Abstract
Osteoporosis is characterized by low BMD and has strong genetic determination. However, specific genetic variants influencing BMD and contributing to the pathogenesis of osteoporosis are largely uncharacterized. Current genetic studies in bone, which are aimed at identification of osteoporosis risk genes, are focused mostly on DNA, RNA, or the protein level individually, lacking integrative evidence from the three levels of genetic information flow to confidently ascertain the significance of genes for osteoporosis. Our previous proteomics study discovered that superoxide dismutase 2 (SOD2) in circulating monocytes (CMCs, ie, potential osteoclast precursors) was significantly upregulated at protein level in vivo in Chinese with low versus high hip BMD. Herein, at mRNA level, we found that SOD2 gene expression also was upregulated in CMCs (p < 0.05) in Chinese with low versus high hip BMD. At the DNA level, in 1627 unrelated Chinese subjects, we identified eight single-nucleotide polymorphisms (SNPs) at the SOD2 gene locus that were suggestively associated with hip BMD (peak signal at rs11968525, p = 0.048). Among the eight SNPs, three SNPs (rs7754103, rs7754295, and rs2053949) were associated with the SOD2 mRNA expression level (p < 0.05), suggesting that they are expression quantitative trait loci (eQTLs) regulating SOD2 gene expression. In conclusion, this integrative evidence from DNA, RNA, and protein levels support SOD2 as a susceptibility gene for osteoporosis.