The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women

Abstract

The objective was to identify single nucleotide polymorphisms (SNPs) in exons of the osteoprotegerin gene and to analyze the relationship between the SNPs and bone mineral density in postmenopausal women. We used polymerase chain reaction (PCR) and direct sequencing methods to identify SNPs and genotypes in 205 postmenopausal women. BMD at the lumbar spine (L2-4) and femoral neck (FN) were measured by dual-energy X-ray absorptiometry (DEXA). Serum osteocalcin (OC), osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL) and urinary N-telopeptide of type I collagen (NTx) were also measured. In exon 1 of the OPG gene, we found the Lys3Asn SNP. In 205 postmenopausal women, the Asn-allele frequency was 26.0%, and the distribution of Lys3Asn genotypes was Lys-Lys 56.6%, Lys-Asn 34.6% and Asn-Asn 8.8%, respectively. BMD at the lumbar spine (L2-4) of the Asn-Asn genotype was significantly higher (9.5-12.6%) than Lys-Asn and Lys-Lys genotypes (P=0.012), with evidence for an allele dose effect (P=0.008). Results remained similar after adjustment for age and body mass index. The Lys3Asn polymorphism of the OPG gene alone accounted for 7.7% of the variance of the L2-4 BMD in a multiple regression model. Logistic regression analysis revealed that the OPG genotype Lys-Lys had a 2.7 times (95% CI: 0.83-9.11) greater risk for osteopenia/osteoporosis than the Asn-Asn genotype. The Lys3Asn polymorphism in the OPG gene is associated with L2-4 BMD in postmenopausal women. The Lys-allele is associated with lower BMD and an increased risk for osteoporosis.

Association analysis between the OPG g.27667T>A genetic variant and bone mineral density in Chinese postmenopausal women

“…These results suggest that the T allele could be an increased risk for BMD and osteoporosis in Chinese postmenopausal women. Several previous studies have reported associations of many SNPs with BMD and osteoporosis, such as A163G, T245G, T950C, G1181C, G23276A, C21775T, and T23367C, which is consistent with our results that genetic variants of OPG may contribute a genetic influence on osteoporosis and BMD (Arko et al, 2002;Langdahl et al, 2002;Ohmori et al, 2002;Jorgensen et al, 2004;Zhao et al, 2005;Kim et al, 2007;Ueland et al, 2007;Garcia-Unzueta et al, 2008;Moffett et al, 2008;Lee et al, 2010;Feng et al, 2012;Zhang et al, 2013). The g.27667T>A SNP might be linked to other known non-synonymous SNPs influencing the function of the OPG protein, such as lysine (Lys)3asparagine (Asn), isoleucine (Ile)184methionine (Met), and Thr154Met, which have all been shown to be significantly associated with the risk of BMD and osteoporosis (Zhao et al, 2005;Feng et al, 2012;Zhang et al, 2013).…”

“…Several studies demonstrated that common genetic variants of OPG likely contribute to BMD and osteoporosis (Pocock et al, 1987;Hofbauer and Schoppet, 2002;Langdahl et al, 2002;Yamada et al, 2003;Arko et al, 2002Arko et al, , 2005Vidal et al, 2011;Feng et al, 2012;Zhang et al, 2013). The association of the A163G, T245G, T950C, G1181C, G23276A, C21775T, and T23367C genetic variants of OPG with BMD and osteoporosis has been investigated (Arko et al, 2002;Langdahl et al, 2002;Ohmori et al, 2002;Jorgensen et al, 2004;Zhao et al, 2005;Kim et al, 2007;Ueland et al, 2007;Garcia-Unzueta et al, 2008;Moffett et al, 2008;Lee et al, 2010;Feng et al, 2012;Zhang et al, 2013). However, associations of g.27667T>A genetic variant of OPG with BMD and osteoporosis have not yet been detected.…”

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

“…(36) Previous candidate gene association studies also have reported an association between rs2073618 and LS BMD a . (15,25,26,29) This association has been confirmed in a meta-analysis study by Lee and colleagues as well. (44) In our study, the minor alleles of rs2073618 and rs9594738 were associated with lower LS BMD a .…”

“…After correcting for multiple testing, only four OPG SNPs (rs2073618, rs10505348, rs6469804, and rs6993813) and two RANKL SNPs (rs9594738 and rs9594759) remained significantly associated with CTX-I. Previous studies have reported association between rs2073618 and urinary levels of two other bone resorption markers, N-terminal cross-linking telopeptide of type I collagen (NTX-1) (26) and deoxypyridinoline (DPD). (27) In contrast, other studies did not find any significant association between rs2073618 and bone turnover markers, but these studies were relatively small.…”

Association of the g.19074G>A genetic variant in the osteoprotegerin gene with bone mineral density in Chinese postmenopausal women

“…Among these candidate genes, OPG is one of the most important. The potential association of the A163G, T245G, T950C, G1181C, C21775T, G23276A, and T23367C genetic variants of the OPG gene with BMD and primary osteoporosis have been analyzed (Arko et al, 2002;Langdahl et al, 2002;Ohmori et al, 2002;Jorgensen et al, 2004;Zhao et al, 2005;Kim et al, 2007;Ueland et al, 2007;Garcia-Unzueta et al, 2008;Moffett et al, 2008;Lee et al, 2010;Feng et al, 2012;Zhang et al, 2013), and the results indicated that these genetic variants contributed to BMD and primary osteoporosis. However, the potential association between the g.19074G>A genetic variant of OPG and BMD and primary osteoporosis have not been reported.…”