Abstract
IntroductionWe aimed to explore the involvement of a multiallelic functional polymorphism in knee osteoarthritis (OA) susceptibility as a prototype of possible genetic factors escaping GWAS detection.MethodsOA patients and controls from three European populations (Greece, Spain and the UK) adding up to 1003 patients (716 women, 287 men) that had undergone total knee joint replacement (TKR) due to severe primary OA and 1543 controls (758 women, 785 men) lacking clinical signs or symptoms of OA were genotyped for the D6S1276 microsatellite in intron 1 of BMP5. Genotype and mutiallelic trend tests were used to compare cases and controls.ResultsSignificant association was found between the microsatellite and knee OA in women (P from 3.1 x10-4 to 4.1 x10-4 depending on the test), but not in men. Three of the alleles showed significant differences between patients and controls, one of them of increased risk and two of protection. The gender association and the allele direction of change were very concordant with those previously reported for hip OA.ConclusionsWe have found association of knee OA in women with the D6S1276 functional microsatellite that modifies in cis the expression of BMP5 making this a sounder OA genetic factor and extending its involvement to other joints. This result also shows the interest of analysing other multiallelic polymorphisms.
Highlights
We aimed to explore the involvement of a multiallelic functional polymorphism in knee osteoarthritis (OA) susceptibility as a prototype of possible genetic factors escaping genome wide association studies (GWAS) detection
Investigation of the genetic component of osteoarthritis (OA) susceptibility has yielded the identification of several loci achieving genome-wide significance or consistent replication [1,2,3]
Some have a particular importance in OA, like the difficulties in discriminating between cases and controls, the variability in phenotype definitions and the relatively small size of genome wide association studies (GWAS) in which OA has been studied in comparison with other diseases [3,8]
Summary
We aimed to explore the involvement of a multiallelic functional polymorphism in knee osteoarthritis (OA) susceptibility as a prototype of possible genetic factors escaping GWAS detection. BMP5 is a good candidate gene for OA because BMPs are members of the transforming growth factor (TGF)-beta superfamily that were identified by their involvement in cartilage and bone development. They are known to give morphogenetic signals directing tissue organization throughout the body. BMP5 is implicated in bone morphogenesis and in the formation of the skeletal pattern, in addition to having roles in other organs [15] It is expressed in proliferating zone chondrocytes of the growth plate and is very markedly increased by hypertrophic differentiation. These changes in expression together with the BMP5 chondrogenic role and involvement in chondrocyte hypertrophy indicate BMP5 relevance for OA pathogenesis
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