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1.
Int J Obes (Lond) ; 46(10): 1918-1924, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35978102

RESUMEN

OBJECTIVE: Many animal experiments and epidemiological studies have shown that the gut microbiota (GM) plays an important role in the development of obesity, but the specific biological mechanism involved in the pathogenesis of disease remain unknown. We aimed to examine the relationships and functional mechanisms of GM on obesity in peri- and post-menopausal women. METHODS: We recruited 499 Chinese peri- and post-menopausal women and performed comprehensive analyses of the gut microbiome, targeted metabolomics for short-chain fatty acids in serum, and host whole-genome sequencing by various association analysis methods. RESULTS: Through constrained linear regression analysis, we found that an elevated abundance of Bacteroides fragilis (B. fragilis) was associated with obesity. We also found that serum levels of acetic acid were negatively associated with obesity, and that B. fragilis was negatively associated with serum acetic acid levels by partial Spearman correlation analysis. Mendelian randomization analysis indicated that B. fragilis increases the risk of obesity and may causally down-regulate acetic acid levels. CONCLUSIONS: We found the gut with B. fragilis may accelerate obesity, in part, by suppressing acetic acid levels. Therefore, B. fragilis and acetic acid may represent important therapeutic targets for obesity intervention in peri- and post-menopausal women.


Asunto(s)
Bacteroides fragilis , Microbioma Gastrointestinal , Ácido Acético , Bacteroides fragilis/fisiología , Femenino , Humanos , Obesidad , Posmenopausia
2.
Hum Mol Genet ; 24(16): 4710-27, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-25941324

RESUMEN

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.


Asunto(s)
Regiones no Traducidas 3' , Densidad Ósea/genética , Sitios Genéticos , MicroARNs/genética , Polimorfismo Genético , Receptor Tipo 5 de Factor de Crecimiento de Fibroblastos/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino
3.
Hum Mol Genet ; 23(3): 820-30, 2014 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-24064335

RESUMEN

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.


Asunto(s)
Predisposición Genética a la Enfermedad , Obesidad/genética , Polimorfismo de Nucleótido Simple , Tejido Adiposo/fisiología , Catepsinas/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de la Membrana/genética , Proteínas Serina-Treonina Quinasas/genética
4.
Hum Mol Genet ; 23(7): 1923-33, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24249740

RESUMEN

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.


Asunto(s)
Densidad Ósea/genética , Claudinas/genética , Osteonectina/genética , Osteoporosis/genética , Anciano , Huesos/metabolismo , Femenino , Cuello Femoral/fisiología , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Cadera/fisiología , Humanos , Vértebras Lumbares/fisiología , Masculino , Persona de Mediana Edad , Osteoclastos/citología , Osteogénesis/genética , Osteoporosis/terapia , Polimorfismo de Nucleótido Simple
5.
PLoS Genet ; 6(1): e1000806, 2010 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-20072603

RESUMEN

Osteoporosis is a major public health problem. It is mainly characterized by low bone mineral density (BMD) and/or low-trauma osteoporotic fractures (OF), both of which have strong genetic determination. The specific genes influencing these phenotypic traits, however, are largely unknown. Using the Affymetrix 500K array set, we performed a case-control genome-wide association study (GWAS) in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip OF and 516 controls. We found that a SNP, rs13182402 within the ALDH7A1 gene on chromosome 5q31, was strongly associated with OF with evidence combined GWAS and replication studies (P = 2.08x10(-9), odds ratio = 2.25). In order to explore the target risk factors and potential mechanism underlying hip OF risk, we further examined this candidate SNP's relevance to hip BMD both in Chinese and Caucasian populations involving 9,962 additional subjects. This SNP was confirmed as consistently associated with hip BMD even across ethnic boundaries, in both Chinese and Caucasians (combined P = 6.39x10(-6)), further attesting to its potential effect on osteoporosis. ALDH7A1 degrades and detoxifies acetaldehyde, which inhibits osteoblast proliferation and results in decreased bone formation. Our findings may provide new insights into the pathogenesis of osteoporosis.


Asunto(s)
Aldehído Deshidrogenasa/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Osteoporosis/genética , Anciano , Pueblo Asiatico/genética , Densidad Ósea , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/fisiopatología , Polimorfismo de Nucleótido Simple , Población Blanca/genética
6.
Am J Hum Genet ; 84(3): 418-23, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19268274

RESUMEN

Low lean body mass (LBM) is related to a series of health problems, such as osteoporotic fracture and sarcopenia. Here we report a genome-wide association (GWA) study on LBM variation, by using Affymetrix 500K single-nucleotide polymorphism (SNP) arrays. In the GWA scan, we tested 379,319 eligible SNPs in 1,000 unrelated US whites and found that two SNPs, rs16892496 (p = 7.55 x 10(-8)) and rs7832552 (p = 7.58 x 10(-8)), within the thyrotropin-releasing hormone receptor (TRHR) gene were significantly associated with LBM. Subjects carrying unfavorable genotypes at rs16892496 and rs7832552 had, on average, 2.70 and 2.55 kg lower LBM, respectively, compared to those with alternative genotypes. We replicated the significant associations in three independent samples: (1) 1488 unrelated US whites, (2) 2955 Chinese unrelated subjects, and (3) 593 nuclear families comprising 1972 US whites. Meta-analyses of the GWA scan and the replication studies yielded p values of 5.53 x 10(-9) for rs16892496 and 3.88 x 10(-10) for rs7832552. In addition, we found significant interactions between rs16892496 and polymorphisms of several other genes involved in the hypothalamic-pituitary-thyroid and the growth hormone-insulin-like growth factor-I axes. Results of this study, together with the functional relevance of TRHR in muscle metabolism, support the TRHR gene as an important gene for LBM variation.


Asunto(s)
Composición Corporal/genética , Peso Corporal/genética , Receptores de Hormona Liberadora de Tirotropina/genética , Adulto , Anciano , Asiático , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Hormona Liberadora de Tirotropina/metabolismo , Delgadez , Población Blanca
7.
J Hum Genet ; 57(1): 33-7, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22048656

RESUMEN

Lean body mass (LBM) is a heritable trait predicting a series of health problems, such as osteoporotic fracture and sarcopenia. We aim to identify sequence variants associated with LBM by a genome-wide association study (GWAS) of copy number variants (CNVs). We genotyped genome-wide CNVs of 1627 individuals of the Chinese population with Affymetrix SNP6.0 genotyping platform, which comprised of 9 40 000 copy number probes. We then performed a GWAS of CNVs with lean mass at seven sites: left and right arms, left and right legs, total of limb, trunk and whole body. We identified a CNV that is associated with LBM variation at the genome-wide significance level (CNV2073, Bonferroni corrected P-value 0.002 at right arm). CNV2073 locates at chromosome 15q13.3, which has been implicated as a candidate region for LBM by our previous linkage studies. The nearest gene, gremlin1, has a key role in the regulation of skeletal muscle formation and repair. Our results suggest that the gremlin1 gene is a potentially important gene for LBM variation. Our findings also show the utility and efficacy of CNV as genetic markers in association studies.


Asunto(s)
Peso Corporal/genética , Variaciones en el Número de Copia de ADN/genética , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Péptidos y Proteínas de Señalización Intercelular/genética , Delgadez/genética , Adulto , Femenino , Humanos , Masculino
8.
PLoS Genet ; 5(3): e1000420, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19282985

RESUMEN

For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects--all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09 x 10(-3) and 4.37 x 10(-3), respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19 x 10(-5) and 1.02 x 10(-4), respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.


Asunto(s)
Estudio de Asociación del Genoma Completo , Menarquia/genética , Proteoglicanos/genética , Adulto , Factores de Edad , Envejecimiento/genética , Femenino , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genética
9.
Hum Mol Genet ; 18(9): 1661-9, 2009 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19039035

RESUMEN

Human stature, as an important physical index in clinical practice and a usual covariate in gene mapping of complex disorders, is a highly heritable complex trait. To identify specific genes underlying stature, a genome-wide association study was performed in 1000 unrelated homogeneous Caucasian subjects using Affymetrix 500K arrays. A group of seven contiguous markers in the region of SBF2 gene (Set-binding factor 2) are associated with stature, significantly so at the genome-wide level after false discovery rate (FDR) correction (FDR q = 0.034-0.042). Three SNPs in another SNP group in the Filamin B (FLNB) gene were also associated with stature, significantly so with FDR q = 0.042-0.048. In follow-up independent replication studies, rs10734652 in the SBF2 gene was significantly (P = 0.036) and suggestively (P = 0.07) associated with stature in Caucasian families and 1306 unrelated Caucasian subjects, respectively, and rs9834312 in the FLNB gene was also associated with stature in such two independent Caucasian populations (P = 0.008 in unrelated sample and P = 0.049 in family sample). Particularly, additional significant replication association signals were detected in Chinese, an ethnic population different from Caucasian, between rs9834312 and stature in 619 unrelated northern Chinese subjects (P = 0.017), as well as between rs10734652 and stature in 2953 unrelated southern Chinese subjects (P = 0.048). This study also provides additional replication evidence for some of the already published stature loci. These results, together with the known functional relevance of the SBF2 and FLNB genes to skeletal linear growth and bone formation, support that two regions containing FLNB and SBF2 genes are two novel loci underlying stature variation.


Asunto(s)
Estatura , Proteínas Contráctiles/genética , Proteínas de Microfilamentos/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adulto , Anciano , Pueblo Asiatico/etnología , Pueblo Asiatico/genética , Femenino , Filaminas , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genética
10.
Am J Hum Genet ; 83(6): 663-74, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18992858

RESUMEN

Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 x 10(-4), Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 x 10(-4) -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.


Asunto(s)
Dosificación de Gen , Predisposición Genética a la Enfermedad , Genoma Humano , Glucuronosiltransferasa/genética , Osteoporosis/genética , Adulto , Anciano , Pueblo Asiatico/genética , Densidad Ósea/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 4 , Estradiol/sangre , Femenino , Eliminación de Gen , Marcadores Genéticos , Variación Genética , Fracturas de Cadera/genética , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple , Testosterona/sangre , Adulto Joven
11.
J Hum Genet ; 55(7): 441-7, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20448653

RESUMEN

Recent success of genome-wide association studies (GWASs) on human height variation emphasized the effects of individual loci or genes. In this study, we used a developed pathway-based approach to further test biological pathways for potential association with stature, by examining approximately 370,000 single-nucleotide polymorphisms (SNPs) across the human genome in 618 unrelated elder Han Chinese. A total of 626 biological pathways annotated by any of the three major public pathway databases (KEGG, BioCarta and Ambion GeneAssist Pathway Atlas) were tested. The regulation-of-autophagy (ROA) (nominal P=0.012) pathway was marginally significantly associated with human stature after our family wise error rate multiple-testing correction. We also used 1000 random recruited US whites for further replication. Interestingly, the ROA pathway presented the strongest signals in whites for height variation (nominal P=0.002). The results correspond to biological roles of the ROA pathway in human long bone development and growth. Our findings also implied that multiple-genetic factors may work jointly as a functional unit (pathway), and the traditional GWASs could have missed important genetic information imbedded in those less significant markers.


Asunto(s)
Pueblo Asiatico/genética , Autofagia/genética , Estatura/genética , Variación Genética , Redes y Vías Metabólicas/genética , Adulto , Anciano , China , Cromosomas Humanos Par 9/genética , Femenino , Haplotipos/genética , Humanos , Masculino , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple/genética , Estados Unidos , Población Blanca/genética
12.
Hum Genet ; 125(1): 1-9, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19030899

RESUMEN

In Caucasian, several studies have identified some common variants associated with human stature variation. However, no such study was performed in Chinese, which is the largest population in the world and evidently differs from Caucasian in genetic background. To identify common or ethnic specific genes for stature in Chinese, an initial GWAS and follow-up replication study were performed. Our initial GWAS study found that a group of 13 contiguous SNPs, which span a region of approximately 150 kb containing two neighboring genes, zinc finger protein (ZNP) 510 and ZNP782, achieved strong signals for association with stature, with P values ranging from 9.71 x 10(-5) to 3.11 x 10(-6). After false discovery rate correction for multiple testing, 9 of the 13 SNPs remain significant (FDR q=0.036-0.046). The follow-up replication study in an independent 2,953 unrelated southern Chinese confirmed the association of rs10816533 with stature (P=0.029). All the 13 SNPs were in consistently strong linkage disequilibrium (D'>0.99) and formed a single perfect haplotype block. The minor allele frequencies for the 13 contiguous SNPs have evidently ethnic difference, which range from 0.21 to 0.33 in Chinese but have as low as approximately 0.017 reported in dbSNP database in Caucasian. The present results suggest that the genomic region containing the ZNP510 and ZNP782 genes is an ethnic specific locus associated with stature variation in Chinese.


Asunto(s)
Pueblo Asiatico/genética , Estatura/genética , Estudio de Asociación del Genoma Completo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto Joven
13.
Proteomics ; 8(20): 4259-72, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18924182

RESUMEN

Osteoporosis (OP) is a major public health problem, mainly characterized by low bone mineral density (BMD). Circulating monocytes (CMCs) may serve as progenitors of osteoclasts and produce a wide variety of factors important to bone metabolism. However, the specific action mechanism of CMCs in the pathogenesis of OP is far from clear. We performed a comparative protein expression profiling study of CMCs in Chinese premenopausal females with extremely discordant BMD, identified a total of 38 differentially expressed proteins, and confirmed with Western blotting five proteins: ras suppressor protein1 (RSU1), gelsolin (GSN), manganese-containing superoxide dismutase (SOD2), glutathione peroxidase 1(GPX1), and prolyl 4-hydroxylase beta subunit (P4HB). These proteins might affect CMCs' trans-endothelium, differentiation, and/or downstream osteoclast functions, thus contribute to differential osteoclastogenesis and finally lead to BMD variation. The findings promote our understanding of the role of CMCs in BMD determination, and provide an insight into the pathogenesis of human OP.


Asunto(s)
Densidad Ósea/fisiología , Perfilación de la Expresión Génica , Monocitos/metabolismo , Premenopausia/fisiología , Adulto , Pueblo Asiatico , China , Femenino , Gelsolina/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Osteoporosis/etiología , Procolágeno-Prolina Dioxigenasa/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Superóxido Dismutasa/metabolismo , Factores de Transcripción/metabolismo , Glutatión Peroxidasa GPX1
14.
Ann Hum Biol ; 35(3): 342-8, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18568597

RESUMEN

BACKGROUND: Trunk obesity has adverse health implications in adults, but valid and practical methods to correctly measure trunk obesity in China are insufficient. AIM: This study aimed to assess the validity of anthropometric indices as screening the predictors of trunk obesity in young Chinese adults. SUBJECTS AND METHODS: A total of 1946 (853 women, 1093 men) Chinese volunteers aged 20-40 years were recruited. Trunk fat mass was measured by dual-energy X-ray absorptiometry. Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and conicity index (C index) were measured or calculated. Receiver operating characteristic (ROC) curves were used to compare the validity of each anthropometric index to predict trunk adiposity. RESULTS: BMI and WC performed better as the anthropometric indices defining trunk obesity than WHR and C index, and the areas under the ROC curves for BMI (0.94 in men and 0.89 in women) were similar to those for WC (0.93 in men and 0.88 in women). CONCLUSIONS: Both BMI and WC are more effective predictors of trunk obesity than WHR and C index in Chinese young adults.


Asunto(s)
Distribución de la Grasa Corporal/estadística & datos numéricos , Índice de Masa Corporal , Obesidad/epidemiología , Obesidad/patología , Relación Cintura-Cadera/estadística & datos numéricos , Absorciometría de Fotón , Adulto , Pueblo Asiatico/estadística & datos numéricos , Estatura , China/epidemiología , Femenino , Humanos , Masculino , Curva ROC , Factores de Riesgo , Grasa Subcutánea Abdominal/diagnóstico por imagen
15.
Nutr Metab Cardiovasc Dis ; 17(9): 676-83, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17008072

RESUMEN

BACKGROUND AND AIMS: Obesity is a worldwide problem, and excess trunk fat mass (FM(trunk)) has been associated with an increased risk of diseases. The early measurement of FM(trunk) has potential importance to evaluate trunk obesity. We sought to evaluate the correlation and predication of FM(trunk) with five anthropometric indices in Chinese females. METHODS AND RESULTS: A sample of 850 China females aged 20-40 years were recruited and divided into four age groups with a 5-year range in each group. Five anthropometric indices were measured or calculated. FM(trunk) in kg was measured using a dual-energy X-ray absorptiometry scanner. Principal component analysis (PCA) and multiple regression analysis were performed to develop prediction equations. There was an increasing trend of FM(trunk) and five anthropometric indices in successively older age groups. Four formed principal components (PCs) interpreted over 99% of the total variation of five relative anthropometric indices in all age groups. Regression analyses showed that four PCs combined explained a greater variance (R(2)=45.2-81.6%) in FM(trunk) than did each of the five indices alone (R(2)=2.4-72.2%). CONCLUSIONS: Our results suggested that there is an increasing trend of FM(trunk) and five anthropometric indices with aging; that age obviously influences the relationship of FM(trunk) and the anthropometric indices studied; and that the accuracy of predicting the FM(trunk) using five anthropometric indices combined is greater than using the five indices alone.


Asunto(s)
Tejido Adiposo/anatomía & histología , Tejido Adiposo/metabolismo , Envejecimiento/fisiología , Composición Corporal/fisiología , Obesidad/epidemiología , Absorciometría de Fotón/métodos , Adulto , Factores de Edad , Antropometría , Índice de Masa Corporal , China/epidemiología , Estudios Transversales , Femenino , Humanos , Obesidad/etnología , Valor Predictivo de las Pruebas , Análisis de Componente Principal/métodos , Grasa Subcutánea Abdominal/anatomía & histología , Relación Cintura-Cadera
16.
Clin Nutr ; 25(6): 1030-9, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16884832

RESUMEN

BACKGROUND & AIMS: Recent data suggest that current obesity diagnostic criterion based on body mass index (BMI) above 30 in Caucasians may not be appropriate for Asian populations. Our aim was to identify the usefulness of BMI, waist circumference (WC) and waist-to-hip ratio (WHR) in screening for obesity in an Asian population. METHODS: A cross-sectional sample of 1109 males and 879 females aged 20-45-yr were recruited. Height, weight, WC, hip circumference and percentage body fat (PBF) were measured in all subjects. Then receiver-operating characteristic analyses were used to evaluate the performances of the three anthropometric indices. RESULTS: BMI, WC and WHR showed strong positive correlation with PBF (r=0.47-0.75) in both males and females within both age groups. True-positive rates ranged from 82.4% to 94.1% and 68.8% to 86.3% in males and females, respectively. True-negative rates ranged from 64.1% to 84.7% and from 56.9% to 79.0%, respectively. The areas under the curves (AUCs) for WC and BMI were high (0.76-0.92) in both sexes and divided age groups (20-30-yr and 31-45-yr), and those for WHR were a little lower (0.74-0.88). CONCLUSIONS: BMI and WC are two important predictors for obesity in Chinese, and WHR is an alternative.


Asunto(s)
Pueblo Asiatico , Composición Corporal/fisiología , Índice de Masa Corporal , Obesidad/diagnóstico , Relación Cintura-Cadera , Tejido Adiposo/metabolismo , Adulto , Área Bajo la Curva , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores Sexuales
17.
J Bone Miner Res ; 31(2): 358-68, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26256109

RESUMEN

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.


Asunto(s)
Densidad Ósea/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Proteínas Wnt/genética , Estudios de Cohortes , Femenino , Cuello Femoral/metabolismo , Humanos , Vértebras Lumbares/metabolismo , Masculino , Fosforilación , Proteínas Wnt/metabolismo
18.
J Bone Miner Res ; 28(12): 2498-507, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23712400

RESUMEN

Bone mineral density (BMD) is a major index for diagnosing osteoporosis. PhosSNPs are nonsynonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aimed to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genomewide phosSNP association study for BMD in three independent population samples, involving ∼5000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, ie, rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying the AA genotype have significantly lower hip BMD than carriers of the GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, by regulating BDNF protein phosphorylation and osteoblast differentiation, influences hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases.


Asunto(s)
Densidad Ósea/genética , Diferenciación Celular/genética , Osteoblastos/citología , Polimorfismo de Nucleótido Simple/genética , Adulto , Alelos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular , Genotipo , Humanos , Persona de Mediana Edad , Osteoblastos/enzimología , Fosforilación/genética , Reproducibilidad de los Resultados , Especificidad por Sustrato
19.
PLoS One ; 8(4): e60362, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23593202

RESUMEN

Femoral neck geometric parameters (FNGPs), which include cortical thickness (CT), periosteal diameter (W), buckling ratio (BR), cross-sectional area (CSA), and section modulus (Z), contribute to bone strength and may predict hip fracture risk. Age at menarche (AAM) is an important risk factor for osteoporosis and bone fractures in women. Some FNGPs are genetically correlated with AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to identify new candidate genes responsible for both FNGPs and AAM. In the discovery stage, we tested 760,794 SNPs in 1,728 unrelated Caucasian subject, followed by replication analyses in independent samples of US Caucasians (with 501 subjects) and Chinese (with 826 subjects). We found six SNPs that were associated with FNGPs and AAM. These SNPs are located in three genes (i.e. NRCAM, IDS and LOC148145), suggesting these three genes may co-regulate FNGPs and AAM. Our findings may help improve the understanding of genetic architecture and pathophysiological mechanisms underlying both osteoporosis and AAM.


Asunto(s)
Cuello Femoral/metabolismo , Estudio de Asociación del Genoma Completo , Menarquia/genética , Adulto , Factores de Edad , Anciano , Pueblo Asiatico/genética , Femenino , Cuello Femoral/anatomía & histología , Cuello Femoral/crecimiento & desarrollo , Genotipo , Humanos , Desequilibrio de Ligamiento , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto Joven
20.
PLoS One ; 7(1): e30860, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22295116

RESUMEN

Alcohol dependence (AD) is a complex disorder characterized by psychiatric and physiological dependence on alcohol. AD is reflected by regular alcohol drinking, which is highly inheritable. In this study, to identify susceptibility genes associated with alcohol drinking, we performed a genome-wide association study of copy number variants (CNVs) in 2,286 Caucasian subjects with Affymetrix SNP6.0 genotyping array. We replicated our findings in 1,627 Chinese subjects with the same genotyping array. We identified two CNVs, CNV207 (combined p-value 1.91E-03) and CNV1836 (combined p-value 3.05E-03) that were associated with alcohol drinking. CNV207 and CNV1836 are located at the downstream of genes LTBP1 (870 kb) and FGD4 (400 kb), respectively. LTBP1, by interacting TGFB1, may down-regulate enzymes directly participating in alcohol metabolism. FGD4 plays a role in clustering and trafficking GABA(A) receptor and subsequently influence alcohol drinking through activating CDC42. Our results provide suggestive evidence that the newly identified CNV regions and relevant genes may contribute to the genetic mechanism of alcohol dependence.


Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Variaciones en el Número de Copia de ADN/genética , Estudio de Asociación del Genoma Completo , Proteínas de Unión a TGF-beta Latente/genética , Proteínas de Microfilamentos/genética , Adulto , Pueblo Asiatico/genética , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética
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