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Endochondral ossification pathway genes and postmenopausal osteoporosis: Association and specific allele related serum bone sialoprotein levels in Han Chinese.

Zhang Y, Liu H, Zhang C, Zhang T, Zhang B, Li L, Chen G, Fu D, Wang K - Sci Rep (2015)

Bottom Line: Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels.Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5' end of PTHLH was associated with postmenopausal osteoporosis.Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels.

View Article: PubMed Central - PubMed

Affiliation: The First Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

ABSTRACT
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and disrupted bone architecture, predisposing the patient to increased fracture risk. Evidence from early genetic epidemiological studies has indicated a major role for genetics in the development of osteoporosis and the variation in BMD. In this study, we focused on two key genes in the endochondral ossification pathway, IBSP and PTHLH. Over 9,000 postmenopausal Han Chinese women were recruited, and 54 SNPs were genotyped. Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels. Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5' end of PTHLH was associated with postmenopausal osteoporosis. Our results provide evidence for the association of these two key endochondral ossification pathway genes with BMD and osteoporosis in postmenopausal Han Chinese women. Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels.

No MeSH data available.


Related in: MedlinePlus

Association of bone mineral density and significant SNPs for postmenopausal osteoporosis.(a) SNP rs17013181; (b) SNP rs1054627. LS-BMD stands for BMD of lumbar spine. FN-BMD stands for BMD of femoral neck. The P values of association analyses in combine sample set were indicated for each BMD group.
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f1: Association of bone mineral density and significant SNPs for postmenopausal osteoporosis.(a) SNP rs17013181; (b) SNP rs1054627. LS-BMD stands for BMD of lumbar spine. FN-BMD stands for BMD of femoral neck. The P values of association analyses in combine sample set were indicated for each BMD group.

Mentions: The results of HWE and MAF are shown in Supplemental Table S1. All 54 SNPs passed the HWE test in the discovery stage. Two SNPs within the IBSP gene (rs1054627, P = 1.00 × 10−4; rs17013181, P = 4.99 × 10−5) passed the Bonferroni correction P value threshold in the discovery stage. We genotyped these 2 SNPs plus 11 additional SNPs in the same LD clusters in an independent analysis of the replication stage. The significance of both SNPs was successfully replicated in the second stage (rs1054627, P = 0.0001; rs17013181, P = 0.0003 with Bonferroni correction threshold of 0.05/13 ≈ 0.0038). After conditioning on SNP rs1054627, the significance of SNP rs17013181 was maintained (P = 0.0015). We did not identify any other SNPs with independent effects through single marker based analyses. The results of single marker based analyses of the 13 markers included in the replication stage are summarized in Table 2. We also performed association mapping analysis based on two BMD measurements (lumbar spine and femoral neck). The full results of association mapping for OP and BMD based on the discovery sample set are shown in Supplemental Table S3. The results of association mapping for BMD based on the replication sample set are presented in Supplemental Table S4. We confirmed the significance of both SNPs (rs1054627 and rs17013181) that we identified to be associated with OP in both stages in association analyses based on the BMD of the combined datasets (Fig. 1). As shown in Supplemental Figure S1 and S2, we constructed 18 LD blocks for the two genes (IBSP and PTHLH) based on the discovery sample set data. Haplotype analyses based on the discovery sample set data are summarized in Supplemental Table S5. We identified some significant haplotypes in the IBSP gene (rs6828578-rs958848, P = 2.98 × 10−6; rs4693878-rs1054627, P = 1.48 × 10−7; rs13144371-rs17013181, P = 3.26 × 10−7) and the PTHLH gene (rs12425376-rs10843047-rs42294, P = 5.75 × 10−6).


Endochondral ossification pathway genes and postmenopausal osteoporosis: Association and specific allele related serum bone sialoprotein levels in Han Chinese.

Zhang Y, Liu H, Zhang C, Zhang T, Zhang B, Li L, Chen G, Fu D, Wang K - Sci Rep (2015)

Association of bone mineral density and significant SNPs for postmenopausal osteoporosis.(a) SNP rs17013181; (b) SNP rs1054627. LS-BMD stands for BMD of lumbar spine. FN-BMD stands for BMD of femoral neck. The P values of association analyses in combine sample set were indicated for each BMD group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645187&req=5

f1: Association of bone mineral density and significant SNPs for postmenopausal osteoporosis.(a) SNP rs17013181; (b) SNP rs1054627. LS-BMD stands for BMD of lumbar spine. FN-BMD stands for BMD of femoral neck. The P values of association analyses in combine sample set were indicated for each BMD group.
Mentions: The results of HWE and MAF are shown in Supplemental Table S1. All 54 SNPs passed the HWE test in the discovery stage. Two SNPs within the IBSP gene (rs1054627, P = 1.00 × 10−4; rs17013181, P = 4.99 × 10−5) passed the Bonferroni correction P value threshold in the discovery stage. We genotyped these 2 SNPs plus 11 additional SNPs in the same LD clusters in an independent analysis of the replication stage. The significance of both SNPs was successfully replicated in the second stage (rs1054627, P = 0.0001; rs17013181, P = 0.0003 with Bonferroni correction threshold of 0.05/13 ≈ 0.0038). After conditioning on SNP rs1054627, the significance of SNP rs17013181 was maintained (P = 0.0015). We did not identify any other SNPs with independent effects through single marker based analyses. The results of single marker based analyses of the 13 markers included in the replication stage are summarized in Table 2. We also performed association mapping analysis based on two BMD measurements (lumbar spine and femoral neck). The full results of association mapping for OP and BMD based on the discovery sample set are shown in Supplemental Table S3. The results of association mapping for BMD based on the replication sample set are presented in Supplemental Table S4. We confirmed the significance of both SNPs (rs1054627 and rs17013181) that we identified to be associated with OP in both stages in association analyses based on the BMD of the combined datasets (Fig. 1). As shown in Supplemental Figure S1 and S2, we constructed 18 LD blocks for the two genes (IBSP and PTHLH) based on the discovery sample set data. Haplotype analyses based on the discovery sample set data are summarized in Supplemental Table S5. We identified some significant haplotypes in the IBSP gene (rs6828578-rs958848, P = 2.98 × 10−6; rs4693878-rs1054627, P = 1.48 × 10−7; rs13144371-rs17013181, P = 3.26 × 10−7) and the PTHLH gene (rs12425376-rs10843047-rs42294, P = 5.75 × 10−6).

Bottom Line: Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels.Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5' end of PTHLH was associated with postmenopausal osteoporosis.Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels.

View Article: PubMed Central - PubMed

Affiliation: The First Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

ABSTRACT
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and disrupted bone architecture, predisposing the patient to increased fracture risk. Evidence from early genetic epidemiological studies has indicated a major role for genetics in the development of osteoporosis and the variation in BMD. In this study, we focused on two key genes in the endochondral ossification pathway, IBSP and PTHLH. Over 9,000 postmenopausal Han Chinese women were recruited, and 54 SNPs were genotyped. Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels. Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5' end of PTHLH was associated with postmenopausal osteoporosis. Our results provide evidence for the association of these two key endochondral ossification pathway genes with BMD and osteoporosis in postmenopausal Han Chinese women. Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels.

No MeSH data available.


Related in: MedlinePlus