A bibliometric analysis of primary ovarian insufficiency from 2010 to 2020.

OBJECTIVE: This study aimed to carry out a bibliometric analysis of primary ovarian insufficiency (POI) from 2010 to 2020 and to reveal the research status and hotspots in the future. METHOD: A total of 3087 articles and reviews related to POI published from 2010 to 2020 retrieved from the Web of Science Core Collection were used for bibliometric analysis. CiteSpace and VOSviewer were adopted to analyze countries and regions, organizations, authors, journals, keywords and co-cited references. RESULTS: The number of publications about POI increased year by year. The USA produced the largest number of publications and the most influence in this field. The main research directions of POI can be roughly divided into four aspects according to the analysis of keywords and co-cited references: genetic research of POI; stem cell therapy for patients with POI; prediction of ovarian function; and fertility preservation of cancer patients. Genetic research and stem cell therapy may become research hotspots in the future. CONCLUSION: This study might be the first bibliometric study to analyze publications of POI from multiple indicators, in order to provide new opinions for the research trends and possible hotspots of POI.

Estimates of the effects of physical activity on osteoporosis using multivariable Mendelian randomization analysis.

This study estimates causality of physical activity (PA) on bone mineral density (BMD) by conducting multivariable Mendelian randomization (MR). The findings suggest that habitual vigorous PA increases lumbar spine BMD, and higher overall acceleration average would improve forearm BMD. The results could promote PA intervention targeting individuals with optimized type. INTRODUCTION: Evidence from epidemiologic studies showed type, frequency, and duration of PA influenced BMD. However, these observational studies may be confounded by many factors, resulting in spurious associations. We aimed to conduct multivariable MR to estimate the causal effect of self-reported and device-measured PA on osteoporosis. METHODS: Three self-reported and two device-measured PA-related traits were selected as exposures. Outcomes were BMD at different skeletal sites: femoral neck BMD (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD). Exposure datasets were obtained from UK Biobank with total 377,234 subjects. Outcome datasets were obtained from GEFOS consortium with 53,236 subjects. Standard MR analysis and multivariable MR were conducted to assess the total and direct causal effect of PA on BMD. RESULTS: For self-reported PA, inverse-normalized moderate-to-vigorous had a direct causal effect on FN BMD independently (ß = - 1.116 (95% confidence interval, 95%CI: - 2.210, - 0.023), P = 0.045); vigorous PA showed a direct effect (ß = 3.592 (95%CI: 0.310, 6.874), P = 0.032) on LS BMD independently. While overall acceleration average and fraction of accelerations both had a direct causal effect on FA BMD independently. CONCLUSIONS: Habitual vigorous PA could increase LS BMD. Individuals with higher overall acceleration average would have a higher FA BMD.

Detecting causal relationship between metabolic traits and osteoporosis using multivariable Mendelian randomization.

By adopting the extension approaches of Mendelian randomization, we successfully detected and prioritized the potential causal risk factors for BMD traits, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases. INTRODUCTION: Osteoporosis (OP) is a common metabolic skeletal disease characterized by reduced bone mineral density (BMD). The identified SNPs for BMD can only explain approximately 10% of the variability, and very few causal factors have been identified so far. METHODS: The Mendelian randomization (MR) approach enables us to assess the potential causal effect of a risk factor on the outcome by using genetic IVs. By using extension methods of MR-multivariable MR (mvMR) and MR based on Bayesian model averaging (MR-BMA)-we intend to estimate the causal relationship between fifteen metabolic risk factors for BMD and try to prioritize the most potential causal risk factors for BMD. RESULTS: Our analysis identified three risk factors T2D, FG, and HCadjBMI for FN BMD; four risk factors FI, T2D, HCadjBMI, and WCadjBMI for FA BMD; and three risk factors FI, T2D, and HDL cholesterol for LS BMD, and all risk factors were causally associated with heel BMD except for triglycerides and WCadjBMI. Consistent with the mvMR results, MR-BMA confirmed those risk factors as top risk factors for each BMD trait individually. CONCLUSIONS: By combining MR approaches, we identified the potential causal risk factors for FN, FA, LS, and heel BMD individually and we also prioritized and ranked the potential causal risk factors for BMD, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases.

Racial and gender differences in the relationship between sarcopenia and bone mineral density among older adults.

Both sarcopenia and low bone mineral density (BMD) have become public health concerns. We found that presarcopenic and/or sarcopenic individuals were more likely to have lower BMD. And this relationship has race and sex-specific discrepancy. PURPOSE: The purpose of the study was to investigate the racial and gender differences in the relationship between sarcopenia and BMD among older adults. METHODS: Totally, 5476 subjects (mean age = 65.7 ± 6.4) of non-Hispanic White (n = 3297), non-Hispanic Black (n = 1265), and non-Hispanic Asian (n = 914) were analyzed. Sarcopenia was defined according to the revised European consensus on definition and diagnosis of sarcopenia (EWGSOP2). General linear model and multivariable linear regression model were used to examine the relationship between sarcopenia and regional/whole body BMD stratified by race and sex. Adjustments were conducted for physiological, behavioral, and disease factors. RESULTS: Comparing with normal older participants, presarcopenic and sarcopenic elderly were more likely to have lower BMD. Although the difference was not statistically significant in a few sub-groups, among the three racial groups, the strongest association between sarcopenia and BMD was found in non-Hispanic Black people, followed by non-Hispanic White people and non-Hispanic Asian people. In addition, significant differences of BMD across sarcopenia stages were found in more sub-groups in women than in men after adjusting for covariates. CONCLUSIONS: In this older cohort, sarcopenia is significantly related to low regional/whole-body BMD, and these associations vary by race and sex. Consideration in race and sex is warranted when developing strategies to maintain or minimize BMD loss.

Pleiotropic loci underlying bone mineral density and bone size identified by a bivariate genome-wide association analysis.

Aiming to identify pleiotropic genomic loci for bone mineral density and bone size, we performed a bivariate GWAS in five discovery samples and replicated in two large-scale samples. We identified 2 novel loci at 2q37.1 and 6q26. Our findings provide insight into common genetic architecture underlying both traits. INTRODUCTION: Bone mineral density (BMD) and bone size (BS) are two important factors that contribute to the development of osteoporosis and osteoporotic fracture. Both BMD and BS are highly heritable and they are genetically correlated. In this study, we aim to identify pleiotropic loci associated with BMD and BS. METHODS: We conducted a bivariate genome-wide association (GWA) analysis of hip BMD and hip BS in 6180 participants from 5 samples, followed by in silico replication in the UK Biobank study of BMD (N = 426,824) and the deCODE study of BS (N = 28,954), respectively. RESULTS: SNPs from 2 genomic loci were significant at the genome-wide significance (GWS) level (p lt; 5 × 10-8) in the discovery samples and were successfully replicated in the replication samples (2q37.1, lead SNP rs7575512, discovery p = 1.49 × 10-10, replication p = 0.05; 6q26, lead SNP rs1040724, discovery p = 1.95 × 10-8, replication p = 0.03). Functional annotations suggested functional relevance of the identified variants to bone development. CONCLUSION: Our findings provide insight into the common genetic architecture underlying BMD and BS, and enhance our understanding of the potential mechanism of osteoporosis fracture.

Gene-based GWAS analysis for consecutive studies of GEFOS.

By integrating the multilevel biological evidence and bioinformatics analyses, the present study represents a systemic endeavor to identify BMD-associated genes and their roles in skeletal metabolism. INTRODUCTION: Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) have already identified about 100 loci associated with bone mineral density (BMD), but these loci only explain a small proportion of heritability to osteoporosis risk. In the present study, we performed a gene-based analysis of the largest GWASs in the bone field to identify additional BMD-associated genes. METHODS: BMD-associated genes were identified by combining the summary statistic P values of SNPs across individual genes in the two consecutive meta-analyses of GWASs from the Genetic Factors for Osteoporosis (GEFOS) studies. The potential functionality of these genes to bone was partially assessed by differential gene expression analysis. Additionally, the consistency of the identification of potential bone mineral density (BMD)-associated variants were evaluated by estimating the correlation of the P values of the same single-nucleotide polymorphisms (SNPs)/genes between the two consecutive Genetic Factors for Osteoporosis Studies (GEFOS) with largely overlapping samples. RESULTS: Compared to the SNP-based analysis, the gene-based strategy identified additional BMD-associated genes with genome-wide significance and increased their mutual replication between the two GEFOS datasets. Among these BMD-associated genes, three novel genes (UBTF, AAAS, and C11orf58) were partially validated at the gene expression level. The correlation analysis presented a moderately high between-study consistency of potential BMD-associated variants. CONCLUSIONS: Gene-based analysis as a supplementary strategy to SNP-based genome-wide association studies, when applied here, is shown that it helped identify some novel BMD-associated genes. In addition to its empirically increased statistical power, gene-based analysis also provides a higher testing stability for identification of BMD genes.

Network based subcellular proteomics in monocyte membrane revealed novel candidate genes involved in osteoporosis.

In this study, label-free-based quantitative subcellular proteomics integrated with network analysis highlighted several candidate genes including P4HB, ITGB1, CD36, and ACTN1 that may be involved in osteoporosis. All of them are predicted as significant membrane proteins with high confidence and enriched in bone-related biological process. The results were further verified in transcriptomic and genomic levels. INTRODUCTION: Osteoporosis is a metabolic bone disease mainly characterized by low bone mineral density (BMD). As the precursors of osteoclasts, peripheral blood monocytes (PBMs) are supported to be important candidates for identifying genes related to osteoporosis. We performed subcellular proteomics study to identify significant membrane proteins that involved in osteoporosis. METHODS: To investigate the association between monocytes, membrane proteins, and osteoporosis, we performed label-free quantitative subcellular proteomics in 59 male subjects with discordant BMD levels, with 30 high vs. 29 low BMD subjects. Subsequently, we performed integrated gene enrichment analysis, functional annotation, and pathway and network analysis based on multiple bioinformatics tools. RESULTS: A total of 1070 membrane proteins were identified and quantified. By comparing the proteins' expression level, we found 36 proteins that were differentially expressed between high and low BMD groups. Protein localization prediction supported the notion that the differentially expressed proteins, P4HB (p = 0.0021), CD36 (p = 0.0104), ACTN1 (p = 0.0381), and ITGB1 (p = 0.0385), are significant membrane proteins. Functional annotation and pathway and network analysis highlighted that P4HB, ITGB1, CD36, and ACTN1 are enriched in osteoporosis-related pathways and terms including "ECM-receptor interaction," "calcium ion binding," "leukocyte transendothelial migration," and "reduction of cytosolic calcium levels." Results from transcriptomic and genomic levels provided additional supporting evidences. CONCLUSION: Our study strongly supports the significance of the genes P4HB, ITGB1, CD36, and ACTN1 to the etiology of osteoporosis risk.

Socioeconomic status and bone mineral density in adults by race/ethnicity and gender: the Louisiana osteoporosis study.

Low bone mineral density (BMD) and osteoporosis have become a public health problem. We found that non-Hispanic white, black, and Asian adults with extremely low education and personal income are more likely to have lower BMD. This relationship is gender-specific. These findings are valuable to guide bone health interventions. INTRODUCTION: The evidence is limited regarding the relationship between socioeconomic status (SES) and bone mineral density (BMD) for minority populations in the USA, as well as the relationship between SES and BMD for men. This study explored and examined the relationship between SES and BMD by race/ethnicity and gender. METHODS: Data (n = 6568) from the Louisiana Osteoporosis Study (LOS) was examined, including data for non-Hispanic whites (n = 4153), non-Hispanic blacks (n = 1907), and non-Hispanic Asians (n = 508). General linear models were used to estimate the relationship of SES and BMD (total hip and lumbar spine) stratified by race/ethnicity and gender. Adjustments were made for physiological and behavioral factors. RESULTS: After adjusting for covariates, men with education levels below high school graduate experienced relatively low hip BMD than their counterparts with college or graduate education (p < 0.05). In addition, women reporting a personal annual income under $20,000 had relatively low hip and spine BMD than their counterparts with higher income level(s) (p < 0.05). CONCLUSIONS: Establishing a conclusive positive or negative association between BMD and SES proved to be difficult. However, individuals who are at an extreme SES disadvantage are the most vulnerable to have relatively low BMD in the study population. Efforts to promote bone health may benefit from focusing on men with low education levels and women with low individual income.

Genetic association, mRNA and protein expression analysis identify ATG4C as a susceptibility gene for Kashin-Beck disease.

OBJECTIVE: Recent study observed defective autophagy in chondrocytes with Kashin-Beck Disease (KBD). To clarify the potential role of autophagy-related ATG4C gene in the development of KBD, we conducted an integrative analysis of genetic association, messenger ribonucleic acid (mRNA) and protein expression of ATG4C in KBD patients. METHODS: 1026 subjects (559 KBD patients and 467 healthy cases) were enrolled in discovery association study. Four single nucleotide polymorphisms (SNPs) of ATG4C gene (rs11208030, rs4409690, rs12097658 and rs6587988) were genotyped by Sequenom MassARRAY platform. Association analysis was conducted by PLINK software. The significant SNPs of ATG4C were replicated using an independent sample of 899 subjects (including 90 KBD patients and 809 healthy controls). Ungenotyped SNPs in ATG4C gene were imputed by IMPUTE 2.0. Knee cartilage specimens were collected from five KBD patients and five healthy subjects. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were performed to compare the mRNA and protein expression levels of ATG4C between KBD cartilage and control cartilage. RESULTS: We observed significant association between KBD and rs11208030 (P value = 0.003), rs4409690 (P value = 0.004), rs12097658 (P value = 0.003) and rs6587988 (P value = 0.003) in both discovery and replication samples. The mRNA expression level of ATG4C (ratio = 0.168, P value = 0.007) in KBD chondrocytes was significantly lower than that in normal chondrocytes. Western blot (P value < 0.001) further confirmed the reduced expression of ATG4C protein in both KBD cartilage and chondrocytes. CONCLUSION: Our results strongly suggest that ATG4C was a novel autophagy-related susceptibility gene of KBD.

Cytosolic proteome profiling of monocytes for male osteoporosis.

In male Caucasians with discordant hip bone mineral density (BMD), we applied the subcellular separation and proteome profiling to investigate the monocytic cytosol. Three BMD-associated proteins (ALDOA, MYH14, and Rap1B) were identified based on multiple omics evidence, and they may influence the pathogenic mechanisms of osteoporosis by regulating the activities of monocytes. INTRODUCTION: Osteoporosis is a serious public health problem, leading to significant mortality not only in aging females but also in males. Peripheral blood monocytes (PBMs) play important roles in bone metabolism by acting as precursors of osteoclasts and producing cytokines important for osteoclast development. The first cytosolic sub-proteome profiling analysis was performed in male PBMs to identify differentially expressed proteins (DEPs) that are associated with BMDs and risk of osteoporosis. METHODS: Here, we conducted a comparative proteomics analysis in PBMs from Caucasian male subjects with discordant hip BMD (29 low BMD vs. 30 high BMD). To decrease the proteome complexity and expand the coverage range of the cellular proteome, we separated the PBM proteome into several subcellular compartments and focused on the cytosolic fractions, which are involved in a wide range of fundamental biochemical processes. RESULTS: Of the total of 3796 detected cytosolic proteins, we identified 16 significant (P < 0.05) and an additional 22 suggestive (P < 0.1) DEPs between samples with low vs. high hip BMDs. Some of the genes for DEPs, including ALDOA, MYH14, and Rap1B, showed an association with BMD in multiple omics studies (proteomic, transcriptomic, and genomic). Further bioinformatics analysis revealed the enrichment of DEPs in functional terms for monocyte proliferation, differentiation, and migration. CONCLUSIONS: The combination strategy of subcellular separation and proteome profiling allows an in-depth and refined investigation into the composition and functions of cytosolic proteome, which may shed light on the monocyte-mediated pathogenic mechanisms of osteoporosis.

Association of 3q13.32 variants with hip trochanter and intertrochanter bone mineral density identified by a genome-wide association study.

We performed a GWAS of trochanter and intertrochanter bone mineral density (BMD) in the Framingham Heart Study and replicated in three independent studies. Our results identified one novel locus around the associated variations at chromosomal region 3q13.32 and replicated two loci at chromosomal regions 3p21 and 8q24. Our findings provide useful insights that enhance our understanding of bone development, osteoporosis, and fracture pathogenesis. INTRODUCTION: Hip trochanter (TRO) and intertrochanter (INT) subregions have important clinical relevance to subtrochanteric and intertrochanteric fractures but have rarely been studied by genome-wide association studies (GWASs). METHODS: Aiming to identify genomic loci associated with BMD variation at TRO and INT regions, we performed a GWAS utilizing the Framingham Heart Study (FHS, N = 6,912) as discovery sample and utilized the Women's Health Initiative (WHI) African-American subsample (N = 845), WHI Hispanic subsample (N = 446), and Omaha osteoporosis study (N = 971), for replication. RESULTS: Combining the evidence from both the discovery and the replication samples, we identified one novel locus around the associated variations at chromosomal region 3q13.32 (rs1949542, discovery p = 6.16 × 10-8, replication p = 2.86 × 10-4 for INT-BMD; discovery p = 1.35 × 10-7, replication p = 4.16 × 10-4 for TRO-BMD, closest gene RP11-384F7.1). We also replicated two loci at chromosomal regions 3p21 (rs148725943, discovery p = 6.61 × 10-7, replication p = 5.22 × 10-4 for TRO-BMD, closest gene CTNNB1) and 8q24 (rs7839059, discovery p = 2.28 × 10-7, replication p = 1.55 × 10-3 for TRO-BMD, closest gene TNFRSF11B) that were reported previously. We demonstrated that the effects at both 3q13.32 and 3p21 were specific to the TRO, but not to the femoral neck and spine. In contrast, the effect at 8q24 was common to all the sites. CONCLUSION: Our findings provide useful insights that enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.

Evaluation of the relationship and genetic overlap between Kashin-Beck disease and body mass index.

OBJECTIVES: Body mass index (BMI) is one of the major factors affecting the development of osteoarthritis (OA) but there is currently no information available regarding the relationship between BMI and Kashin-Beck disease (KBD). Our aim in this study was to investigate the relationship and genetic overlap between BMI and KBD. METHOD: A total of 2050 Han Chinese subjects participated in this study. Using a cohort of 333 grade I KBD patients, logistic regression analysis was conducted to evaluate the correlation between BMI and KBD. Another independent sample of 1717 subjects was genotyped for a genome-wide association study (GWAS) using Affymetrix Human SNP 6.0 Arrays. Single nucleotide polymorphism (SNP) effect concordance analysis (SECA) was applied to the GWAS summaries of KBD and BMI for pleiotropy analysis. Genome-wide bivariate association analysis (GWBAA) of KBD and BMI was carried out to identify the genes with pleiotropic effects on KBD and BMI. The relevance of identified genes with KBD was validated by gene expression profiling and immunohistochemistry. RESULTS: BMI correlated positively with knee movement disorder in KBD (coefficient ß = 0.068, p = 0.045). SECA identified a significant pleiotropic effect (empirical p = 0.021) between KBD and BMI. In the GWBAA, the rs1893577 of the ADAMTS1 gene achieved the most significant association signal (p = 7.38 × 10-9). ADAMTS1 was also up-regulated in KBD vs. normal (ratio = 2.64 ± 2.80) and KBD vs. OA (ratio = 2.31 ± 2.01). The rate of ADAMTS1-positive chondrocytes in KBD was significantly higher than that in OA (p < 0.05) and healthy controls (p < 0.05). CONCLUSIONS: Our results suggest that ADAMTS1 is a novel susceptibility gene for KBD.

Epigenomic elements analyses for promoters identify ESRRG as a new susceptibility gene for obesity-related traits.

OBJECTIVES: With ENCODE epigenomic data and results from published genome-wide association studies (GWASs), we aimed to find regulatory signatures of obesity genes and discover novel susceptibility genes. METHODS: Obesity genes were obtained from public GWAS databases and their promoters were annotated based on the regulatory element information. Significantly enriched or depleted epigenomic elements in the promoters of obesity genes were evaluated and all human genes were then prioritized according to the existence of the selected elements to predict new candidate genes. Top-ranked genes were subsequently applied to validate their associations with obesity-related traits in three independent in-house GWAS samples. RESULTS: We identified RAD21 and EZH2 as over-represented, and STAT2 (signal transducer and activator of transcription 2) and IRF3 (interferon regulatory transcription factor 3) as depleted transcription factors. Histone modification of H3K9me3 and chromatin state segmentation of 'poised promoter' and 'repressed' were over-represented. All genes were prioritized and we selected the top five genes for validation at the population level. Combining results from the three GWAS samples, rs7522101 in ESRRG (estrogen-related receptor-γ) remained significantly associated with body mass index after multiple testing corrections (P=7.25 × 10(-5)). It was also associated with ß-cell function (P=1.99 × 10(-3)) and fasting glucose level (P<0.05) in the meta-analyses of glucose and insulin-related traits consortium (MAGIC) data set.Cnoclusions:In summary, we identified epigenomic characteristics for obesity genes and suggested ESRRG as a novel obesity-susceptibility gene.

Relationship of sarcopenia and body composition with osteoporosis.

UNLABELLED: The purpose of the study is to investigate the relationship between sarcopenia and body composition and osteoporosis in cohorts of three different races with a total of 17,891 subjects. Lean mass and grip strength were positively associated with bone mineral densities (BMDs). Subjects with sarcopenia were two times more likely to have osteoporosis compared with normal subjects. INTRODUCTION: The relationship between sarcopenia and osteoporosis is not totally clear. First, the present study assessed this relationship by using two different definitions for sarcopenia. Second, we examined the associations of body composition (including muscle mass as a major and important component) and muscle strength on regional and whole-body BMDs. METHODS: In total, 17,891 subjects of African American, Caucasian, and Chinese ethnicities were analyzed. Sarcopenia was defined by relative appendicular skeletal muscle mass (RASM) cut points and also by the definition of the European Working Group on Sarcopenia in Older People (low RASM plus low muscle function). Multiple regression analyses were conducted to examine the association of fat mass, lean mass (including muscle mass), and grip strength with regional and whole-body BMDs. Multivariate logistic regression analysis was performed to explore the association between sarcopenia and osteopenia/osteoporosis. RESULTS: BMDs were positively associated with lean mass and negatively associated with fat mass, after controlling for potential confounders. Grip strength was significantly associated with higher BMDs. Each standard deviation (SD) increase in RASM resulted in a ~37 % reduction in risk of osteopenia/osteoporosis (odds ratio (OR) = 0.63; 95 % confidence interval (CI) = 0.59, 0.66). Subjects with sarcopenia defined by RASM were two times more likely to have osteopenia/osteoporosis compared with the normal subjects (OR = 2.04; 95 % CI = 1.61, 2.60). Similarly, subjects with sarcopenia (low muscle mass and low grip strength) were ~1.8 times more likely to have osteopenia/osteoporosis than normal subjects (OR = 1.87; 95 % CI = 1.09, 3.20). CONCLUSIONS: High lean mass and muscle strength were positively associated with BMDs. Sarcopenia is associated with low BMD and osteoporosis.

Integrative analysis of genome-wide association studies and gene expression profiles identified candidate genes for osteoporosis in Kashin-Beck disease patients.

SUMMARY: The molecular mechanism of osteoporosis (OP) in Kashin-Beck disease (KBD) patients was unclear. Our results suggest that KBD and OP shared some common causal genes, functionally involved in skeletal growth and development and chronic inflammation. Our results provide novel clues for clarifying the molecular mechanism of OP in KBD patients. INTRODUCTION: KBD is a chronic skeletal disorder with osteopenia and OP. The pathogenesis of OP in KBD patients remains elusive. METHODS: A total of 1717 subjects participated in this study. KBD was diagnosed according to the clinical diagnosis criteria of China (GB16395-1996). The bone mineral density (BMD) and bone areas of the ulna and radius, hip, and lumbar (L1-L4) were measured with a Hologic 4500 W dual-energy X-ray absorptiometry scanner. Genotyping was conducted using Affymetrix SNP Array 6.0. Gene expression profiling of peripheral blood mononuclear cells of KBD and OP patients were compared using Affymetrix HG-U133 plus 2.0 arrays and Agilent Human 1A arrays, respectively. Genome-wide association studies (GWAS) were conducted by PLINK. SCEA and DAVID were applied for pleiotropy and functional enrichment analysis, respectively. RESULTS: SCEA analysis observed significant pleiotropic effects between KBD and the ulna and radius BMD (P value = 5.99 × 10(-3)). GWAS meta-analysis identified six candidate genes with pleiotropic effects, including PDGFD, SOX5, DPYD, CTR9, SPP1, and COL4A1. GO analysis identified 16 significant GO shared by KBD and the ulna and radius BMD, involved in cell morphogenesis and apoptosis. Pathway enrichment analysis detected two common pathways for KBD and the ulna and radius BMD, including calcium signaling pathway and vascular smooth muscle contraction pathway. Gene expression analysis detected three up-regulated inflammation-related genes for KBD and OP, including IL1B, IL8, and CCL1. CONCLUSION: This study reported several candidate genes involved in the development of OP in KBD patients.

Circulating monocytes: an appropriate model for bone-related study.

Peripheral blood monocytes (PBMs) are an important source of precursors of osteoclasts, the bone-resorbing cells and the cytokines produced by PBMs that have profound effects on osteoclast differentiation, activation, and apoptosis. So PBMs represent a highly valuable and unique working cell model for bone-related study. Finding an appropriate working cell model for clinical and (epi-)genomic studies of human skeletal disorders is a challenge. Peripheral blood monocytes (PBMs) can give rise to osteoclasts, the bone-resorbing cells. Particularly, PBMs provide the sole source of osteoclast precursors for adult peripheral skeleton where the bone marrow is normally hematopoietically inactive. PBMs can secrete potent pro- and anti-inflammatory cytokines, which are important for osteoclast differentiation, activation, and apoptosis. Reduced production of PBM cytokines represents a major mechanism for the inhibitory effects of sex hormones on osteoclastogenesis and bone resorption. Abnormalities in PBMs have been linked to various skeletal disorders/traits, strongly supporting for the biological relevance of PBMs with bone metabolism and disorders. Here, we briefly review the origin and further differentiation of PBMs. In particular, we discuss the close relationship between PBMs and osteoclasts, and highlight the utility of PBMs in study the pathophysiological mechanisms underlying various skeletal disorders.

Development and characterization of new microsatellite markers of Fenneropenaeus penicillatus.

Thirteen new polymorphic microsatellite markers in Fenneropenaeus penicillatus were isolated and characterized. The polymorphism of the thirteen microsatellite markers was tested by 30 individuals from Lianjiang, China. It showed that the number of al-leles per locus ranged from 3 to 6 and the Polymorphism Information Content (PIC) was from 0.324 to 0.706. The observed and expected heterozygosities were 0.3217-0.8023 and 0.1977-0.6783, respectively. Only one loci (LJ-19) deviated significantly from Hardy-Weinberg equilibrium (HWE) (P < 0.00385) after Bonferroni correction, while the other twelve markers were in HWE after Bonferroni correction (P > 0.00385). The thirteen polymorphic microsatellite markers could pro-vide more genetic data for further research on cultivation and recovery of F. penicillatus.

Development and characterization of polymorphic microsatellite loci in the sea cucumber Holothuria leucospilota.

Holothuria leucospilota is a tropical holothurian species that is widely distributed in the tropical and sub-tropical India-Western Pacific Region. Eight polymorphic microsatellite loci were developed from H. leucospilota by using the protocol fast isolation by amplified fragment length polymorphism of sequences containing repeats and tested in 30 individuals from Hainan Island in China. The number of alleles was 2-6 and polymorphism information content ranged from 0.371-0.694. The levels of expected and observed heterozygosities varied from 0.3913-0.6701 and from 0.1154-0.7000, respectively. No significant linkage disequilibrium was detected for any pairwise combination of loci. Only loci YZHS1-42 deviated from Hardy-Weinberg equilibrium. These polymorphic microsatellite loci may be useful for germplasm conservation of H. leucospilota.

Isolation of new polymorphic microsatellite markers from the marbled rockfish Sebastiscus marmoratus.

The marbled rockfish, Sebastiscus marmoratus, is an important commercially near-shore fish that inhabits the beach rocky bottom from Japan to the South China Sea. Eleven polymorphic microsatellite loci were developed from S. marmoratus and were used to identify polymorphisms in 30 samples from a wild population. The allele locus number ranged from 2 to 7. Polymorphism data content ranged from 0.032 to 0.751. The observed and expected heterozygosity levels were 0.0333-0.9667 and 0.0328-0.7675, respectively. Two loci, Smd1-112 and Smd2-80, deviated from Hardy-Weinberg equilibrium. These polymorphic microsatellite markers will facilitate further studies of genetic diversity and genetic differentiation of S. marmoratus.

Ethnic differentiation of copy number variation on chromosome 16p12.3 for association with obesity phenotypes in European and Chinese populations.

OBJECTIVE: Genomic copy number variations (CNVs) have been strongly implicated as important genetic factors for obesity. A recent genome-wide association study identified a novel variant, rs12444979, which is in high linkage disequilibrium with CNV 16p12.3, for association with obesity in Europeans. The aim of this study was to directly examine the relationship between the CNV 16p12.3 and obesity phenotypes, including body mass index (BMI) and body fat mass. SUBJECTS: Subjects were a multi-ethnic sample, including 2286 unrelated subjects from a European population and 1627 unrelated Han subjects from a Chinese population. Body fat mass was measured using dual energy X-ray absorptiometry. RESULTS: Using Affymetrix Genome-Wide Human SNP Array 6.0, we directly detected CNV 16p12.3, with the deletion frequency of 27.26 and 0.8% in the European and Chinese populations, respectively. We confirmed the significant association between this CNV and obesity (BMI: P=1.38 × 10(-2); body fat mass: P=2.13 × 10(-3)) in the European population. Less copy numbers were associated with lower BMI and body fat mass, and the effect size was estimated to be 0.62 (BMI) and 1.41 (body fat mass), respectively. However, for the Chinese population, we did not observe significant association signal, and the frequencies of this deletion CNV are quite different between the European and Chinese populations (P<0.001). CONCLUSION: Our findings first suggest that CNV 16p12.3 might be ethnic specific and cause ethnic phenotypic diversity, which may provide some new clues into the understanding of the genetic architecture of obesity.