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Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk.

Xiao SM, Gao Y, Cheung CL, Bow CH, Lau KS, Sham PC, Tan KC, Kung AW - Osteoporos Int (2012)

Bottom Line: BMD was measured by dual X-ray absorptiometry.The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. xiaosm@hku.hk

ABSTRACT

Summary: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future.

Introduction: The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis.

Methods: We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).

Results: Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 × 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA.

Conclusions: Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.

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Related in: MedlinePlus

Association results of BMD variation with single SNPs from the imputed genotyping data after the adjustment of age, height, weight, and gender in all of the 1,572 extreme subjects. X-axis the genomic position (B36); Y-axis the −log10 (P value) of association results (left scale) and the fine scale recombination rate (B36, right scale); circle dots genotyped SNPs; square dots untyped SNPs. The colors of dots are coded according to the degree of linkage disequilibrium (r2) with rs9547970 identified as the most significant SNP in this study (PFDR < 0.05), and this imputed top SNP was then directly genotyped in the 1,572 extreme subjects for validation; rs1977278, the SNP had strongest association with BMD variation in the Framingham Study; rs7322993 and rs7338244, the selected tSNPs showed significant associations with BMD variation after the correction of multiple testing in the tSNP-based analyses (PFDR < 0.05)
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Fig1: Association results of BMD variation with single SNPs from the imputed genotyping data after the adjustment of age, height, weight, and gender in all of the 1,572 extreme subjects. X-axis the genomic position (B36); Y-axis the −log10 (P value) of association results (left scale) and the fine scale recombination rate (B36, right scale); circle dots genotyped SNPs; square dots untyped SNPs. The colors of dots are coded according to the degree of linkage disequilibrium (r2) with rs9547970 identified as the most significant SNP in this study (PFDR < 0.05), and this imputed top SNP was then directly genotyped in the 1,572 extreme subjects for validation; rs1977278, the SNP had strongest association with BMD variation in the Framingham Study; rs7322993 and rs7338244, the selected tSNPs showed significant associations with BMD variation after the correction of multiple testing in the tSNP-based analyses (PFDR < 0.05)

Mentions: The strongest evidence for an association with BMD variation in the imputed data is undoubtedly for the untyped SNP rs9547970 (PFDR < 0.05), which is located at −2,327 bp upstream of POSTN (Fig. 1). An additional 27 SNPs displayed convincing evidence of association (P < 0.005) and were in high LD (r2 > 0.5) with rs9547970 based on the HapMap Asian population data. The most significant untyped-SNP rs9547970 had a high imputation quality (r2 = 0.9983). Subsequently, it was also directly genotyped in the 1,572 extreme samples to verify its association with BMD variation. The frequency of minor allele G (0.265) of rs9547970 was similar to the MAF of HapMap CHB (0.233). The results demonstrated the association between rs9547970 and BMD variation, with P (OR, 95%CI) values of 6.8 × 10−4 (1.41, 1.16–1.73) in all subjects, 0.007 (1.38, 1.09–1.76) and 0.019 (1.42, 1.06–1.91) for LS and FN subgroups, respectively. Its G allele was related to the higher risk of low BMD (Table 3).Fig. 1


Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk.

Xiao SM, Gao Y, Cheung CL, Bow CH, Lau KS, Sham PC, Tan KC, Kung AW - Osteoporos Int (2012)

Association results of BMD variation with single SNPs from the imputed genotyping data after the adjustment of age, height, weight, and gender in all of the 1,572 extreme subjects. X-axis the genomic position (B36); Y-axis the −log10 (P value) of association results (left scale) and the fine scale recombination rate (B36, right scale); circle dots genotyped SNPs; square dots untyped SNPs. The colors of dots are coded according to the degree of linkage disequilibrium (r2) with rs9547970 identified as the most significant SNP in this study (PFDR < 0.05), and this imputed top SNP was then directly genotyped in the 1,572 extreme subjects for validation; rs1977278, the SNP had strongest association with BMD variation in the Framingham Study; rs7322993 and rs7338244, the selected tSNPs showed significant associations with BMD variation after the correction of multiple testing in the tSNP-based analyses (PFDR < 0.05)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368110&req=5

Fig1: Association results of BMD variation with single SNPs from the imputed genotyping data after the adjustment of age, height, weight, and gender in all of the 1,572 extreme subjects. X-axis the genomic position (B36); Y-axis the −log10 (P value) of association results (left scale) and the fine scale recombination rate (B36, right scale); circle dots genotyped SNPs; square dots untyped SNPs. The colors of dots are coded according to the degree of linkage disequilibrium (r2) with rs9547970 identified as the most significant SNP in this study (PFDR < 0.05), and this imputed top SNP was then directly genotyped in the 1,572 extreme subjects for validation; rs1977278, the SNP had strongest association with BMD variation in the Framingham Study; rs7322993 and rs7338244, the selected tSNPs showed significant associations with BMD variation after the correction of multiple testing in the tSNP-based analyses (PFDR < 0.05)
Mentions: The strongest evidence for an association with BMD variation in the imputed data is undoubtedly for the untyped SNP rs9547970 (PFDR < 0.05), which is located at −2,327 bp upstream of POSTN (Fig. 1). An additional 27 SNPs displayed convincing evidence of association (P < 0.005) and were in high LD (r2 > 0.5) with rs9547970 based on the HapMap Asian population data. The most significant untyped-SNP rs9547970 had a high imputation quality (r2 = 0.9983). Subsequently, it was also directly genotyped in the 1,572 extreme samples to verify its association with BMD variation. The frequency of minor allele G (0.265) of rs9547970 was similar to the MAF of HapMap CHB (0.233). The results demonstrated the association between rs9547970 and BMD variation, with P (OR, 95%CI) values of 6.8 × 10−4 (1.41, 1.16–1.73) in all subjects, 0.007 (1.38, 1.09–1.76) and 0.019 (1.42, 1.06–1.91) for LS and FN subgroups, respectively. Its G allele was related to the higher risk of low BMD (Table 3).Fig. 1

Bottom Line: BMD was measured by dual X-ray absorptiometry.The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. xiaosm@hku.hk

ABSTRACT

Summary: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future.

Introduction: The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis.

Methods: We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).

Results: Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 × 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA.

Conclusions: Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.

Show MeSH
Related in: MedlinePlus