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Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells.

ABSTRACT: A large number of SNPs significant for osteoporosis (OP) had been identified by genome-wide association studies. However, the underlying association mechanisms were largely unknown. From the perspective of protein phosphorylation, gene expression regulation, and bone cell activity, this study aims to illustrate association mechanisms for representative SNPs of interest. We utilized public databases and bioinformatics tool to identify OP-associated SNPs which potentially influence protein phosphorylation (phosSNPs). Associations with hip/spine BMD, as well as fracture risk, in human populations for one significant phosSNP, that is, rs227584 (major/minor allele: C/A, EAS population) located in C17orf53 gene, were suggested in prior meta-analyses. Specifically, carriers of allele C had significant higher BMD and lower risk of low-trauma fractures than carriers of A. We pursued to test the molecular and cellular functions of rs227584 in bone through osteoblastic cell culture and multiple assays. We identified five phosSNPs significant for OP (P < 0.01). The osteoblastic cells, which was transfected with wild-type C17orf53 (allele C at rs227584, P126), demonstrated specific interaction with NEK2 kinase, increased expression levels of osteoblastic genes significantly (OPN, OCN, COL1A1, P < 0.05), and promoted osteoblast growth and ALP activity, in contrast to those transfected with mutant C17orf53 (allele A at rs227584, T126). In the light of the consistent evidences between the present functional study in human bone cells and the prior association studies in human populations, we conclude that the SNP rs227584, via altering protein-kinase interaction, regulates osteoblastic gene expression, influences osteoblast growth and activity, hence to affect BMD and fracture risk in humans.

SUBMITTER: Zhou X

PROVIDER: S-EPMC6349212 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells.

Zhou Xu X Qiu Ying-Hua YH He Pei P Jiang Fei F Wu Long-Fei LF Lu Xin X Lei Shu-Feng SF Deng Fei-Yan FY

Journal of cellular and molecular medicine 20181028 2

A large number of SNPs significant for osteoporosis (OP) had been identified by genome-wide association studies. However, the underlying association mechanisms were largely unknown. From the perspective of protein phosphorylation, gene expression regulation, and bone cell activity, this study aims to illustrate association mechanisms for representative SNPs of interest. We utilized public databases and bioinformatics tool to identify OP-associated SNPs which potentially influence protein phospho ...[more]

PMID: 30370607

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Project description:Serum proteomics analysis may lead to the discovery of novel osteoporosis biomarkers. The Osteoporotic Fractures in Men (MrOS) study comprises men ?65 years old in the US who have had repeated BMD measures and have been followed for incident fracture. High-throughput quantitative proteomic analysis was performed on baseline fasting serum samples from non-Hispanic white men using a multidimensional approach coupling liquid chromatography, ion-mobility separation, and mass spectrometry (LC-IMS-MS). We followed the participants for a mean of 4.6 years for changes in femoral neck bone mineral density (BMD) and for incident hip fracture. Change in BMD was determined from mixed effects regression models taking age and weight into account. Participants were categorized into three groups: BMD maintenance (no decline; estimated change ?0?g/cm2 , n?=?453); expected loss (estimated change 0 to 1 SD below the estimated mean change, -0.034?g/cm2 for femoral neck, n?=?1184); and accelerated loss (estimated change ?1 SD below mean change, n?=?237). Differential abundance values of 3946 peptides were summarized by meta-analysis to determine differential abundance of each of 339 corresponding proteins for accelerated BMD loss versus maintenance. Using this meta-analytic standardized fold change at cutoffs of ?1.1 or ?0.9 (p?<?0.10), 20 proteins were associated with accelerated BMD loss. Associations of those 20 proteins with incident hip fracture were tested using Cox proportional hazards models with age and BMI adjustment in 2473 men. Five proteins were associated with incident hip fracture (HR between 1.29 and 1.41 per SD increase in estimated protein abundance). Some proteins have been previously associated with fracture risk (eg, CD14 and SHBG), whereas others have roles in cellular senescence and aging (B2MG and TIMP1) and complement activation and innate immunity (CO7, CO9, CFAD). These findings may inform development of biomarkers for future research in bone biology and fracture prediction. © 2017 American Society for Bone and Mineral Research.

Project description:Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n?=?15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n?=?21,701) and clinical vertebral fracture (n?=?5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]?=?3%) was associated with higher vBMD (??=?0.22, p?=?1.9?×?10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR]?=?0.75; false discovery rate [FDR] p?=?0.01). In 1p36.12, rs12742784 (MAF?=?21%) was associated with higher vBMD (??=?0.09, p?=?1.2?×?10-10 ) and decreased risk of clinical vertebral fracture (OR?=?0.82; FDR p?=?7.4?×?10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (??=?0.28, FDR p?=?0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (??=?0.12, FDR p?=?1.7?×?10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

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Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells.

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Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells.

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