Buchumschlag von Identification of IDUA and WNT16 Phosphorylation‐Related Non‐Synonymous Polymorphisms for Bone Mineral Density in Meta‐Analyses of Genome‐Wide Association Studies

Identification of IDUA and WNT16 Phosphorylation‐Related Non‐Synonymous Polymorphisms for Bone Mineral Density in Meta‐Analyses of Genome‐Wide Association Studies

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Zeitschriftentitel:	Journal of Bone and Mineral Research
Personen und Körperschaften:	Niu, Tianhua, Liu, Ning, Yu, Xun, Zhao, Ming, Choi, Hyung Jin, Leo, Paul J, Brown, Matthew A, Zhang, Lei, Pei, Yu‐Fang, Shen, Hui, He, Hao, Fu, Xiaoying, Lu, Shan, Chen, Xiang‐Ding, Tan, Li‐Jun, Yang, Tie‐Lin, Guo, Yan, Cho, Nam H, Shen, Jie, Guo, Yan‐Fang, Nicholson, Geoffrey C, Prince, Richard L, Eisman, John A, Jones, Graeme, Sambrook, Philip N, Tian, Qing, Zhu, Xue‐Zhen, Papasian, Christopher J, Duncan, Emma L, Uitterlinden, André G, Shin, Chan Soo, Xiang, Shuanglin, Deng, Hong‐Wen
In:	Journal of Bone and Mineral Research, 31, 2016, 2, S. 358-368
Medientyp:	E-Article
Sprache:	Englisch
veröffentlicht:	Oxford University Press (OUP)
Schlagwörter:	Orthopedics and Sports Medicine Endocrinology, Diabetes and Metabolism

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Zusammenfassung:	<jats:title>ABSTRACT</jats:title><jats:sec><jats:label /><jats:p>Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single‐nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome‐wide association (GWA) study, we conducted a three‐stage meta‐analysis targeting phosphorylation‐related SNPs (phosSNPs) for femoral neck (FN)‐bone mineral density (BMD), total hip (HIP)‐BMD, and lumbar spine (LS)‐BMD phenotypes. In stage 1, 9593 phosSNPs were meta‐analyzed in 11,140 individuals of various ancestries. Genome‐wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10<jats:sup>–6</jats:sup> (0.05/9593) and 1.00 × 10<jats:sup>–4</jats:sup>, respectively. In stage 2, nine stage 1–discovered phosSNPs (based on α = 1.00 × 10<jats:sup>–4</jats:sup>) were in silico meta‐analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10<jats:sup>–3</jats:sup>, 0.05/9) were de novo genotyped in two independent cohorts. <jats:italic>IDUA</jats:italic> rs3755955 and rs6831280, and <jats:italic>WNT16</jats:italic> rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN‐BMD (<jats:italic>p</jats:italic> = 8.36 × 10<jats:sup>–10</jats:sup>, <jats:italic>p</jats:italic> = 5.26 × 10<jats:sup>–10</jats:sup>, and <jats:italic>p</jats:italic> = 3.01 × 10<jats:sup>–10</jats:sup>, respectively) and HIP‐BMD (<jats:italic>p</jats:italic> = 3.26 × 10<jats:sup>–6</jats:sup>, <jats:italic>p</jats:italic> = 1.97 × 10<jats:sup>–6</jats:sup>, and <jats:italic>p</jats:italic> = 1.63 × 10<jats:sup>–12</jats:sup>, respectively). Although in vitro studies demonstrated no differences in expressions of wild‐type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that <jats:italic>WNT16</jats:italic> rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that <jats:italic>IDUA</jats:italic> phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD‐associated non‐synonymous variants. © 2015 American Society for Bone and Mineral Research.</jats:p></jats:sec>
Umfang:	358-368
ISSN:	0884-0431 1523-4681
DOI:	10.1002/jbmr.2687