Abstract
In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment. © 2010 American Society for Bone and Mineral Research
Highlights
Bone mineral density (BMD) is an established determinant of bone strength and osteoporotic fracture risk
Of the 4108 single-nucleotide polymorphisms (SNPs) genotyped in the discovery analysis, 191 SNPs in 72 genes were associated with cortical Volumetric BMD (vBMD) and were genotyped in the validation sample (Fig. 1A)
Studies in humans and animal models suggest that the genetic determinants of trabecular and cortical BMD may differ, but few specific loci have been identified for these bone strength–related traits
Summary
Bone mineral density (BMD) is an established determinant of bone strength and osteoporotic fracture risk. BMD assessed by conventional dual-energy X-ray absorptiometry (DXA) measures the total bone mineral content in a projected area (integral areal BMD) and cannot directly measure other skeletal features that may contribute to bone strength, such as the relative amounts of cortical and trabecular bone. Quantitative computed tomography (QCT) provides a direct measure of cortical and trabecular volumetric BMD, both of which may contribute to bone strength and fracture risk.[1,2]. The individual genetic factors contributing to BMD variation may differ between women and men, between skeletal sites, and between trabecular and cortical bone.[4,5,6,7,8,9,10,11] Volumetric BMD (vBMD) for both compartments is heritable, with heritability estimates of 17% to 42% for cortical vBMD and 59% to 73% for trabecular vBMD.[9,10,11] the vast majority of studies in humans have searched for genetic
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