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Featured researches published by Wen-Zhen Fu.


American Journal of Human Genetics | 2012

Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy.

Zhen-Lin Zhang; Weibo Xia; Jin-Wei He; Zeng Zhang; Yao-Hua Ke; Hua Yue; Chun Wang; Hao Zhang; Jie-Mei Gu; Wei-Wei Hu; Wen-Zhen Fu; Yun-Qiu Hu; Miao Li; Yu-juan Liu

By using whole-exome sequencing, we identified a homozygous guanine-to-adenine transition at the invariant -1 position of the acceptor site of intron 1 (c.97-1G>A) in solute carrier organic anion transporter family member 2A1 (SLCO2A1), which encodes a prostaglandin transporter protein, as the causative mutation in a single individual with primary hypertrophic osteoarthropathy (PHO) from a consanguineous family. In two other affected individuals with PHO from two unrelated nonconsanguineous families, we identified two different compound heterozygous mutations by using Sanger sequencing. These findings confirm that SLCO2A1 mutations inactivate prostaglandin E(2) (PGE(2)) transport, and they indicate that mutations in SLCO2A1 are the pathogenic cause of PHO. Moreover, this study might also help to explain the cause of secondary hypertrophic osteoarthropathy.


PLOS ONE | 2012

High Prevalence of Vitamin D Insufficiency in China: Relationship with the Levels of Parathyroid Hormone and Markers of Bone Turnover

Han-Kui Lu; Zeng Zhang; Yao-Hua Ke; Jin-Wei He; Wen-Zhen Fu; Changqing Zhang; Zhen‑Lin Zhang

There is a lack of large-scale studies on vitamin D status and its relationship to parathyroid hormone (PTH) and bone turnover markers in adults living in Shanghai. The objectives were to determine the prevalence of vitamin D insufficiency in Shanghai and to investigate the relationship of 25(OH)D with parathyroid function and bone turnover markers. This cross-sectional study involved 649 men and 1939 women aged 20–89 years who were randomly sampled in Shanghai. Serum concentrations of 25(OH)D, PTH, albumin, and bone turnover markers were measured. During the winter season, the prevalence of vitamin D insufficiency (<30 ng/mL) was 84% in males and 89% in females. The prevalence of vitamin D deficiency (<20 ng/mL) was 30% in males and 46% in females. With increasing serum 25(OH)D concentrations categorized as <10, 10–20, 20–30, and ≥30 ng/mL, the mean PTH and bone turnover markers levels gradually decreasd in both sexes (p<0.001). There was an inverse relationship between the serum 25(OH)D and PTH concentrations in both genders, but no threshold of 25(OH)D at which PTH levels plateaued was observed. There were modest but significantly inverse relationships between the levels of 25(OH)D and bone turnover markers, but no plateau was observed for serum 25(OH)D levels up to 40 ng/mL.


BMC Medical Genetics | 2010

No association of the polymorphisms of the frizzled-related protein gene with peak bone mineral density in Chinese nuclear families

Gao Gao; Zhen-Lin Zhang; Jin-Wei He; Hao Zhang; Hua Yue; Wei-Wei Hu; Jie-Mei Gu; Wen-Zhen Fu; Yun-Qiu Hu; Miao Li; Yu-juan Liu; Jin-Bo Yu

BackgroundThe Wnt/beta-catenin signaling pathway plays an important role in skeletal development. Polymorphisms of frizzled-related protein (FRZB), an antagonist of this pathway, may generate variations in bone mineral density (BMD). In this study, we analyzed the association between FRZB genotypes and peak BMD variation in the spines and hips of two relatively large samples of Chinese female-offspring and male-offspring nuclear families.MethodsWe recruited 1,260 subjects from 401 female-offspring nuclear families and 1,296 subjects from 427 male-offspring nuclear families and genotyped four tagging single nucleotide polymorphisms (tagSNPs) (rs6433993, rs409238, rs288324, and rs4666865) spanning the entire FRZB gene. The SNPs rs288326 and rs7775, which are associated with hip osteoarthritis, were not selected in this study because of their low minor allele frequencies (MAFs) in Chinese people. The quantitative transmission disequilibrium test (QTDT) was used to analyze the association between each SNP and haplotype with peak BMD in female- and male-offspring nuclear families.ResultsIn the female-offspring nuclear families, we found no evidence of an association between either single SNPs or haplotypes and peak BMD in the spine or hip. In the male-offspring nuclear families, no within-family association was observed for either SNPs or haplotypes, although a significant total association was found between rs4666865 and spine BMD (P = 0.0299).ConclusionOur results suggest that natural variation in FRZB is not a major contributor to the observed variability in peak BMD in either Chinese females or males. Because ethnic differences in the FRZB genotypes may exist, other studies in different population are required to confirm such results.


Journal of Bone and Mineral Research | 2013

An analysis of the association between the vitamin D pathway and serum 25-hydroxyvitamin D levels in a healthy Chinese population.

Zeng Zhang; Jin-Wei He; Wen-Zhen Fu; Changqing Zhang; Zhen-Lin Zhang

Vitamin D deficiency has been recognized as a major public health issue worldwide. Recent studies have indicated that genetic factors might play an important role in determining serum 25‐hydroxyvitamin D [25(OH)D] levels in Caucasians and African Americans. However, the genes that contribute to the variation in serum 25(OH)D levels in Chinese are unknown. In this study, we screened 15 key genes within the vitamin D metabolic pathway using 96 single‐nucleotide polymorphism (SNP) markers in a group of 2897 unrelated healthy Chinese subjects. Significant confounding factors that may influence the variability in serum 25(OH)D levels were used as covariates for association analyses. An association test for quantitative traits was performed to evaluate the association between candidate genes and serum 25(OH)D levels. In the present study, variants and/or haplotypes in GC, CYP2R1, and DHCR7/NADSYN1 were identified as being associated with 25(OH)D levels. Participants with three or four risk alleles of the two variants (GC‐rs4588 and CYP2R1‐rs10766197) had an increased chance of presenting with a 25(OH)D concentration lower than 20 ng/mL (odds ratio 2.121, 95% confidence interval 1.586–2.836, p = 6.1 × 10−8) compared with those lacking the risk alleles. Each additional copy of a risk allele was significantly associated with a 0.12‐fold decrease in the log‐25(OH)D concentration (p = 3.7 × 10−12). Haplotype TGA of GC rs705117‐rs2282679‐rs1491710, haplotype GAGTAC of GC rs842999‐rs705120‐rs222040‐rs4588‐rs7041‐rs10488854, haplotype CA of GC rs1155563‐rs222029, and haplotype AAGA of CYP2R1 rs7936142‐rs12794714‐rs2060793‐rs16930609 were genetic risk factors toward a lower 25(OH)D concentration. In contrast, haplotype TGGGCCC of DHCR7/NADSYN1 rs1790349‐rs7122671‐rs1790329‐rs11606033‐rs2276360‐rs1629220‐rs2282618 were genetic protective factors. The results suggest that the GC, CYP2R1, and DHCR7/NADSYN1 genes might contribute to variability in the serum 25(OH)D levels in a healthy Chinese population in Shanghai. These markers could be used as tools in Mendelian randomization analyses of vitamin D, and they could potentially be drug targets in the Chinese population in Shanghai.


Acta Pharmacologica Sinica | 2009

Association between VDR and ESR1 gene polymorphisms with bone and obesity phenotypes in Chinese male nuclear families.

Jie-Mei Gu; Wen-jin Xiao; Jin-wei He; Hao Zhang; Wei-Wei Hu; Yun-Qiu Hu; Miao Li; Yu-juan Liu; Wen-Zhen Fu; Jin-Bo Yu; Gao Gao; Hua Yue; Yao-Hua Ke; Zhen-lin Zhang

AbstractAim:The goal of this study was to determine whether polymorphisms in the vitamin D receptor (VDR) and estrogen receptor alpha (ESR1) genes are associated with variations of peak bone mineral density (BMD) and obesity phenotypes in young Chinese men.Methods:A total of 1215 subjects from 400 Chinese nuclear families were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific multiple PCR (ASM-PCR) analysis at the ApaI, FokI, and CDX2 sites in the VDR gene and the PvuII and XbaI sites in the ESR1 gene. BMD at the lumbar spine and hip, total fat mass, and total lean mass were measured using dual energy X-ray absorptiometry. The associations between VDR and ESR1 gene polymorphisms with peak BMD, body mass index (BMI), total fat mass, total lean mass, and percentage fat mass (PFM) were determined using quantitative transmission disequilibrium tests (QTDTs).Results:Using QTDTs, no significant within-family associations were obtained between genotypes or haplotypes of the VDR and ESR1 genes and peak BMD. For the obesity phenotypes, the within-family associations were significant between CDX2 genotypes and BMI (P=0.046), fat mass (P=0.004), and PFM (P=0.020). Further, PvuII was significantly associated with the variation of fat mass and PFM (P=0.002 and P=0.039, respectively). A subsequent 1000 permutations were in agreement with these within-family association results.Conclusion:Our findings showed that VDR and ESR1 polymorphisms were associated with total fat mass in young Chinese men, but we failed to find a significant association between VDR and ESR1 genotypes and peak BMD. These findings suggested that the VDR and ESR1 genes are quantitative trait loci (QTL) underlying fat mass variation in young Chinese men.


Journal of Bone and Mineral Research | 2012

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

Chun Wang; Zeng Zhang; Hao Zhang; Jin-Wei He; Jie-Mei Gu; Wei-Wei Hu; Yun-Qiu Hu; Miao Li; Yu-juan Liu; Wen-Zhen Fu; Hua Yue; Yao-Hua Ke; Zhen-Lin Zhang

To identify the susceptibility genes for osteoporotic fracture in postmenopausal Chinese women, a two‐stage case‐control association study using joint analysis was conducted in 1046 patients with nontraumatic vertebra, hip, or distal radius fractures and 2303 healthy controls. First, 113 single‐nucleotide polymorphisms (SNPs) in 16 potential osteoporosis candidate genes reported in recent genomewide association studies, meta‐analyses studies, large‐scale association studies, and functional studies were genotyped in a small‐sample‐size subgroup consisting of 541 patients with osteoporotic fractures and 554 healthy controls. Variants and haplotypes in SPTBN1, TNFRSF11B, CNR2, LRP4, and ESR1 that have been identified as being associated with osteoporotic fractures were further reanalyzed in the entire case‐control group. We identified one SNP in TNFRSF11B (rs3102734), three SNPs in ESR1 (rs9397448, rs2234693, and rs1643821), two SNPs in LRP4 (rs17790156 and rs898604), and four SNPs in SPTBN1 (rs2971886, rs2941583, rs2941584, and rs12475342) were associated with all of the broadly defined osteoporotic fractures. The most significant polymorphism was rs3102734, with increased risk of osteoporotic fractures (odds ratio, 1.35; 95% confidence interval [CI], 1.17–1.55, Bonferroni p = 2.6 × 10−4). Furthermore, rs3102734, rs2941584, rs12475342, rs9397448, rs2234693, and rs898604 exhibited significant allelic, genotypic, and/or haplotypic associations with vertebral fractures. SNPs rs12475342, rs9397448, and rs2234693 showed significant genotypic associations with hip fractures, whereas rs3102734, rs2073617, rs1643821, rs12475342, and rs2971886 exhibited significant genotypic and/or haplotypic associations with distal radius fractures. Accordingly, we suggest that in addition to the clinical risk factors, the variants in TNFRSF11B, SPTBN1, ESR1, and LRP4 are susceptibility genetic loci for osteoporotic fracture in postmenopausal Chinese women.


The Journal of Clinical Endocrinology and Metabolism | 2013

Mutations in the SLCO2A1 Gene and Primary Hypertrophic Osteoarthropathy: A Clinical and Biochemical Characterization

Zeng Zhang; Jinwei He; Wen-Zhen Fu; Changqing Zhang; Zhenlin Zhang

CONTEXT We previously demonstrated that deficiency of the prostaglandin transporter (SLCO2A1) is a cause of primary hypertrophic osteoarthropathy (PHO). However, its clinical and metabolic characteristics have not been well defined. OBJECTIVE The objective of the study was to expand this mutational spectrum to better delineate the SLCO2A1 deficiency phenotype and investigate the clinical and metabolic characteristics of a cohort of subjects with PHO. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE Eleven affected individuals and their available healthy family members from 9 unrelated Chinese families with PHO (7 of which were previously undescribed) were clinically studied. The SLCO2A1 gene was screened and analyzed. Urinary levels of prostaglandin E₂ (PGE₂) and prostaglandin E metabolite (PGE-M) were measured using competitive ELISAs. The serum levels of total T, estradiol, sex hormone-binding protein, LH, FSH, and fasting gastrin were detected. RESULTS Nine different SLCO2A1 mutations were identified in affected individuals in the 7 previously undescribed families, 7 of which (Glu165X, Ala286GlnfsX35, Gln356AlafsX77, Gly369Asp, Gly379Glu, Glu465Lys, and c.861+2T>C) were novel. The urinary levels of PGE₂ and PGE-M were much higher in the SLCO2A1-deficient individuals and decreased with age. There was no relationship between sex hormones and PGE₂ or PGE-M. There was no significant difference in the levels of fasting serum gastrin between PHO patients with watery diarrhea and their relatives. CONCLUSIONS The present findings broaden the allelic spectrum of SLCO2A1 mutations. The urinary levels of PGE₂ and PGE-M in the SLCO2A1-deficient individuals decreased with age. The measurement of the excreted PGE₂ and PGE-M may have implications in the differential diagnosis, treatment, and follow-up of PHO.


Journal of Bone and Mineral Metabolism | 2009

Identification of the CLCN7 gene mutations in two Chinese families with autosomal dominant osteopetrosis (type II)

Zhen-lin Zhang; Jin-wei He; Hao Zhang; Wei-Wei Hu; Wen-Zhen Fu; Jie-Mei Gu; Jin-Bo Yu; Gao Gao; Yun-Qiu Hu; Miao Li; Yu-juan Liu

Here we report the identification of two different mutations in chloride channel 7 gene in two unrelated patients with autosomal dominant osteopetrosis type II. We determined that one patient (a 32-year-old woman) carried a heterozygous gene for a R767W mutation in exon 24, and another patient (a 17-year-old boy) carried a heterozygous gene for a novel frameshift mutation (Glu798FS) in exon 25. Recent studies have reported loss-of-function mutations in the chloride channel 7 (CLCN7) gene as a cause of autosomal dominant osteopetrosis type II (ADO-II). The identification of gene mutations in Chinese with ADO has not been reported previously. In this study, we identified mutations of the CLCN7 gene in two unrelated Chinese families with ADO-II. Two probands with ADO-II were diagnosed based on their bone characteristics on X-rays and their laboratory results. All 25 exons of the CLCN7 gene, including the exon–intron boundaries, were sequenced. We found in family 1 that the proband (a 32-year-old woman) was heterozygous for a CLCN7 mutation. The nonsynonymous mutation consisted of a heterozygous C/T transition at codon 2327 in exon 24, which resulted in an arginine (CGG)-to tryptophan (TGG) substitution at position 767 (R767W). The same heterozygous mutation (C/T) was determined in her father and son, who were asymptomatic with normal skeleton radiography. In family 2, we found that the proband (a 17-year-old boy) carried a novel frameshift mutation (Glu798FS) resulting from a G insertion between codon 60 and codon 61 in exon 25. The heterozygous –/G insertion is predicted to elongate the peptide of CLCN7 by 120 amino acids after position 797 amino acids. Similarly, some individuals of this family carried the same heterozygous mutation, but they are all asymptomatic. Furthermore, the R767W and Glu798FS mutations were not found in 100 unrelated controls. Our present findings suggest that the novel Glu798FS mutation in exon 25 and R767W in exon 24 in the CLCN7 gene were responsible for ADO-II in these Chinese patients.


Acta Pharmacologica Sinica | 2014

Serum osteocalcin levels are inversely associated with plasma glucose and body mass index in healthy Chinese women

Wei-Wei Hu; Yao-Hua Ke; Jin-wei He; Wen-Zhen Fu; Yu-juan Liu; Di Chen; Zhen-lin Zhang

Aim:Osteocalcin, a biochemical marker of bone formation, has been suggested to be involved in the regulation of energy metabolism. The aim of this study was to investigate the possible association between serum osteocalcin and markers of glucose and lipid metabolism in a large sample of healthy Chinese women.Methods:A total of 2032 healthy Chinese women in Shanghai, aged 20–94 (including 1396 discovery-study subjects and 636 postmenopausal women for a reduplication analysis) were recruited. Their serum osteocalcin, calcium and the relevant measurements were analyzed. A Spearman correlation analysis was performed between osteocalcin and the other markers of energy metabolism including triglyceride, total cholesterol, fasting plasma glucose (FPG), serum insulin, body mass index and homeostasis model assessment-insulin resistance. Separate multiple regression analyses were performed with data from the discovery and reduplication subjects to determine whether serum osteocalcin concentration was an independent predictor of the glucose or lipid metabolism markers.Results:For the discovery-study subjects, serum osteocalcin was found to be negatively associated with weight (r=−0.08, P=0.002), BMI (−0.13, P<0.001) and FPG (r=−0.13, P=0.001). Similar results were also found in the reduplication subjects (weight: r=−0.19, P=0.016; BMI: r=−0.23, P=0.003; FPG: r=−0.28, P<0.001). In the multiple regression analysis, serum osteocalcin was revealed as a potential independent predictor for FPG (β=−0.07 and –0.210 for discovery and reduplication, respectively, P<0.01) and BMI (β=−0.127 and –0.299 for discovery and reduplication, respectively, P<0.01).Conclusion:Serum osteocalcin is negatively associated with weight BMI and FPG in healthy Chinese women. Therefore, osteocalcin might contribute to obesity and diabetes.


Journal of Clinical Densitometry | 2012

Lean Mass Predicts Hip Geometry and Bone Mineral Density in Chinese Men and Women and Age Comparisons of Body Composition

Wei-Wei Hu; Hao Zhang; Chun Wang; Jie-Mei Gu; Hua Yue; Yao-Hua Ke; Yun-Qiu Hu; Wen-Zhen Fu; Miao Li; Zhen-Lin Zhang

Previous studies have suggested that changes in hip geometry increase the risk of hip fracture. The aim of this study was to identify whether body composition were associated with hip geometry or bone mineral density (BMD) in a large sample of Chinese people. A total of 2072 subjects aged 20-79 yr (including 700 males and 1372 females) were selected. The following measurements were taken: lumbar spine (L1-4); proximal femur BMD; lean mass (LM); fat mass (FM); and hip geometric parameters, including hip axis length (HAL), cross-sectional moment of inertia (CSMI), cross-sectional area (CSA), neck-shaft angle, and femur strength index (SI) by dual-energy X-ray absorptiometry. FM and LM were positively correlated with HAL, CSMI, and CSA, and negatively correlated with SI in both men and women. Multiple regression analysis showed that leg LM contributions to HAL, CSMI, and CSA variance were 12.6-37.6%. Compared with FM, LM was generally more strongly related to hip geometry and BMD in young and old men and women. Body composition was a good predictor for hip geometry parameter variation and BMD variation.

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Zhen-Lin Zhang

Shanghai Jiao Tong University

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Hao Zhang

Shanghai Jiao Tong University

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Jin-Wei He

Shanghai Jiao Tong University

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Jie-Mei Gu

Shanghai Jiao Tong University

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Wei-Wei Hu

Shanghai Jiao Tong University

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Chun Wang

Shanghai Jiao Tong University

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Hua Yue

Shanghai Jiao Tong University

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Yu-juan Liu

Shanghai Jiao Tong University

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Yun-Qiu Hu

Shanghai Jiao Tong University

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Yao-Hua Ke

Shanghai Jiao Tong University

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