title: Variations of SOST mRNA expression in human bone are associated with DNA polymorphism and DNA methylation in the SOST gene.
abstract: SOST encodes sclerostin, an inhibitor of bone formation that antagonizes canonical Wnt signaling. Variations of SOST expression have an impact on bone mineral density (BMD) and bone strength. We hypothesized that genetic and epigenetic DNA modifications have an impact on SOST gene expression. By analyzing 43 bone samples from women, we found that rs851054 (G/A) is associated with SOST mRNA expression, donors with one or two G allele(s) displaying higher SOST expression (p<0.05). Beside this polymorphism, we also investigated the role of CpG methylation in SOST mRNA expression, and analyzed methylation variation at 13 CpG sites on the 1st exon of SOST in 14 human bone samples. Principal component analysis identified three groups of CpG sites that explained most of the methylation variation. We calculated the percentage of methylation in the main group of CpGs, and showed that higher rates of methylated CpGs are associated with higher SOST mRNA expression. To demonstrate that change in SOST expression might be related to human bone disease, we analyzed 131 patients with osteogenesis imperfecta (OI), a rare disease characterized by low BMD, bone fragility, and marked intra-familial variability of bone phenotypes. We found an association between rs851054 of the SOST promoter and the fracture rate only during childhood (p<0.01). In conclusion, genetic and epigenetic changes contribute to variation in SOST expression in human bone. Our data also indicate that these variations may be related to the severity of OI.
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Leila
authors: L
authors: Lhaneche
authors: Department of Endocrinology and Internal Medicine, THG, Aarhus University Hospital, DK-8000 Aarhus, Denmark.
authors: Jannie D
authors: JD
authors: Hald
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Aline
authors: A
authors: Domingues
authors: Department of Orthopaedic Surgery, Hôpital Lariboisière, AP-HP, 75010 Paris, France.
authors: Didier
authors: D
authors: Hannouche
authors: Centre National de Genotypage, Institut Génomique, Commissariat à l'énergie Atomique, 2 rue Gaston Crémieux, CP5721 91057 Evry Cedex, France.
authors: Marc
authors: M
authors: Delepine
authors: Centre National de Genotypage, Institut Génomique, Commissariat à l'énergie Atomique, 2 rue Gaston Crémieux, CP5721 91057 Evry Cedex, France.
authors: Diana
authors: D
authors: Zelenika
authors: Centre National de Genotypage, Institut Génomique, Commissariat à l'énergie Atomique, 2 rue Gaston Crémieux, CP5721 91057 Evry Cedex, France.
authors: Anne
authors: A
authors: Boland
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Agnes
authors: A
authors: Ostertag
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; Service de Rhumatologie, GH Saint-Louis Lariboisière Fernand Widal, 75010 Paris, France.
authors: Martine
authors: M
authors: Cohen-Solal
authors: Department of Endocrinology and Internal Medicine, THG, Aarhus University Hospital, DK-8000 Aarhus, Denmark.
authors: Bente L
authors: BL
authors: Langdahl
authors: Department of Endocrinology and Internal Medicine, THG, Aarhus University Hospital, DK-8000 Aarhus, Denmark.
authors: Torben
authors: T
authors: Harsløf
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; Service de Rhumatologie, GH Saint-Louis Lariboisière Fernand Widal, 75010 Paris, France.
authors: Marie-Christine
authors: MC
authors: de Vernejoul
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Valérie
authors: V
authors: Geoffroy
authors: INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: frederic.jehan@inserm.fr.
authors: Frédéric
authors: F
authors: Jehan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005819:Genetic Markers / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D012333:RNA, Messenger; C422903:SOST protein, human
keywords: Bone; DNA methylation; Gene expression; Osteogenesis imperfecta; Polymorphism; SOST