Association of a functional microsatellite within intron 1 of the BMP5 gene with susceptibility to osteoarthritis.

Abstract

BACKGROUND:

In a previous study carried out by our group, the genotyping of 36 microsatellite markers from within a narrow interval of chromosome 6p12.3-q13 generated evidence for linkage and for association to female hip osteoarthritis (OA), with the most compelling association found for a marker within intron 1 of the bone morphogenetic protein 5 gene (BMP5). In this study, we aimed to further categorize the association of variants within intron 1 of BMP5 with OA through an expanded genetic association study of the intron and subsequent functional analysis of associated polymorphisms.

METHODS:

We genotyped 18 common polymorphisms including 8 microsatellites and 9 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion (INDEL) from within highly conserved regions between human and mouse within intron 1 of BMP5. These markers were then tested for association to OA by a two-stage approach in which the polymorphisms were initially genotyped in a case-control cohort comprising 361 individuals with associated polymorphisms (P < or = 0.05) then genotyped in a second case-control cohort comprising 1185 individuals.

RESULTS:

Two BMP5 intron 1 polymorphisms demonstrated association in the combined case-control cohort of 1546 individuals (765 cases and 781 controls): microsatellite D6S1276 (P = 0.018) and SNP rs921126 (P = 0.013). Functional analyses in osteoblastic, chondrocytic, and adipocytic cell lines indicated that allelic variants of D6S1276 have significant effects on the transcriptional activity of the BMP5 promoter in vitro.

CONCLUSION:

Variability in gene expression of BMP5 may be an important contributor to OA genetic susceptibility.

• Authors: James M Wilkins, Lorraine Southam, Zehra Mustafa, Kay Chapman, John Loughlin
• Journal: BMC medical genetics (BMC Med Genet) Vol. 10 Pg. 141 (Dec 19 2009) ISSN: 1471-2350 [Electronic] England
• PMID: 20021689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMP5 protein, human
• Bmp5 protein, mouse
• Bone Morphogenetic Protein 5
• Luciferases

Topics

• Aged
• Aged, 80 and over
• Animals
• Bone Morphogenetic Protein 5 (genetics)
• Case-Control Studies
• Cell Line
• Female
• Genes, Reporter
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• INDEL Mutation
• Introns
• Luciferases
• Mice
• Microsatellite Repeats (genetics)
• Middle Aged
• Osteoarthritis, Hip (genetics)
• Plasmids
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic