title: SNP rs6265 regulates protein phosphorylation and osteoblast differentiation and influences BMD in humans.
abstract: Bone mineral density (BMD) is a major index for diagnosing osteoporosis. PhosSNPs are nonsynonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aimed to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genomewide phosSNP association study for BMD in three independent population samples, involving ∼5000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, ie, rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying the AA genotype have significantly lower hip BMD than carriers of the GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, by regulating BDNF protein phosphorylation and osteoblast differentiation, influences hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases.
authors.affiliation: Center of Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, PR China; Center for Bioinformatics and Genomics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA; Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Deng
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Tan
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Xue-Zhen
authors.initials: XZ
authors.lastname: Zhu
authors.forename: Xiang-Ding
authors.initials: XD
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D000328:Adult; D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology* / Q000201:enzymology; D010766:Phosphorylation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D013379:Substrate Specificity
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human
keywords: BDNF; BMD; OSTEOBLAST; PROTEIN PHOSPHORYLATION; SNP