (31%, 48%), γ-GT (17%, 20%), total cholesterol (19%, 15%), LDL-cholesterol (28%, 20%), triglycerides (11%, 18%) of Groups C and D were significantly ( P < 0.01-0.05) decreased with NS-5 treatment of hypercholesterolemic subjects compared to baseline values, without affecting the serum HDL-cholesterol levels. The serum levels of total antioxidant status (TAS) were increased (10%, 14%; P < 0.05) in Groups A and B, increased (19%, 24%; P < 0.02), and blood pressure (systolic/diastolic, 5/6%, 3/5%) in Groups C and D with NS-5 treatment, compared to respective baseline values. CONCLUSIONS: The consumption of NS-5 mixture decreased significantly serum NO, CRP and γ-GT levels, improved TAS and lipid profiles at risk cardiovascular and hold promise for delaying onset of age-associated diseases.

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