Gene Expression Analysis Suggests Bone Development-Related Genes GDF5 and DIO2 Are Involved in the Development of Kashin-Beck Disease in Children Rather than Adults

Wen, Yan; Zhang, Na; Li, Chunyan; He, Shulan; Tan, Wenfeng; Lei, Yanxia; Qiang, Zhang; Sun, Yu; Zheng, Jingjing; Guo, Xiong

doi:10.1371/journal.pone.0103618

Cited by 13 publications

(15 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…None of the genes nearest to the novel signals identified by this study have been previously linked to bone biology, and available eQTL data do not implicate any obvious candidate genes that may be therapeutic targets for osteoporosis and bone strength. When we expanded our search for bone‐related functions to genes residing in the TADs surrounding the signal SNPs, where SNP‐promoter interactions are more likely to occur, we found four potentially interesting target genes: GPX2 (“glutathione peroxidase 2”), a member of the glutathione peroxidase family that was found upregulated in adults affected with Kashin‐Beck disease (KBD), an endemic, chronic osteochondropathy with unknown etiology diffused in China, near the SPTB locus (associated with radius BMD in females); ATG14 (“autophagy related 14”), whose decreased expression promoted cisplatin‐induced apoptosis in a drug‐resistant osteosarcoma cell line in vitro; KTN1 (“kinectin 1”), responsible for various functions related to tumorigenesis and found upregulated in giant cells tumors of bone (GCTB), benign bone tumors that cause osteolytic destruction; and LGALS3 (“lectin, galactoside binding soluble 3”), a downstream regulator of matrix metalloproteinase‐9 functioning during endochondral bone formation; these three genes all reside near the TBPL2 locus (associated with femoral neck BMD).…”

Section: Discussionmentioning

confidence: 99%

A Genomewide Association Study Identifies Two Sex‐Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites

Chesi

Mitchell

Kalkwarf

et al. 2017

J of Bone & Mineral Res

View full text Add to dashboard Cite

Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genome-wide association study of areal bone mineral density (BMD) measured by dual energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip and femoral neck in a cohort of 933 healthy European American children. We took forward signals with P<5x10−5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, eQTL effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children.

show abstract

Section: Discussionmentioning

confidence: 99%

A Genomewide Association Study Identifies Two Sex‐Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites

Chesi

Mitchell

Kalkwarf

et al. 2017

J of Bone & Mineral Res

View full text Add to dashboard Cite

show abstract

“…Wang et al . and Wen et al . studied the expression levels of 367 genes in children and adults using a customized oligonucleotide microarray and subsequently confirmed their results with a quantitative reverse transcriptase‐polymerase chain reaction.…”

Section: Discussionmentioning

confidence: 84%

Association between DIO2 polymorphism and the risk of Kashin–Beck disease in the Tibetan population

Jin

Wang

et al. 2019

The Journal of Gene Medicine

View full text Add to dashboard Cite

Background: Kashin-Beck disease (KBD) is a local, multiple and deformable osteoarthropathy, mostly occurring in Tibet. Type 2 iodothyronine deiodinase (DIO2) is implicated in the activation of thyroid hormones to which the bones are very sensitive. Therefore, it is necessary to explore the association between KBD and DIO2 in the Tibetan population. Methods:We carried out a case-control study among 316 cases and 320 controls from a Tibetan population. Seven single nucleotide polymorphisms in DIO2 were selected and genotyped using the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. HaploReg (https://pubs.broadinstitute.org/ mammals/haploreg/haploreg.php) and GTEx (http://www.gtexportal.org) databases were applied for functional assessment of the polymorphisms. Results:The "A/C" genotype of rs1352815 (OR = 3.18, 95% CI = 1.14-8.85, p = 0.027) and the "A/G" genotype of rs1388382 (OR = 3.80, 95% CI = 1.30-11.11, p = 0.015) were associated with the susceptibility of KBD under the codominant model. With gender stratification analysis, rs1388382 showed obvious evidence for correlation with an elevated risk of KBD in females under the codominant model (OR = 3.32, 95% CI = 1.06-10.41, p = 0.039). Conclusions:The results obtained in the present study indicate that DIO2 polymorphisms rs1352815 and rs1388382 were correlated with KBD susceptibility among Tibetans, which also sheds new light on the role of DIO2 in the development of KBD. KEYWORDScase-control study, DIO2, Kashin-Beck disease, single nucleotide polymorphisms, Tibetan

show abstract

“…Furthermore, our group performed another microarray experiment in PBMCs of juvenile KBD using the 20 signature genes. It was demonstrated that these 20 genes are also differentially expressed in PBMCs of children with KBD [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Signature in Endemic Osteoarthritis by Microarray Analysis

Wang¹,

Ning

Zhang

et al. 2015

IJMS

Self Cite

View full text Add to dashboard Cite

Kashin-Beck Disease (KBD) is an endemic osteochondropathy with an unknown pathogenesis. Diagnosis of KBD is effective only in advanced cases, which eliminates the possibility of early treatment and leads to an inevitable exacerbation of symptoms. Therefore, we aim to identify an accurate blood-based gene signature for the detection of KBD. Previously published gene expression profile data on cartilage and peripheral blood mononuclear cells (PBMCs) from adults with KBD were compared to select potential target genes. Microarray analysis was conducted to evaluate the expression of the target genes in a cohort of 100 KBD patients and 100 healthy controls. A gene expression signature was identified using a training set, which was subsequently validated using an independent test set with a minimum redundancy maximum relevance (mRMR) algorithm and support vector machine (SVM) algorithm. Fifty unique genes were differentially expressed between KBD patients and healthy controls. A 20-gene signature was identified that distinguished between KBD patients and controls with 90% accuracy, 85% sensitivity, and 95% specificity. This study identified a 20-gene signature that accurately distinguishes between patients with KBD and controls using peripheral blood samples. These results promote the further development of blood-based genetic biomarkers for detection of KBD.

show abstract

Gene Expression Analysis Suggests Bone Development-Related Genes GDF5 and DIO2 Are Involved in the Development of Kashin-Beck Disease in Children Rather than Adults

Cited by 13 publications

References 17 publications

A Genomewide Association Study Identifies Two Sex‐Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites

A Genomewide Association Study Identifies Two Sex‐Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites

Association between DIO2 polymorphism and the risk of Kashin–Beck disease in the Tibetan population

Gene Expression Signature in Endemic Osteoarthritis by Microarray Analysis

Contact Info

Product

Resources

About