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Abstract Background This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. Methods Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. Results The risk of developing frailty was 1.18 times (95% CI: 1.03–1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03–1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09–1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72–0.98) when compared with participants with low levels of hs-CRP. Conclusions Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.

ABSTRACT Background This study aimed to investigate the effect of systemic inflammation, assessed by high sensitivity C‐reactive protein (hs‐CRP) levels, on prediabetes progression and regression in middle‐aged and older adults based on the China Health and Retirement Longitudinal Study (CHARLS). Methods Participants with prediabetes from CHARLS were followed up 4 years later with blood samples collected for measuring fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The level of hs‐CRP was assessed at baseline and categorized into tertiles (low, middle, and high groups). Prediabetes at baseline and follow‐up was defined primarily according to the American Diabetes Association (ADA) criteria. Logistic regression models were used to estimate the odds ratios (ORs) and confidence intervals (CIs). We also performed stratified analyses according to age, gender, BMI, the presence of hypertension, and the disease history of heart disease and dyslipidemia and sensitivity analyses excluding a subset of participants with incomplete data. Results Of the 2,874 prediabetes included at baseline, 834 participants remained as having prediabetes, 146 progressed to diabetes, and 1,894 regressed to normoglycemia based on ADA criteria with a 4 year follow‐up. After multivariate logistics regression analysis, prediabetes with middle (0.67–1.62 mg/L) and high (>1.62 mg/L) hs‐CRP levels had an increased incidence of progressing to diabetes compared with prediabetes with low hs‐CRP levels (

BackgroundCreatinine-cystatin C ratio (CCR) has been demonstrated as an objective marker of sarcopenia in clinical conditions but has not been evaluated as an osteoporosis marker in individuals with normal renal function.MethodsWe selected 271,831 participants with normal renal function from UK Biobank cohort. Multivariable linear/logistic regression and Cox proportional hazards model were used to investigate the phenotypic relationship between CCR and osteoporosis in total subjects and gender-stratified subjects. Based on the genome-wide association study (GWAS) data, linkage disequilibrium regression (LDSC) and Mendelian randomization (MR) analysis were performed to reveal the shared genetic correlations and infer the causal effects, respectively.ResultsAmongst total subjects and gender-stratified subjects, serum CCR was positively associated with eBMD after adjusting for potential risk factors (all P

Background Reference ranges for bone turnover markers (BTMs) are still lacking in the healthy Chinese population. Aim To establish reference intervals for BTMs and to investigate the correlations between BTMs and bone mineral density (BMD) in Chinese older adults. Subjects and methods A community-based cross-sectional study was conducted among 2511 Chinese subjects aged over 50 yrs residing in Zhenjiang, Southeast China. Reference intervals for BTMs (i.e. procollagen type I N-terminal propeptide, P1NP; β cross-linked C-terminal telopeptide of type I collagen, β-CTX) were calculated as the central 95% range of all measurements in Chinese older adults. Results The reference intervals of P1NP, β-CTX and P1NP/β-CTX were 15.8–119.9 ng/mL, 0.041–0.675 ng/mL and 49.9–1261.5 for females and 13.6–111.4 ng/mL, 0.038–0.627 ng/mL and 41.0–1269.1 for males, respectively. In the multiple linear regression analysis, only β-CTX was negatively associated with BMD after adjusting for age and body mass index (BMI) in both sex-stratified groups (all p

PurposeTo reveal relationship between air pollution exposure and osteoporosis (OP) risk.MethodsBased on large-scale data from the UK Biobank, we evaluated the relationship between OP risk and several air pollutants. Then air pollution scores (APS) were constructed to assess the combined effects of multiple air pollutants on OP risk. Finally, we constructed a genetic risk score (GRS) based on a large genome-wide association study of femoral neck bone mineral density and assessed whether single or combined exposure to air pollutants modifies the effect of genetic risk on OP and fracture risk.ResultsPM2.5, NO2, NOx, and APS were significantly associated with an increased risk of OP/fracture. OP and fracture risk raised with increasing concentrations of air pollutants: compared to the lowest APS quintile group, subjects in the highest quintile group had a hazard ratio (HR) (95% CI) estimated at 1.140 (1.072–1.213) for OP and 1.080 (1.026–1.136) for fracture. Moreover, participants with low GRS and the highest air pollutant concentration had the highest risk of OP, the HRs (95% CI) of OP were 1.706 (1.483–1.964), 1.658 (1.434–1.916), 1.696 (1.478–1.947), 1.740 (1.506–2.001) and 1.659 (1.442–1.908), respectively, for PM2.5, PM10, PM2.5−10, NO2, and NOx. Similar results were also observed for fractures. Finally, we assessed the joint effect of APS and GRS on the risk of OP. Participants with higher APS and lower GRS had a higher risk of developing OP. Similar results were observed in the joint effect of GRS and APS on fracture.ConclusionsWe found that exposure to air pollution, individually or jointly, could improve the risk of developing OP and fractures, and increased the risk by interacting with genetic factors.

Recent evidence has gradually recognized that the immune and skeletal systems are two closely correlated systems, but the specific immune factors on bone mineral density (BMD) are largely unknown. Based on the summary-level data of genome-wide association studies (GWASs), we performed a series of analyses including two-sample Mendelian randomization (MR) analysis to test potential causal links between 731 immune traits [including median fluorescence intensities (MFIs), absolute cell (AC) counts, relative cell (RC) counts, and morphological parameters (MP)] and BMD. After false discovery rate (FDR) correction, 9 MFI-BMD, 16 AC-BMD, 22 RC-BMD, and 5 MP-BMD pairs reached the level of significance (FDR-adjusted p< 0.05). For MFI traits, the T- and B-cell panels had the largest number of significant immune trait pairs than other panels. CD40, as a molecule expressed by four subsets of monocytes, was highlighted due to its consistently positive correlation with BMD at four sites. For both AC and RC traits, immune traits from the T-cell panel were also highlighted, with CD39-positive T-cell subsets being the most frequently observed feature. For MP traits, the most significant association immune trait with BMD was SSC-A on CD14+ monocyte. Sensitivity analyses suggested that the identified immune factors were robust to pleiotropy. Multivariable MR analysis confirmed the independent causal effect of several immune traits on BMD. Mediation analyses showed that CD40 on monocytes could mediate multiple immune traits, especially the suggestive associations of CD27 on several memory B cells with BMD mediated by CD40 on CD14+ CD16− monocyte. Our study represents the first comprehensive evaluation of the causal effects of immune traits on the risk of osteoporosis. The findings highlighted the complex and important role of immune-derived factors in the pathogenesis of osteoporosis.

Objectives: We aimed to explore how healthy lifestyles and genetic factors influence the risk of Osteoporosis (OP).Methods: In this prospective cohort study, we first performed a genome-wide association study (GWAS) of estimated bone mineral density (eBMD) and constructed the genetic risk score (GRS) based on the effect of single nucleotide polymorphism (SNP) on eBMD. We then assessed the effect of three-level GRS and adherence to healthy lifestyles on the risk of OP and fracture, respectively. Finally, we assessed the joint effects of GRS and lifestyle on the OP and fracture risk.Results: People with higher GRS have a lower risk of OP and fracture. Negative associations were detected between healthy lifestyle factors and the risk of OP and fracture. Compare with the group with high GRS and favorable lifestyles, the group with low GRS and unfavorable lifestyles had a high Hazard Ratio (HR).Conclusion: The findings suggest that adherence to healthy lifestyles can reduce the risk of OP and fracture in people with different genetic risks.

PurposeOsteoporosis is associated with metabolic alterations, but the causal roles of serum metabolites on osteoporosis have not been identified.MethodsBased on the large individual-level datasets from UK Biobank as well as GWAS summary datasets, we first constructed genetic risk scores (GRSs) for 308 of 486 human serum metabolites and evaluated the effect of each GRS on 2 major osteoporosis phenotypes, i.e., estimated bone miner density (eBMD) and fracture, respectively. Then, two-sample Mendelian Randomization (MR) was performed to validate the casual metabolites on osteoporosis. Multivariable MR analysis tested whether the effects of metabolites on osteoporosis are independent of possible confounders. Finally, we conducted metabolic pathway analysis for the metabolites involved in bone metabolism.ResultsWe identified causal effects of 18 metabolites on eBMD and 1 metabolite on fracture with the GRS method after adjusting for multiple tests. Then, 9 of them were further validated with MR as replication, where comprehensive sensitive analyses proved robust of the causal associations. Although not identified in GRS, 3 metabolites were associated with at least three osteoporosis traits in MR results. Multivariable MR analysis determined the independent causal effect of several metabolites on osteoporosis. Besides, 23 bone metabolic pathways were detected, such as valine, leucine, isoleucine biosynthesis (p = 0.053), and Aminoacyl-tRNA biosynthesis (p = 0.076), and D-glutamine and D-glutamate metabolism (p = 0.004).ConclusionsThe systematic causal analyses strongly suggested that blood metabolites have causal effects on osteoporosis risk.

BackgroundEffective identification of high-risk rheumatoid arthritis (RA) individuals is still a challenge. Whether the combined effects of multiple previously reported genetic loci together with lifestyle factors can improve the prediction of RA risk remains unclear.MethodsBased on previously reported results and a large-scale Biobank dataset, we constructed a polygenic risk score (PRS) for RA to evaluate the combined effects of the previously identified genetic loci in both case-control and prospective cohorts. We then evaluated the relationships between several lifestyles and RA risk and determined healthy lifestyles. Then, the joint effects of healthy lifestyles and genetic risk on RA risk were evaluated.ResultsWe found a positive association between PRS and RA risk (OR = 1.407, 95% confidence interval (CI) = 1.354~1.463; HR = 1.316, 95% CI = 1.257~1.377). Compared with the low genetic risk group, the group with intermediate or high genetic risk had a higher risk (OR = 1.347, 95% CI = 1.213~1.496; HR = 1.246, 95% CI = 1.108~1.400) (OR = 2.169, 95% CI = 1.946~2.417; HR = 1.762, 95% CI = 1.557~1.995). After adjusting for covariates, we found protective effects of three lifestyles (no current smoking, regular physical activity, and moderate body mass index) on RA risk and defined them as healthy lifestyles. Compared with the individuals with low genetic risks and favorable lifestyles, those with high genetic risks and unfavorable lifestyles had as high as OR of 4.637 (95%CI = 3.767~5.708) and HR of 3.532 (95%CI = 2.799~4.458).ConclusionsIn conclusion, the integration of PRS and lifestyles can improve the prediction of RA risk. High RA risk can be alleviated by adopting healthy lifestyles but aggravated by adopting unfavorable lifestyles.

BackgroundWith the prolonging of human life expectancy and subsequent population aging, osteoporosis (OP) has become an important public health issue. ObjectiveThis study aimed to understand the global public search interests and dynamic trends in “osteoporosis” using the data derived from Google Trends. MethodsAn online search was performed using the term “osteoporosis” in Google Trends from January 1, 2004, to December 31, 2019, under the category “Health.” Cosinor analysis was used to test the seasonality of relative search volume (RSV) for “osteoporosis.” An analysis was conducted to investigate the public search topic rising in RSV for “osteoporosis.” ResultsThere was a descending trend of global RSV for “osteoporosis” from January 2004 to December 2014, and a slowly increasing trend from January 2015 to December 2019. Cosinor analysis showed significant seasonal variations in global RSV for “osteoporosis” (P=.01), with a peak in March and a trough in September. In addition, similar decreasing trends of RSV for “osteoporosis” were found in Australia, New Zealand, Ireland, and Canada from January 2004 to December 2019. Cosinor test revealed significant seasonal variations in RSV for “osteoporosis” in Australia, New Zealand, Canada, Ireland, UK, and USA (all P

BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Abstract Human monocyte is an important cell type which is involved in various complex human diseases. To better understand the biology of human monocytes and facilitate further studies, we developed the first comprehensive proteome knowledge base specifically for human monocytes by integrating both in vivo and in vitro datasets. The top 2000 expressed genes from in vitro datasets and 779 genes from in vivo experiments were integrated into this study. Altogether, a total of 2237 unique monocyte-expressed genes were cataloged. Biological functions of these monocyte-expressed genes were annotated and classified via Gene Ontology (GO) analysis. Furthermore, by extracting the overlapped genes from in vivo and in vitro datasets, a core gene list including 541 unique genes was generated. Based on the core gene list, further gene-disease associations, pathway and network analyses were performed. Data analyses based on multiple bioinformatics tools produced a large body of biologically meaningful information, and revealed a number of genes such as SAMHD1, G6PD, GPD2 and ENO1, which have been reported to be related to immune response, blood biology, bone remodeling, and cancer respectively. As a unique resource, this study can serve as a reference map for future in-depth research on monocytes biology and monocyte-involved human diseases.

Gelsolin (GSN) protein, expressed in circulating monocytes, was previously reported to be associated with osteoporosis in both Chinese and Caucasian women. This study aims to test if plasma GSN protein level is associated with hip bone mineral density (BMD) in Chinese population. Based on two study Groups containing 6,308 old Chinese, we adopted extreme sampling scheme and selected 3 independent samples (Subgroups 1-3) for discovery, replication, and validation purposes. We tested plasma GSN concentration, and analyzed whether plasma GSN level differs between subjects with extremely low vs. high hip BMD. In Group 1 (N = 1,860), the plasma GSN level increased in the female with low BMD, which was discovered in the Subgroup 1 (N = 42, p = 0.093) and replicated in the Subgroup 2 (N = 39, p = 0.095). With more extreme sampling for the Subgroup 3 from the Group 2 (N = 4,448), the difference of plasma GSN level in the female with low BMD vs. high BMD is more significant (N = 45, p = 0.037). After the subjects were pooled from Subgroups 2 and 3, the difference in plasma GSN between low and high BMD subjects became even more significant (p = 0.016). The plasma GSN level was negatively correlated with total hip BMD (r = -0.26, p = 0.033). We concluded that plasma GSN was associated with hip BMD in Chinese postmenopausal women and plasma GSN might be a potential risk biomarker for osteoporosis.

Low bone mineral density (BMD) is a risk factor of osteoporotic fracture (OF). Peripheral blood monocytes (PBM) can differentiate into osteoclasts to resorb bone. It was known that PBM-expressed Anxa2 protein is associated with BMD, and extracellular Anxa2 protein promotes osteoclastogenesis. This study aimed to test 1) whether Anxa2 protein level in PBM differs significantly between subjects with OF and without fracture history (NF); 2) whether Anxa2 level in plasma is associated with BMD; 3) how Anxa2 protein at various concentrations would affect osteoblastic activity in vitro. All the study subjects were Chinese Han elderly. Firstly, Anxa2 protein in PBM was identified and quantitated by LC-MS/MS and compared between 45 OF cases and 42 healthy controls. Secondly, plasma Anxa2 protein level was quantitated by ELISA and compared between unrelated subjects with extremely low vs. high hip BMD (0.63±0.10 vs. 1.05±0.10 g/cm2, n = 75). Furthermore, in vitro functional assay was utilized to test the effects of extracellular Anxa2 protein on osteoblastic growth. We found that Anxa2 protein expression in PBM was significantly up-regulated in OF vs. NF subjects (fold change [FC)] = 1.16, P

OBJECTIVE:Systemic lupus erythematosus (SLE) is a complex auto-immune disease. Gene expression studies have been conducted to identify SLE-related genes in various types of samples. It is unknown whether there are common marker genes significant for SLE but independent of sample types, which may have potentials for follow-up translational research. The aim of this study is to identify common marker genes across various sample types for SLE. METHODS:Based on four public microarray gene expression datasets for SLE covering three representative types of blood-born samples (monocyte; peripheral blood mononuclear cell, PBMC; whole blood), we utilized three statistics (fold-change, FC; t-test p value; false discovery rate adjusted p value) to scrutinize genes simultaneously regulated with SLE across various sample types. For common marker genes, we conducted the Gene Ontology enrichment analysis and Protein-Protein Interaction analysis to gain insights into their functions. RESULTS:We identified 10 common marker genes associated with SLE (IFI6, IFI27, IFI44L, OAS1, OAS2, EIF2AK2, PLSCR1, STAT1, RNASE2, and GSTO1). Significant up-regulation of IFI6, IFI27, and IFI44L with SLE was observed in all the studied sample types, though the FC was most striking in monocyte, compared with PBMC and whole blood (8.82-251.66 vs. 3.73-74.05 vs. 1.19-1.87). Eight of the above 10 genes, except RNASE2 and GSTO1, interact with each other and with known SLE susceptibility genes, participate in immune response, RNA and protein catabolism, and cell death. CONCLUSION:Our data suggest that there exist common marker genes across various sample types for SLE. The 10 common marker genes, identified herein, deserve follow-up studies to dissert their potentials as diagnostic or therapeutic markers to predict SLE or treatment response.

Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations.Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects). For the newly identified RA-associated genes, gene set enrichment analyses and protein-protein interactions analyses were carried out with DAVID and STRING version 10.0, respectively. Differential expression verification was conducted using 4 GEO datasets. The expression levels of three selected 'highly verified' genes were measured by ELISA among our in-house RA cases and controls.A total of 221 RA-associated genes were newly identified by gene-based association study, including 71'overlapped', 76 'European-specific' and 74 'Asian-specific' genes. Among them, 105 genes had significant differential expressions between RA patients and health controls at least in one dataset, especially for 20 genes including 11 'overlapped' (ABCF1, FLOT1, HLA-F, IER3, TUBB, ZKSCAN4, BTN3A3, HSP90AB1, CUTA, BRD2, HLA-DMA), 5 'European-specific' (PHTF1, RPS18, BAK1, TNFRSF14, SUOX) and 4 'Asian-specific' (RNASET2, HFE, BTN2A2, MAPK13) genes whose differential expressions were significant at least in three datasets. The protein expressions of two selected genes FLOT1 (P value = 1.70E-02) and HLA-DMA (P value = 4.70E-02) in plasma were significantly different in our in-house samples.Our study identified 221 novel RA-associated genes and especially highlighted the importance of 20 candidate genes on RA. The results addressed ethnic genetic background differences for RA susceptibility between European and Asian populations and detected a long list of overlapped or ethnic specific RA genes. The study not only greatly increases our understanding of genetic susceptibility to RA, but also provides important insights into the ethno-genetic homogeneity and heterogeneity of RA in both ethnicities.

Rheumatic diseases have some common symptoms. Extensive gene expression studies, accumulated thus far, have successfully identified signature molecules for each rheumatic disease, individually. However, whether there exist shared factors across rheumatic diseases has yet to be tested.We collected and utilized 6 public microarray datasets covering 4 types of representative rheumatic diseases including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and osteoarthritis. Then we detected overlaps of differentially expressed genes across datasets and performed a meta-analysis aiming at identifying common differentially expressed genes that discriminate between pathological cases and normal controls. To further gain insights into the functions of the identified common differentially expressed genes, we conducted gene ontology enrichment analysis and protein-protein interaction analysis.We identified a total of eight differentially expressed genes (TNFSF10, CX3CR1, LY96, TLR5, TXN, TIA1, PRKCH, PRF1), each associated with at least 3 of the 4 studied rheumatic diseases. Meta-analysis warranted the significance of the eight genes and highlighted the general significance of four genes (CX3CR1, LY96, TLR5, and PRF1). Protein-protein interaction and gene ontology enrichment analyses indicated that the eight genes interact with each other to exert functions related to immune response and immune regulation.The findings support that there exist common factors underlying rheumatic diseases. For rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and osteoarthritis diseases, those common factors include TNFSF10, CX3CR1, LY96, TLR5, TXN, TIA1, PRKCH, and PRF1. In-depth studies on these common factors may provide keys to understanding the pathogenesis and developing intervention strategies for rheumatic diseases.

Genetic factors contribute to the variation of bone mineral density (BMD), which is a major risk factor of osteoporosis. The aim of this study was to identify more "novel" genes for BMD. Based on the publicly available SNP-based P values, we performed an initial gene-based analysis in a total of 32,961 individuals. Furthermore, we performed differential expression, pathway and protein-protein interaction analyses to find supplementary evidence to support the significance of the identified genes. About 21,695 genes for femoral neck (FN)-BMD and 21,683 genes for lumbar spine (LS)-BMD were analyzed using gene-based association analysis. A total of 35 FN-BMD associated genes and 53 LS-BMD associated genes were identified (P < 2.3×10(-6)) after Bonferroni correction. Among them, 64 genes have not been reported in previous SNP-based genome-wide association studies. Differential expression analysis further supported the significant associations of 14 genes with FN-BMD and 19 genes with LS-BMD. Especially, WNT3 and WNT9B in the Wnt signaling pathway for FN-BMD were further supported by pathway analysis and protein-protein interaction analysis. The present study took the advantage of gene-based association method to perform a supplementary analysis of the GWAS dataset and found some BMD-associated genes. The evidence taken together supported the importance of Wnt signaling pathway genes in determining osteoporosis. Our findings provided more insights into the genetic basis of osteoporosis.

Systemic lupus erythematosus (SLE) is a serious prototype autoimmune disease characterized by chronic inflammation, auto-antibody production and multi-organ damage. Recent association studies have identified a long list of loci that were associated with SLE with relatively high statistical power. However, most of them only established the statistical associations of genetic markers and SLE at the DNA level without supporting evidence of functional relevance. Here, using publically available datasets, we performed integrative analyses (gene relationship across implicated loci analysis, differential gene expression analysis and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTLs) results to dissect functional mechanisms underlying the associations for SLE. We found that 14 SNPs, which were significantly associated with SLE in previous studies, have cis-regulation effects on four eQTL genes (HLA-DQA1, HLA-DQB1, HLA-DQB2, and IRF5) that were also differentially expressed in SLE-related cell groups. The functional evidence, taken together, suggested the functional mechanisms underlying the associations of 14 SNPs and SLE. The study may serve as an example of mining publically available datasets and results in validation of significant disease-association results. Utilization of public data resources for integrative analyses may provide novel insights into the molecular genetic mechanisms underlying human diseases.

Human height is a highly heritable trait considered as an important factor for health. There has been limited success in identifying the genetic factors underlying height variation. We aim to identify sequence variants associated with adult height by a genome-wide association study of copy number variants (CNVs) in Chinese.Genome-wide CNV association analyses were conducted in 1,625 unrelated Chinese adults and sex specific subgroup for height variation, respectively. Height was measured with a stadiometer. Affymetrix SNP6.0 genotyping platform was used to identify copy number polymorphisms (CNPs). We constructed a genomic map containing 1,009 CNPs in Chinese individuals and performed a genome-wide association study of CNPs with height.We detected 10 significant association signals for height (p

Osteoporotic hip fracture (HF) is a serious global public health problem associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of key measurable risk factors for HF, independent of bone mineral density (BMD). Hip BS is highly genetically determined, but genetic factors underlying BS variation are still poorly defined. Here, we performed an initial genome-wide copy number variation (CNV) association analysis for hip BS in 1,627 Chinese Han subjects using Affymetrix GeneChip Human Mapping SNP 6.0 Array and a follow-up replicate study in 2,286 unrelated US Caucasians sample. We found that a copy number polymorphism (CNP267) located at chromosome 2q12.2 was significantly associated with hip BS in both initial Chinese and replicate Caucasian samples with p values of 4.73E-03 and 5.66E-03, respectively. An important candidate gene, four and a half LIM domains 2 (FHL2), was detected at the downstream of CNP267, which plays important roles in bone metabolism by binding to several bone formation regulator, such as insulin-like growth factor-binding protein 5 (IGFBP-5) and androgen receptor (AR). Our findings suggest that CNP267 region may be associated with hip BS which might influence the FHL2 gene downstream.

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