Identification of <em>PIEZO1</em> polymorphisms for human bone mineral density

Bai, Wei-Yang; Wang, Lijun; Ying, Zhi-Min; Hu, Bin; Xu, Lin; Zhang, Guo-Qing; Cong, Pei-Kuan; Zhu, Xiaofeng; Zou, Weiguo; Zheng, Hou-Feng

Affiliations

¹Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, China

²Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, China

³State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China

⁴Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China

⁵Department of Orthopedics, The Affiliated Yantai Hospital of Binzhou Medical University, Yantai 264000, China

⁶Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA

Abstract and keywords

Bone mineral density (BMD) is a key indicator for diagnosis and treatment for osteoporosis; the reduction of BMD could increase the risk of osteoporotic fracture. It was very recently found that Piezo1 mediated mechanically evoked responses in bone and further participated in bone formation in mice. Here, we performed cross phenotype meta-analysis for human BMD at lumbar spine (LS), femoral neck (FN), distal radius/forearm (FA) and heel and screened out 14 top SNPs for PIEZO1, these SNPs were overlapped with putative enhancers, DNase-I hypersensitive sites and active promoter flanking regions. We found that the signal of the best SNP rs62048221 was mainly from heel ultrasound estimated BMD (−0.02 SD per T allele, P = 8.50E-09), where calcaneus supported most of the mechanical force of body when standing, walking and doing physical exercises. Each copy of the effect allele T of SNP rs62048221 was associated with a decrease of 0.0035 g/cm² BMD (P = 4.6E-27, SE = 0.0003) in UK Biobank data within 477,760 samples. SNP rs62048221 was located at the enhancer region (HEDD enhancer ID 2331049) of gene PIEZO1, site-directed ChIP assays in human mesenchymal stem cells (hMSCs) showed significant enrichment of H3K4me1 and H3K27ac in this region, luciferase assays showed that rs62048221 could significantly affect the activity of the enhancer where it resides. Our results first suggested that SNP rs62048221 might mediate the PIEZO1 expression level via modulating the activity of cis-regulatory elements and then further affect the BMD.

Keywords: Bone mineral density; PIEZO1; Polymorphism; Mechanical force; Regulation

Links

DOI: 10.1016/j.bone.2020.115247

PubMed: 31968281

WoS: 000517355400017

History

Received: 2019-10-23

Revised: 2020-01-18

Accepted: 2020-01-18

Online: 2020-01-20

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Cited By (3)

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2020	Yasri S, Wiwanitkit V. PIEZO1 polymorphisms and bone mineral density. Bone. April 2020;133:115257.
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