Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

Alonso, Nerea; Estrada, Karol; Herrera, Lizbeth; Reppe, Sjur; Olstad, Ole Kristoffer; Gautvik, Kaare M.; Ryan, Niamh; Evans, Kathryn; Nielson, Carrie M.; Hsu, Yi Hsiang; Kiel, Douglas P.; Ntzani, Evangelia; Εvangelou, Εvangelos; Feenstra, Bjarke; Liu, Xueping; Melbye, Mads; Masi, Laura; Brandi, Maria Luisa; Riches, Philip L.; Daroszewska, Anna; Olmos, José M.; Valero, Carmen; Castillo, J.; Riancho, José A.; Husted, Lise Bjerre; Langdahl, Bente; Brown, Matthew A.; Duncan, Emma L.; Kaptoge, Stephen; Khaw, Kay Tee; Usategui-Martín, Ricardo; Pino-Montes, Javier del; González-Sarmiento, Rogelio; Lewis, Joshua R.; Prince, Richard; García-Giralt, Natàlia; Nogués, Xavier; Mencej-Bedrač, Simona; Marc, Janja; Wolstein, Orit; Eisman, John A.; Oei, Ling; Medina-Gómez, Carolina; Schraut, Katharina E.; Navarro, Pau; Wilson, James F.; Davies, Gail; Starr, John M.; Deary, Ian J.; Tanaka, Toshiko; Ferrucci, Luigi; Gianfrancesco, Fernando; Gennari, Luigi; Lucas, Gavin; Elosúa, Roberto; Uitterlinden, André G.; Rivadeneira, Fernando; Ralston, Stuart H.

doi:10.1136/annrheumdis-2017-212469

Cited by 24 publications

(13 citation statements)

References 43 publications

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“…Importantly, this GWAS only explains 12% of the BMD phenotype variance and is unable to identify genetic variants with predominant effects on bone quality. Nevertheless, the homologous skeletal Pi transporter SLC20A1 ( PiT1 ) has recently been identified as the most significant candidate gene in a GWAS of clinical vertebral fractures independent of bone density, further suggesting a critical role for phosphate transport in the determination of bone quality.…”

Section: Discussionmentioning

confidence: 99%

Slc20a2, Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength

Beck-Cormier

Lelliott

Logan

et al. 2019

Journal of Bone and Mineral Research

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Osteoporosis is characterized by low bone mineral density (BMD) and fragility fracture and affects over 200 million people worldwide. Bone quality describes the material properties that contribute to strength independently of BMD, and its quantitative analysis is a major priority in osteoporosis research. Tissue mineralization is a fundamental process requiring calcium and phosphate transporters. Here we identify impaired bone quality and strength in Slc20a2–/– mice lacking the phosphate transporter SLC20A2. Juveniles had abnormal endochondral and intramembranous ossification, decreased mineral accrual, and short stature. Adults exhibited only small reductions in bone mass and mineralization but a profound impairment of bone strength. Bone quality was severely impaired in Slc20a2–/– mice: yield load (–2.3 SD), maximum load (–1.7 SD), and stiffness (–2.7 SD) were all below values predicted from their bone mineral content as determined in a cohort of 320 wild‐type controls. These studies identify Slc20a2 as a physiological regulator of tissue mineralization and highlight its critical role in the determination of bone quality and strength. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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Section: Discussionmentioning

confidence: 99%

Slc20a2, Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength

Beck-Cormier

Lelliott

Logan

et al. 2019

Journal of Bone and Mineral Research

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“…Although the 16q24 locus was found associated with BMD and vertebral defects at birth before, the association with vertebral fracture risk could not be replicated by de-novo genotyping across 15 studies worldwide, likely due to the heterogeneity underlying the different fracture definitions. A subsequent publication focusing on clinical vertebral fractures (i.e., those presenting with clinical manifestations) identified and replicated a locus tagged by rs10190845 on chromosome 2q13 where differential expression of the positional candidate genes TTL and SLC20A1 was shown (51).…”

Section: Recent Advances In the Genetics Of Osteoporotic Fracturesmentioning

confidence: 98%

Recent Advances in the Genetics of Fractures in Osteoporosis

et al. 2019

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Genetic susceptibility, together with old age, female sex, and low bone mineral density (BMD) are amongst the strongest determinants of fracture risk. Tmost recent large-scale genome-wide association study (GWAS) meta-analysis has yielded fifteen loci. This review focuses on the advances in the research of genetic determinants of fracture risk. We first discuss the genetic architecture of fracture risk, touching upon different methods and overall findings. We then discuss in a second paragraph the most recent advances in the field and focus on the genetics of fracture risk and also of other endophenotypes closely related to fracture risk such as bone mineral density (BMD). Application of state-of-the-art methodology such as Mendelian randzation in fracture GWAS are reviewed. The final part of this review touches upon potential future directions in genetic research of osteoporotic fractures.

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“…The vitamin D receptor polymorphisms change vitamin D pathways, which are associated with the development of osteoporosis [ 38 ]. A genome-wide associated study on over 1000 patients with menopausal women uncovered that locus rs10190845 at chromosome 2q13 is relevant to vertebral fractures, and that three loci at chromosome 1p31, 11q12, and 15q11 are associated with low bone mass [ 39 ].…”

Section: Genetic Variation Dna Methylation and Osteoporosismentioning

confidence: 99%

Epigenetic Regulation of Skeletal Tissue Integrity and Osteoporosis Development

Chen

Lian

Kuo

et al. 2020

IJMS

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Bone turnover is sophisticatedly balanced by a dynamic coupling of bone formation and resorption at various rates. The orchestration of this continuous remodeling of the skeleton further affects other skeletal tissues through organ crosstalk. Chronic excessive bone resorption compromises bone mass and its porous microstructure as well as proper biomechanics. This accelerates the development of osteoporotic disorders, a leading cause of skeletal degeneration-associated disability and premature death. Bone-forming cells play important roles in maintaining bone deposit and osteoclastic resorption. A poor organelle machinery, such as mitochondrial dysfunction, endoplasmic reticulum stress, and defective autophagy, etc., dysregulates growth factor secretion, mineralization matrix production, or osteoclast-regulatory capacity in osteoblastic cells. A plethora of epigenetic pathways regulate bone formation, skeletal integrity, and the development of osteoporosis. MicroRNAs inhibit protein translation by binding the 3′-untranslated region of mRNAs or promote translation through post-transcriptional pathways. DNA methylation and post-translational modification of histones alter the chromatin structure, hindering histone enrichment in promoter regions. MicroRNA-processing enzymes and DNA as well as histone modification enzymes catalyze these modifying reactions. Gain and loss of these epigenetic modifiers in bone-forming cells affect their epigenetic landscapes, influencing bone homeostasis, microarchitectural integrity, and osteoporotic changes. This article conveys productive insights into biological roles of DNA methylation, microRNA, and histone modification and highlights their interactions during skeletal development and bone loss under physiological and pathological conditions.

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Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

Cited by 24 publications

References 43 publications

Slc20a2, Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength

Slc20a2, Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength

Recent Advances in the Genetics of Fractures in Osteoporosis

Epigenetic Regulation of Skeletal Tissue Integrity and Osteoporosis Development

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