Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis.
Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P=0.001-0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P=0.002-0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD.
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. ben.mullin@health.wa.gov.au
Ben H
BH
Mullin
Richard L
RL
Prince
Cyril
C
Mamotte
Tim D
TD
Spector
Deborah J
DJ
Hart
Frank
F
Dudbridge
Scott G
SG
Wilson
D000483:Alleles; D015519:Bone Density / Q000235:genetics; D015331:Cohort Studies; D003710:Demography; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008875:Middle Aged; D010024:Osteoporosis / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C576601:ARHGEF3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D020741:rho GTP-Binding Proteins