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Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

2012-10Journal article Open access
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dc.contributor.authorMichou, Laetitia
dc.contributor.authorConceicao, Natercia
dc.contributor.authorMorissette, Jean
dc.contributor.authorGagnon, Edith
dc.contributor.authorMiltenberger-Miltenyi, Gabriel
dc.contributor.authorSiris, Ethel S.
dc.contributor.authorBrown, Jacques P.
dc.contributor.authorLeonor Cancela, M.
dc.date.accessioned2018-12-07T14:58:04Z
dc.date.available2018-12-07T14:58:04Z
dc.date.issued2012-10
dc.description.abstractWe performed a genetic association study of rare variants and single nucleotide polymorphisms (SNPs) of UCMA/GRP and OPTN genes, in French-Canadian patients with Paget's disease of bone (PDB) and in healthy controls from the same population. We reproduced the variant found in the UCMA/GRP basal promoter and tested its functionality using in vitro transient transfection assays. Interestingly, this SNP rs17152980 appears to affect the transcription level of UCMA/GRP. In addition, we have identified five rare genetic variants in UCMA/GRP gene, four of them being population-specific, although none were found to be associated with PDB. Six Tag SNPs of UCMA/GRP gene were associated with PDB, particularly the SNP rs17152980 (uncorrected P = 3.8 x 10(-3)), although not significant after Bonferroni's correction. More importantly, we replicated the strong and statistically significant genetic association of two SNPs of the OPTN gene, the rs1561570 (uncorrected P = 5.7 x 10(-7)) and the rs2095388 (uncorrected P = 4.9 x 10(-3)), With PDB. In addition, we identified a very rare variant found to be located close to the basal promoter of the OPTN gene, at -232 bp from its distal transcription start site. Furthermore, depending on the type of allele present (G or A), the binding of several important nuclear factors such as the vitamin D or the retinoic acid receptors is predicted to be altered at this position, suggesting a significant effect in the regulation of transcription of the OPTN gene. In conclusion, we identified a functional SNP located in the basal promoter of the UCMA/GRP gene which provided a weak genetic association with PDB. In addition, we replicated the strong genetic association of two already known SNPs of the OPTN gene, with PDB in a founder effect population. We also identified a very rare variant in the promoter of OPTN, and through bioinformatic analysis, identified putative transcription factor binding sites likely to affect OPTN gene transcription. (C) 2012 Elsevier Inc. All rights reserved.
dc.description.sponsorshipFonds de la Recherche du Quebec - Sante (FRQS), Canada; Portuguese Science and Technology Foundation, Portugal [SFRH/BPD/48206/2008]; Catalyst Grant (Bone Health) from the Canadian Institutes of Health Research (Canada); CHUQ Foundation (Canada); Groupe de Recherche en Maladies Osseuses (Canada); Canadian Foundation for Innovation (Canada); FRSQ (Canada); Laval University (Canada); CHUQ (CHUL) Research Centre (Canada); Centre of Marine Sciences (CCMAR) (Portugal)
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1016/j.bone.2012.06.028
dc.identifier.issn8756-3282
dc.identifier.urihttp://hdl.handle.net/10400.1/11844
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier Science Inc
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectGenome-Wide Association
dc.subjectGla-Rich Protein
dc.subjectCell
dc.subjectSequestosome-1
dc.subjectOptineurin
dc.subjectMutations
dc.subjectCartilage
dc.subjectTnfrsf11A
dc.subjectVariants
dc.subject10P13
dc.titleGenetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F48206%2F2008/PT
oaire.citation.endPage728
oaire.citation.issue4
oaire.citation.startPage720
oaire.citation.titleBONE
oaire.citation.volume51
oaire.fundingStreamSFRH
person.familyNameConceição
person.familyNameCancela
person.givenNameNatércia
person.givenNameM. Leonor
person.identifier.ciencia-id7C11-760D-F425
person.identifier.orcid0000-0002-5057-0912
person.identifier.orcid0000-0003-3114-6662
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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