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1.  A genomewide scan for quantitative trait loci underlying areal bone size variation in 451 Caucasian families 
Journal of Medical Genetics  2006;43(11):873-880.
Bone size is an important determinant of bone strength and is under strong genetic control.
To identify quantitative trait loci (QTL) for areal bone size variation, a large‐scale genomewide linkage scan was carried out in 451 Caucasian families.
Participants and methods
Of 4124 people with phenotypes, 3899 were genotyped with 410 microsatellite markers. Multipoint linkage analyses were carried out in the entire sample, as well as in men and women separately. Potential epistatic interactions between identified genomic regions were also assessed.
Several potentially important genomic regions were identified, such as 8q24 for hip bone size (logarithm of the ratio of the odds that two loci are linked (LOD) 3.27) and 2p24 (LOD 2.04) for spine bone size. 8q24 may also interact with 19p13 to affect hip bone size. Several sex‐specific QTL were also detected, such as 14q21 (LOD 2.94) for wrist bone size in women and 16q12 (LOD 2.19) for hip bone size in men.
Together with previous findings, this study has further delineated the genetic basis of bone size and laid a foundation for future studies to eventually elucidate the mechanisms of bone size regulation and associated fracture risks.
PMCID: PMC2563191  PMID: 16825438
3.  Alteration of vitamin D metabolic enzyme expression and calcium transporter abundance in kidney involved in type 1 diabetes-induced bone loss 
This study aimed to delineate the mechanism involved in type 1 diabetes-induced bone loss. The results revealed the alteration of vitamin D metabolic enzyme expression and the downregulation of renal calcium transporter abundance in type 1 diabetic mice.
The purpose of this study was to investigate the changes of the expression of vitamin D metabolic enzymes and transcellular calcium-transporting proteins in kidneys from mice with experimentally induced diabetes.
Male DBA/2J mice were injected with either vehicle (control) or streptozotocin (STZ) daily for five consecutive days. Bone mineral density was measured by peripheral quantitative computerized tomography, and bone histomorphology was analyzed by Safranin O staining. Real-time PCR and Western blotting were applied to determine the expression of target genes and proteins.
Type 1 diabetes produced high urinary calcium excretion and loss of trabecular bone measured at the proximal metaphysis of the tibia and the distal femur. Bone loss was associated with deterioration of trabecular bone microstructure. Quantified PCR results showed that mRNA expression level in the kidney of diabetic mice for 25-hydroxyvitamin D-24-hydroxylase was downregulated at week 10, while those for 25-hydroxyvitamin D-1α-hydroxylase were upregulated at week 20. In addition, mRNA expression levels for renal transient receptor potential V6, plasma membrane Ca-ATPase (PMCA)1b, and vitamin D receptor (VDR) genes were decreased in STZ-treated mice. Western blot analysis showed that protein expression of PMCA1b and VDR was significantly decreased in kidneys from STZ-treated mice compared to that of controls.
The limitation in this study is the lack of vitamin D, parathyroid hormone, and phosphorus levels in serum. However, the present study supports the conclusion that the underlying mechanism contributing to type 1 diabetes-associated bone loss may be alterations of vitamin D metabolic enzyme expression and associated decreases in expression of renal calcium transporters.
PMCID: PMC4537183  PMID: 20878391
Bone; Calcium; Kidney; Type 1 diabetes; Vitamin D
4.  Quantitative proteomic analysis of dexamethasone-induced effects on osteoblast differentiation, proliferation, and apoptosis in MC3T3-E1 cells using SILAC 
The impairment of osteoblast differentiation is one cause of the glucocorticoid-induced osteoporosis (GCOP). The quantitative proteomic analysis of the dexamethasone (DEX)-induced effects of osteoblast differentiation, proliferation, and apoptosis using stable-isotope labeling by amino acids in cell culture (SILAC) demonstrated drastic changes of some key proteins in MC3T3-E1 cells.
The impairment of osteoblast differentiation is one of the main explanations of GCOP. SILAC enables accurate quantitative proteomic analysis of protein changes in cells to explore the underlying mechanism of GCOP.
Osteoprogenitor MC3T3-E1 cells were treated with or without 10−6 M DEX for 7 days, and the differentiation ability, proliferation, and apoptosis of the cells were measured. The protein level changes were analyzed using SILAC and liquid chromatography-coupled tandem mass spectrometry.
In this study, 10−6 M DEX inhibited both osteoblast differentiation and proliferation but induced apoptosis in osteoprogenitor MC3T3-E1 cells on day 7. We found that 10−6 M DEX increased the levels of tubulins (TUBA1A, TUBB2B, and TUBB5), IQGAP1, S100 proteins (S100A11, S100A6, S100A4, and S100A10), myosin proteins (MYH9 and MYH11), and apoptosis and stress proteins, while inhibited the protein levels of ATP synthases (ATP5O, ATP5H, ATP5A1, and ATP5F1), G3BP-1, and Ras-related proteins (Rab-1A, Rab-2A, and Rab-7) in MC3T3-E1 cells.
Several members of the ATP synthases, myosin proteins, small GTPase superfamily, and S100 proteins may participate in functional inhibition of osteoblast progenitor cells by GCs. Such protein expression changes may be of pathological significance in coping with GCOP.
PMCID: PMC4507272  PMID: 21060993
Apoptosis; Dexamethasone; Osteoblast differentiation; Proliferation; Proteomics; SILAC
5.  TAp63 suppress metastasis via miR-133b in colon cancer cells 
Lin, C W | Li, X R | Zhang, Y | Hu, G | Guo, Y H | Zhou, J Y | Du, J | Lv, L | Gao, K | Zhang, Y | Deng, H
British Journal of Cancer  2014;110(9):2310-2320.
TAp63 is a tumour-suppressor protein that is often underexpressed in various types of cancer. It has been shown to activate gene transcription depending on the transcription domain and to be closely related with metastasis. In this study, we demonstrate that TAp63 suppresses metastasis in colon cancer cells through microRNA-133b.
We evaluated the correlation of TAp63 and miR-133b with HT-29 and SW-620 cells and investigated the roles of TAp63 in the expression of RhoA, E-cadherin and vimentin. We further investigated the roles of TAp63-mediated invasion and migration of colon cancer cells.
TAp63 expression is downregulated in colon cancer, and microRNA-133b is a transcriptional target of TAp63. Furthermore, microRNA-133b is essential for the inhibitory effects of TAp63 on RhoA, E-cadherin and vimentin. Moreover, TAp63 inhibits cell migration and invasion through microRNA-133b. Correspondingly, the inhibitory effect of TAp63 on RhoA, E-cadherin, vimentin, migration and invasion can be blocked by the microRNA-133b inhibitor.
TAp63 and microRNA-133b were able to suppress the metastasis of colon cancer. Both TAp63 and microRNA-133b may be potential biomarkers for diagnosis in colon cancer metastasis and may provide unique therapeutic targets for this common malignancy.
PMCID: PMC4007221  PMID: 24594999
TAp63; microRNA-133b; RhoA; colon cancer; metastasis
6.  Response to comment on ‘TAp63 suppress metastasis via miR-133b in colon cancer cells' 
Lin, C W | Li, X R | Zhang, Y | Hu, G | Guo, Y H | Zhou, J Y | Du, J | Lv, L | Gao, K | Zhang, Y | Deng, H
British Journal of Cancer  2014;111(12):2369-2370.
PMCID: PMC4264430  PMID: 25490679
7.  Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells 
Zhou, X | Chen, M | Zeng, X | Yang, J | Deng, H | Yi, L | Mi, M-t
Cell Death & Disease  2014;5(12):e1576-.
Mitochondrial reactive oxygen species (mtROS) homeostasis plays an essential role in preventing oxidative injury in endothelial cells, an initial step in atherogenesis. Resveratrol (RSV) possesses a variety of cardioprotective activities, however, little is known regarding the effects of RSV on mtROS homeostasis in endothelial cells. Sirt3 is a mitochondrial deacetylase, which plays a key role in mitochondrial bioenergetics and is closely associated with oxidative stress. The goal of the study is to investigate whether RSV could attenuate oxidative injury in endothelial cells via mtROS homeostasis regulation through Sirt3 signaling pathway. We found that pretreatment with RSV suppressed tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human umbilical vein endothelial cells (HUVECs) by increasing cell viability, inhibiting cell apoptosis, repressing collapse of mitochondrial membrane potential and decreasing mtROS generation. Moreover, the enzymatic activities of isocitrate dehydrogenase 2 (IDH2), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (SOD2) as well as deacetylation of SOD2 were increased by RSV pretreatment, suggesting RSV notably enhanced mtROS scavenging in t-BHP-induced endothelial cells. Meanwhile, RSV remarkably reduced mtROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of forkhead box O3A (FoxO3A)-mediated mitochondria-encoded gene expression of ATP6, CO1, Cytb, ND2 and ND5, thereby leading to increased complex I activity and ATP synthesis. Furthermore, RSV activated the expressions of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and Sirt3, as well as estrogen-related receptor-α (ERRα)-dependent Sirt3 mRNA transcription, which were abolished in the presence of AMPK inhibitor and AMPK, PGC-1α or Sirt3 siRNA transfection, indicating the effects of RSV on mtROS homeostasis regulation were dependent on AMPK-PGC-1α-ERRα-Sirt3 signaling pathway. Our findings indicated a novel mechanism that RSV-attenuated oxidative injury in endothelial cells through the regulation of mtROS homeostasis, which, in part, was mediated through the activation of the Sirt3 signaling pathway.
PMCID: PMC4454164  PMID: 25522270
8.  A family-based association study identified CYP17 as a candidate gene for obesity susceptibility in Caucasians 
The cytochrome P450c17α gene (CYP17) encodes a key biosynthesis enzyme of estrogen, which is critical in regulating adipogenesis and adipocyte development in humans. We therefore hypothesized that CYP17 is a candidate gene for predicting obesity. In order to test this hypothesis, we performed a family-based association test to investigate the relationship between the CYP17 gene and obesity phenotypes in a large sample comprising 1873 subjects from 405 Caucasian nuclear families of European origin recruited by the Osteoporosis Research Center of Creighton University, USA. Both single SNPs and haplotypes were tested for associations with obesity-related phenotypes, including body mass index (BMI) and fat mass. We identifiedthree SNPs to be significantly associated with BMI, including rs3740397, rs6163, and rs619824. We further characterized the linkage disequilibrium structure for CYP17 and found that the whole CYP17 gene was located in a single-linkage disequilibrium block. This block was observed to be significantly associated with BMI. A major haplotype in this block was significantly associated with both BMI and fat mass. In conclusion, we suggest that the CYP17 gene has an effect on obesity in the Caucasian population. Further independent studies will be needed to confirm our findings.
PMCID: PMC4181562  PMID: 22653668
CYP17; Body mass index; Obesity; Association study
9.  Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations 
Given the biological function of SOX6 and recent genome-wide association finding, we performed a fine-mapping association analyses to investigate the relationship between SOX6 and BMD both in Caucasian and Chinese populations. We identified many single-nucleotide polymorphisms (SNPs) within or near the SOX6 gene to be significantly associated with hip bone mineral density (BMD).
SOX6 gene is an essential transcription factor in chondrogenesis and cartilage formation. Recent genome-wide association studies (GWAS) detected a SNP (rs7117858) located at the downstream of SOX6 significantly associated with hip BMD.
Given the biological function of SOX6 and the GWAS finding, we considered SOX6 as a new candidate for BMD and osteoporosis. Therefore, in this study, we performed a fine-mapping association analyses to investigate the relationship between SNPs within and near the SOX6 gene and BMD at both hip and spine. A total of 301 SNPs were tested in two independent US Caucasian populations (2,286 and 1,000 unrelated subjects, respectively) and a Chinese population (1,627 unrelated Han subjects).
We confirmed that the previously reported rs7117858-A was associated with reduced hip BMD, with combined P value of 2.45×10−4. Besides this SNP, we identified another 19 SNPs within or near the SOX6 gene to be significantly associated with hip BMD after false discovery rate adjustment. The most significant SNP was rs1347677 located at the intron 3 (P=3.15×10−7). Seven additional SNPs in high linkage disequilibrium with rs1347677 were also significantly associated with hip BMD. SNPs in SOX6 showed significant skeletal site specificity since no SNP was detected to be associated with spine BMD.
Our study identified many SNPs in the SOX6 gene associated with hip BMD even across different ethnicities, which further highlighted the importance of the SOX6 gene influencing BMD variation and provided more information to the understanding of the genetic architecture of osteoporosis.
PMCID: PMC4171834  PMID: 21625884
Association; BMD; Osteoporosis; SOX6
10.  The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression 
Lv, L | Deng, H | Li, Y | Zhang, C | Liu, X | Liu, Q | Zhang, D | Wang, L | Pu, Y | Zhang, H | He, Y | Wang, Y | Yu, Y | Yu, T | Zhu, J
Cell Death & Disease  2014;5(9):e1402-.
Chemoresistance hinders the curative cancer chemotherapy. To define the role of the DNA methylation-regulated microRNA (miR) genes in the chemoresistance of bladder cancer, we performed both DNA methylomic and miRomic analyses of a multi-chemosensitive (5637) versus a multi-chemoresistant (H-bc) cell line and found that miR-193a-3p is hypermethylated/silenced in 5637 and hypomethylated/expressed in H-bc cells. A forced reversal of its level turned around the chemoresistance in the cultured cells and the tumor xenografts in nude mice. Three of its targets: SRSF2, PLAU and HIC2, work in concert to relay the miR-193a-3p's impact on the bladder cancer chemoresistance by modulating the activities of the following five signaling pathways: DNA damage, Notch, NF-κB, Myc/Max, and Oxidative Stress. In addition to the mechanistic insights in how the newly identified miR-193a-3p/SRSF2,PLAU,HIC2/five signaling pathway axis regulates the chemoresistance of bladder cancer cells, our study provides a new set of diagnostic targets for the guided personalized chemotherapy of bladder cancer.
PMCID: PMC4540198  PMID: 25188512
11.  A stress-induced cellular aging model with postnatal neural stem cells 
Cell Death & Disease  2014;5(3):e1116-.
Aging refers to the physical and functional decline of the tissues over time that often leads to age-related degenerative diseases. Accumulating evidence implicates that the senescence of neural stem cells (NSCs) is of paramount importance to the aging of central neural system (CNS). However, exploration of the underlying molecular mechanisms has been hindered by the lack of proper aging models to allow the mechanistic examination within a reasonable time window. In the present study, we have utilized a hydroxyurea (HU) treatment protocol and effectively induced postnatal subventricle NSCs to undergo cellular senescence as determined by augmented senescence-associated-β-galactosidase (SA-β-gal) staining, decreased proliferation and differentiation capacity, increased G0/G1 cell cycle arrest, elevated reactive oxygen species (ROS) level and diminished apoptosis. These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70. Further proteomic analysis suggests that multiple pathways are involved in the HU-induced NSC senescence, including genes related to DNA damage and repair, mitochondrial dysfunction and the increase of ROS level. Intriguingly, compensatory mechanisms may have also been initiated to interfere with apoptotic signaling pathways and to minimize the cell death by downregulating Bcl2-associated X protein (BAX) expression. Taken together, we have successfully established a cellular model that will be of broad utilities to the molecular exploration of NSC senescence and aging.
PMCID: PMC3973228  PMID: 24625975
aging; neural stem cells; cellular senescence model; stress; DNA damage
12.  Single-cell clones of liver cancer stem cells have the potential of differentiating into different types of tumor cells 
Liu, H | Zhang, W | Jia, Y | Yu, Q | Grau, G E | Peng, L | Ran, Y | Yang, Z | Deng, H | Lou, J
Cell Death & Disease  2013;4(10):e857-.
Cancer stem cells (CSCs) are believed to be a promising target for cancer therapy because these cells are responsible for tumor development, maintenance and chemotherapy resistance. Finding out the critical factors regulating CSC fate is the key for target therapy of CSCs. Just as normal stem cells are regulated by their microenvironment (niche), CSCs are also regulated by cells in the tumor microenvironment. However, whether various tumor microenvironments can induce CSCs to differentiate into different cancer cells is not clear. Here, we show that single-cell-cloned CSCs, accidentally obtained from a human liver cancer microvascular endothelial cells, express classic stem cell markers, genes associated with self-renewal and pluripotent factors and possess colony-forming ability in vitro and the ability of serial transplantation in vivo. The single-cell-cloned CSCs treated with the different tumor cell/tissue-derived conditioned culture medium, which is a mimic of carcinoma microenvironment, could differentiate into corresponding tumor cells and express specific markers of the respective type of tumor cells at the gene, protein and cell levels, respectively. Interestingly, this multilineage differentiation potential of single-cell-cloned liver CSCs sharply declined after the specific knockdown of octamer-binding transcription factor 4 (Oct4) alone, even though they were under the same induction conditions (carcinoma microenvironments). These data support the hypothesis that single-cell-cloned liver CSCs have the potential of differentiating into different types of tumor cells, and the tumor microenvironment does play a crucial role in deciding differentiation directions. Simultaneously, Oct4 in CSCs is indispensable in this process. These factors are promising targets for liver CSC-specific therapy.
PMCID: PMC3824650  PMID: 24136221
CSCs; carcinoma/cancer microenvironments; multilineage differentiation potential; Oct4; microvascular endothelial cells
13.  Haplotype-dependent HLA susceptibility to nasopharyngeal carcinoma in a Southern Chinese population 
Genes and immunity  2010;11(4):334-342.
We have conducted a comprehensive case–control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A*0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A*0206, HLA-B*3802 alleles plus the A*0207–B*4601 and A*3303–B*5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 (P<0.0001). HLA alleles that associate with low risk for NPC include HLA-A*1101, B*27, and B*55 with a combined OR of 0.42 (P<0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.
PMCID: PMC3737777  PMID: 20072141
HLA; nasopharyngeal carcinoma; haplotype; stratified analysis
14.  Are bone mineral density loci associated with hip osteoporotic fractures? A validation study on previously reported genome-wide association loci in a Chinese population 
Osteoporosis is a heritable disease characterized mainly by low bone mineral density (BMD) and/or osteoporotic fractures (OF). Most genome-wide association studies on osteoporosis have focused on BMD, whereas little effort has been expended to identify genetic variants directly linked to OF. To determine whether BMD-loci are also associated with OF risk, we performed a validation study to examine 23 BMD-loci reported by recent genome-wide association studies for association with hip OF risk. Our sample consisted of 700 elderly Chinese Han subjects, 350 with hip OF and 350 healthy matched controls. We identified four BMD-loci that were significantly associated with hip OF in this Chinese population, including 7q21 (FLJ42280, P = 1.17 × 10−4 for rs4729260; P = 0.008 for rs7781370), 6p21 (MHC, P = 0.004 for rs3130340), 13q14 (TNFSF11, P = 0.012 for rs9533090; P = 0.018 for rs9594759; P = 0.020 for rs9594738; P = 0.044 for rs9594751), and 18q21 (TNFRSF11A, P = 0.015 for rs884205). The SNP rs4729260 at 7q21 remained significantly associated, even after conservative Bonferroni’s correction. Our results further highlight the importance of these loci in the pathogenesis of osteoporosis, and demonstrate that it is feasible and useful to use OF as the direct phenotype to conduct genetic studies, to enhance our understanding of the genetic architecture of osteoporosis.
PMCID: PMC3682464  PMID: 22370887
Osteoporotic fractures; Genome-wide association studies; BMD; SNP
15.  A follow-up association study of two genetic variants for bone mineral density variation in Caucasians 
We tested whether two genetic variants were associated with BMD at multiple clinically relevant skeletal sites in Caucasians. We found that variant rs7776725 is consistently associated with hip, spine, wrist and whole-body BMD, which highlights the potential importance of this variant or linked variants for osteoporosis.
A recent genome-wide association study identified two single nucleotide polymorphisms (SNPs), rs7776725 and rs1721400, that were associated with bone mineral density (BMD) variation at the radius, tibia and calcaneus in a Korean population. In this study, we aimed to test whether the association of these two genetic variants can be replicated in Caucasians and whether their association with BMD can be extended to other clinically relevant skeletal sites.
We performed this study in two large cohorts of unrelated US Caucasians. Area BMD at the hip, spine, wrist (ultra-distal radius) and whole body were measured with Hologic dual-energy X-ray absorptiometer. SNPs were genotyped with Affymetrix human genome-wide genotyping arrays. Association analyses were performed using PLINK.
We detected highly significant association (combined p=1.42×10−16) of rs7776725 with wrist BMD but only borderline association signal (combined p=0.017) for rs1721400 with wrist BMD. In addition, we found that rs7776725 was associated with BMD at the hip, spine and whole body. At the FAM3C gene locus where rs7776725 was located, we identified several other SNPs (rs4727922, rs1803389, rs718766 and rs7793554) that were also associated with BMD.
This is the first follow-up association study of rs7776725 and rs1721400 with BMD. The rs7776725 showed consistent association with BMD at multiple clinically important skeletal sites, which highlighted the potential importance of rs7776725 or linked SNPs for risk of osteoporosis. Further in-depth re-sequencing studies and functional assays are necessary to elucidate the underlying mechanisms.
PMCID: PMC3682467  PMID: 22159821
Bone mineral density; FAM3C; Osteoporosis; Single nucleotide polymorphisms
16.  Association analyses suggest the effects of RANK and RANKL on age at menarche in Chinese women 
Age at menarche (AAM), the time of the first menstrual bleeding, is an important developmental milestone in the female life. It marks the beginning of the reproductive period. AAM is implicated in the risk of many health complications in later life. In this study, we conducted an analysis for association of single nucleotide polymorphisms (SNPs) and common haplotypes of two candidate genes, RANK (receptor activator of the NF-κB) and RANKL (receptor activator of the NF-κB ligand), with AAM in 825 unrelated Chinese women.
In total, 73 SNPs of RANKL and 23 SNPs of RANK were genotyped. The SNPs and common haplotypes were then analyzed for their association with AAM. Age and age2 were used as covariates.
We found five individual SNPs (rs7239261, rs8094884, rs3826620, rs8089829, and rs9956850) of RANK significantly associated with AAM (p < 0.05). Although no significant association was identified for the RANKL gene, three polymorphisms showed nearly significant (0.05 < p < 0.08) association with AAM. Seven haplotypes of RANK were significantly associated with AAM (p < 0.05); the most significant association of the AT haplotype composed by rs1805034 and rs4524034 (p = 9.4 × 10−4) remained significant (p = 0.0235) after the Bonferroni correction for multiple testing. Three haplotypes of RANKL were significantly associated with AAM (p < 0.05). Importantly, the association of rs3826620 replicated our previous findings for Caucasian females.
The results of the present study suggest that the RANK and RANKL are two candidate genes for AAM in Chinese women.
PMCID: PMC3682470  PMID: 22023082
17.  Ethnic differentiation of copy number variation on chromosome 16p12.3 for association with obesity phenotypes in European and Chinese populations 
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 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.
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).
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.
PMCID: PMC3682477  PMID: 22391884
CNV; 16p12.3; BMI; body fat mass; association
18.  TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies 
Neurology  2011;76(10):887-894.
To improve understanding of TRPV4-associated axonal Charcot-Marie-Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism.
A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca2+ channel analysis, and cell viability assay with or without channel blockade.
Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca2+ levels and reversible cell death by the TRPV channel antagonist, ruthenium red.
TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis. Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important. The reversibility of cell death by channel blockade provides an attractive area of investigation in consideration of treatable axonal degeneration.
PMCID: PMC3059145  PMID: 21288981
19.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
20.  Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia(e–Pub ahead of print) 
Neurology  2010;75(9):807-814.
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE).
All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561–726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations.
We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations.
FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and ∼4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.
= amyotrophic lateral sclerosis;
= familial amyotrophic lateral sclerosis;
= familial amyotrophic lateral sclerosis with features of frontotemporal dementia;
= familial amyotrophic lateral sclerosis with features of parkinsonism and dementia;
= sporadic amyotrophic lateral sclerosis.
PMCID: PMC2938970  PMID: 20668259
21.  The differences of femoral neck geometric parameters: effects of age, gender and race 
This study aims at investigating the effects of age, sex, and ethnicity on five femoral neck geometric parameters (FNGPs): femoral neck periosteal diameter, cross-sectional area, cortical thickness, sectional modulus, and buckling ratio and found that the three factors would influence the FNGPs.
Bone geometry is one of the most important predictors of bone strength and osteoporotic fractures. This study aims at investigating the effects of age, sex, and ethnicity on five femoral neck geometric parameters (FNGPs): femoral neck periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), sectional modulus (Z), and buckling ratio (BR).
In the studied 861 Caucasian subjects and 3,021 Chinese individuals, CSA, CT, and Z displayed trends of decrease with age, but W and BR showed increasing trends with age in both Chinese and Caucasian females and males (p < 0.05). W, CSA, CT, and Z were significantly higher (p ≤ 0.001) in Caucasians than in Chinese and higher in males than in females except for BR between Chinese males and Chinese females.
In conclusion, the differences of FNGPs according to gender and ethnicity provide important implications in the different prevalence of osteoporotic fracture among different gender and ethnic groups.
PMCID: PMC2921984  PMID: 19802512
Age; Femoral neck geometric parameters; Race; Sex
22.  Replication study of candidate genes/loci associated with osteoporosis based on genome-wide screening 
Osteoporosis is a major public health problem characterized by low bone mineral density (BMD). This replication study confirmed 38 single-nucleotide polymorphisms (SNPs) out of 139 SNPs previously reported in three recent genome-wide association studies (GWASs) in an independent US white sample. Ten SNPs achieved combined p<3.6×10−4.
BMD is under strong genetic control. This study aims to verify the potential associations between BMD and candidate genes/loci reported by GWAS of FHS100K, Icelandic deCODE, and UK-NL.
Eight promising (at the genome-wide significant level after Bonferroni correction) and 131 available sub-promising (at the most stringent p value, p<5.5×10−5 in the three GWASs reports) SNPs were selected. By using genotypic information from Affymetrix 500 K SNP arrays, we tested their associations with BMD in 1,000 unrelated US whites. Fisher’s combined probability method was used to quantify the overall evidence of association. BMD was measured by dual energy X-ray absorptiometry.
Two promising SNPs, rs3762397 and rs3736228, were replicated in the current study with p<0.05. Besides, 36 sub-promising SNPs were replicated at the same significant level. Ten SNPs achieved significant combined p<3.6×10−4 (0.05/139 SNPs, corrected for multiple testing).
Osteoporosis susceptibility of 38 SNPs was replicated in 1,000 unrelated US whites. This study showed promise for replication of some initial genome-wide association signals.
PMCID: PMC2917903  PMID: 19629617
Bone mineral density; Genome-wide association; Osteoporosis; Replication
23.  Association analyses of vitamin D-binding protein gene with compression strength index variation in Caucasian nuclear families 
This study was conducted to test whether there exists an association between vitamin D-binding protein (DBP) gene and compression strength index (CSI) phenotype. Candidate gene association analyses were conducted in total sample, male subgroup, and female subgroup, respectively. Two single-nucleotide polymorphisms (SNPs) with significant association results were found in males, suggesting the importance of DBP gene polymorphisms on the variation in CSI especially in Caucasian males.
CSI of the femoral neck (FN) is a newly developed phenotype integrating information about bone size, body size, and bone mineral density. It is considered to have the potential to improve the performance of risk assessment for hip fractures because it is based on a combination of phenotypic traits influencing hip fractures rather than a single trait. CSI is under moderate genetic determination (with a heritability of ~44% found in this study), but the relevant genetic study is still rather scarce.
Based on the known physiological role of DBP in bone biology and the relatively high heritability of CSI, we tested 12 SNPs of the DBP gene for association with CSI variation in 405 Caucasian nuclear families comprising 1,873 subjects from the Midwestern US. Association analyses were performed in the total sample, male and female subgroups, respectively.
Significant associations with CSI were found with two SNPs (rs222029, P=0.0019; rs222020, P=0.0042) for the male subgroup. Haplotype-based association tests corroborated the single-SNP results.
Our findings suggest that the DBP gene might be one of the genetic factors influencing CSI phenotype in Caucasians, especially in males.
PMCID: PMC2914268  PMID: 19543766
Association; Compression strength index; DBP; Haplotype; SNP
24.  Age and founder effect of SOD1 A4V mutation causing ALS 
Neurology  2009;72(19):1634-1639.
The alanine to valine mutation at codon 4 (A4V) of SOD1 causes a rapidly progressive dominant form of amyotrophic lateral sclerosis (ALS) with exclusively lower motor neuron disease and is responsible for 50% of SOD1 mutations associated with familial ALS in North America. This mutation is rare in Europe. The authors investigated the origin (geographic and time) of the A4V mutation.
Several cohorts were genotyped: North American patients with confirmed A4V mutation (n = 54), Swedish (n = 3) and Italian (n = 6) A4V patients, patients with ALS with SOD1 non-A4V mutations (n = 66) and patients with sporadic ALS (n = 96), healthy white (n = 96), African American (n = 17), Chinese (n = 53), Amerindian (n = 11), and Hispanic (n = 12) subjects. High-throughput SNP genotyping was performed using Taqman assay in 384-well format. A novel biallelic CA repeat in exon 5 of SOD1, tightly linked to A4V, was genotyped on sequencing gels. Association statistics were estimated using Haploview. p Values less than 0.05 were considered significant. Age of A4V was estimated using a novel method based on r2 degeneration with genetic distance and a Bayesian method incorporated in DMLE+.
A single haplotype of 10 polymorphisms across a 5.86-cM region was associated with A4V (p = 3.0e-11) when white controls were used, suggesting a founder effect. The strength of association of this haplotype progressively decreased when African American, Chinese, Hispanic, and Amerindian subjects were used as controls. The associated European haplotype was different from the North American haplotype, indicating two founder effects for A4V (Amerindian and European). The estimated age of A4V with the r2 degeneration method was 458 ± 59 years (range 398–569) and in agreement with the Bayesian method (554–734 years with 80–90% posterior probability).
North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400–500 years ago.
= alanine to valine mutation at codon 4;
= amyotrophic lateral sclerosis;
= familial ALS;
= linkage disequilibrium;
= sequence detection system;
= single nucleotide polymorphisms.
PMCID: PMC2683645  PMID: 19176896
25.  The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts 
Journal of Medical Genetics  2005;42(11):852-856.
Background: In both familial and sporadic atypical haemolytic-uraemic syndrome (aHUS), mutations have been reported in regulators of the alternative complement pathway including factor H (CFH), membrane cofactor protein (MCP), and the serine protease factor I (IF). A characteristic feature of both MCP and CFH associated HUS is reduced penetrance and variable inheritance; one possible explanation for this is that functional changes in complement proteins act as modifiers.
Objective: To examine single nucleotide polymorphisms in both CFH and MCP genes in two large cohorts of HUS patients (Newcastle and Paris).
Results: In both cohorts there was an association with HUS for both CFH and MCP alleles. CFH and MCP haplotypes were also significantly different in HUS patients compared with controls.
Conclusions: This study suggests that there are naturally occurring susceptibility factors in CFH and MCP for the development of atypical HUS.
PMCID: PMC1735946  PMID: 15784724

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