Identification and analysis of a SMAD3 cis-acting eQTL operating in primary osteoarthritis and in the aneurysms and osteoarthritis syndrome.
Osteoarthritis Cartilage
; 22(5): 698-705, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24583347
OBJECTIVE: The TGF-ß pathway plays a central role in joint development with polymorphism in TGF-ß pathway genes implicated in osteoarthritis susceptibility. One association is to rs12901499, within intron 1 of SMAD3. Since rs12901499 is not in linkage disequilibrium with a non-synonymous polymorphism, it is likely the association is operating by influencing expression of SMAD3. DESIGN: Using tissues from the joints of primary osteoarthritis patients who had undergone joint replacement we measured the overall expression of SMAD3 by quantitative real-time PCR. We also measured allelic expression of SMAD3 using these tissues and vascular smooth muscle cells from patients with aneurysms and osteoarthritis syndrome, a rare condition featuring early-onset osteoarthritis. We tested the functional effect of SNPs in vitro using luciferase assays and assessed association with osteoarthritis using a large osteoarthritis case-control dataset. RESULTS: We observed that genotype at rs12901499 did not correlate with overall SMAD3 expression or allelic expression. However, genotype at a 3'UTR SNP, rs8031440, did correlate with SMAD3 expression in cartilage (P = 0.005) which was supported by allelic expression data showing that the G allele correlated with decreased SMAD3 expression in joint tissues and vascular smooth muscle cells. This G allele was underrepresented in osteoarthritis cases vs controls (P = 0.027, odds ratio = 0.921). rs8031440 is in perfect linkage disequilibrium with five other SMAD3 3'UTR SNPs and our luciferase analysis identified rs3743342 and rs12595334 as being functional. CONCLUSION: SMAD3 is subject to cis-acting regulatory polymorphism in the tissues of relevance to both primary osteoarthritis and the aneurysms-osteoarthritis syndrome.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoartrite do Quadril
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Osteoartrite do Joelho
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Locos de Características Quantitativas
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Proteína Smad3
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Aneurisma
Tipo de estudo:
Diagnostic_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article