Identification and analysis of a SMAD3 cis-acting eQTL operating in primary osteoarthritis and in the aneurysms and osteoarthritis syndrome

Osteoarthritis Cartilage. 2014 May;22(5):698-705. doi: 10.1016/j.joca.2014.02.931. Epub 2014 Feb 28.


Objective: The TGF-β pathway plays a central role in joint development with polymorphism in TGF-β 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.

Keywords: Allelic expression; Aneurysm; Genetics; Osteoarthritis; SMAD3; Susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alleles
  • Aneurysm / genetics*
  • Cartilage, Articular / metabolism
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism
  • Osteoarthritis, Hip / genetics*
  • Osteoarthritis, Hip / metabolism
  • Osteoarthritis, Knee / genetics*
  • Osteoarthritis, Knee / metabolism
  • Quantitative Trait Loci / genetics*
  • Smad3 Protein / genetics*
  • Smad3 Protein / metabolism
  • Syndrome


  • SMAD3 protein, human
  • Smad3 Protein