SPP1 plays a role in bone remodeling. rs4754 and haplotype TGC in SPP1 were
significantly associated with reduced risk of low BMD, the latter has not been explored
previously. Serum ALP, creatinine, LDL, and UA may regulate the bone remodeling
and thus affect the above association. Future longitudinal studies are warranted to
explore these associations.
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Figure 1. The flowchart of participant recruitment
Abbreviation: BMD, Bone mineral density.
1,577 healthy Taiwanese women were recruited from, MJ health screening center (age: 40 to 55 years old )
Participants whose BMD was measured at sites other than spine
(n=85)
Participants lacked of blood sample (n=114)
Participants whose having steroid or other hormone(s)
(n=59)
1,319 participants were included for data analyses
Exclusion
Figure 2. Distribution of BMD
Abbreviations: BMD, Bone mineral density.
BMD was tertiled into T1, T2, and T3. High BMD was defined as T3; low BMD was defined as T1 plus T2.
Hap1: T G C
Hap2: C C C
Hap3: T C T
Hap4: C C T
rs11730582 rs6839524 rs4754
Figure 3. Linkage disequilibrium (LD) plot of SPP1 gene
This plot was generated by Haploview program using the modified Gabriel et al. algorithm using data from this study. Three common haplotype (frequency ≥ 0.05) were identified and formed one block. The SNP name, e.g., rs11730582, rs6839524, and rs4754, indicated three htSNP genotyped in this study. The level of pair-wise D’, which indicated the distance between two SNPs, was shown in the linkage disequilibrium structure in gray scale. The darker a square, the higher the distance is between the two SNPs concerned, which could be defined as a single block. The numbers in cells indicate pairwise r2, which indicated the strength of linkage disequilibrium between two SNPs.
Figure 4. Mean bone mineral density (BMD) e 1 standard error (SE) in the different rs11730582 genotype groups.
Abbreviations: BMD, bone mineral density.
Figure 5. Mean bone mineral density (BMD) ± 1 standard error (SE) in the different rs6839524 genotype groups.
Abbreviations: BMD, bone mineral density.
Figure 6. Mean bone mineral density (BMD) ± 1 standard error (SE) in the different rs4754 genotype groups.
Abbreviations: BMD, bone mineral density.
Figure 7. Postulated mechanisms of SPP1 and BMD
Abbreviations: SPP1, secreted phosphoprotein-1; OPN, osteoporosis; LDL, low-density lipoprotein; ALP, alkaline phosphatase; BMI, body mass index; BMD, bone mineral density.
Biomarkers Sexual
hormone Osteopontin Alkaline
phosphatase
Creatinine Uric acid Low-density
lipoprotein Body mass
Lean mass Fat mass
Bone remodeling
Osteoclast Osteoblast SPP1
Menopause
Inflammation
BMD
Figure 8. Forest plot of low BMD risk for different covariates
Abbreviations: SPP1, secreted phosphoprotein-1; LDL, low-density lipoprotein; ALP, alkaline phosphatase; BMI, body mass index; BMD, bone mineral density. OR, odds ratio; 95% CI, 95% confidence interval.
SPP1
LDL
Uric acid
Creatinine
Hyperglicemia
BMI
Menopause
Age Regular exercise
ALP
Table 1. Definition of low and high BMD groups
Tertile Low BMD (<1.27 g/cm2) High BMD (≥1.27 g/cm2)
T1 (n=434) T2 (n=454) T3 (n=431)
BMD, g/cm2 (Mean ± SD)
1.04 ± 0.07 1.20 ± 0.04
1.34 ± 0.06 1.12 ± 0.10
Abbreviations: BMD, bone mineral density; T1, T2, and T3 denote tertiles of BMD
Table 2. Characteristics of the study population
Abbreviations: BMD, bone mineral density; BMI, body mass index; hyperglycemia, fasting glucose > 100 mg/dl or using drug management; hypertension, systolic blood pressure > 130 mmHg or diastolic blood pressure > 85 mmHg or had medication for controlling blood pressure; hyperlipidemia: low density lipoprotein < 50 mg/dL or triglyceride
> 150 mg/dl; regular exercise: walking or hiking ≧30 mins/day.
Table 3. Characteristics of SPP1 haplotype-tagging SNPs
rs no. Nucleotide change
Location Low BMD ( < 1.27 g/cm2)
High BMD ( ≥ 1.27 g/cm2)
Total
MAF HWE p MAF HWE p MAF HWE p
rs11730582 T→C 5’UTR 0.33 0.55 0.32 0.26 0.33 0.25
rs6839524 C→G intron 0.42 0.96 0.41 0.29 0.42 0.57
rs4754 C→T exon 0.29 0.77 0.34 0.16 0.31 0.49
Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density; HWE, Hardy–Weinberg equilibrium; UTR, untranslated;
MAF, minor allele frequency
Table 4. SPP1 SNPs and the risk of low BMD
SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
AOR (95% CI) p-value BMD
Low/High AOR BMD
Low/High AOR (95% CI) p-value BMD
Low/High AOR (95% CI) p-value
rs11730582 398/207 1.00 389/177 1.21 (0.92-1.60) 0.17 103/48 1.20 (0.78-1.86) 0.41 1.13 (0.93-1.37) 0.20 rs6839524 298/156 1.00 434/198 1.32 (0.98-1.77) 0.07 158/78 0.93 (0.64-1.35) 0.70 1.00 (0.83-1.20) 0.92 rs4754 443/195 1.00 372/180 1.05 (0.80-1.39) 0.71 75/57 0.51 (0.33-0.79)* 0.003 0.82 (0.67-0.99) 0.04 Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density.
All models were adjusted for age, menopausal status, BMI, serum ALP, creatinine, UA, LDL, hyperglycemia, and regular exercise.
*Association remained significant after controlling for FDR.
Table 5. SPP1 haplotypes and the risk of low BMD
Haplotype FAC (%)
Co-dominant model Additive model
0 copies 1 copy 2 copies
AOR (95% CI) p-value BMD
Low/High AOR BMD
Low/High AOR (95% CI) p-value BMD
Low/High AOR (95% CI) p-value
Hap1:TGC 41.3 526/242 1.00 319/153 1.04 (0.79-1.37) 0.83 43/36 0.51 (0.30-0.86) 0.01 0.85 (0.68-1.05) 0.12 Hap2:CCC 26.1 300/159 1.00 436/195 1.31 (0.98-1.74) 0.04 152/77 0.94 (0.65-1.36) 0.62 1.01 (0.84-1.22) 0.94 Hap3:TCT 24.0 856/419 1.00 32/12 1.15 (0.52-2.57) 0.74 0/0 NA 1.15 (0.49-2.71) 0.74 Hap4:CCT 6.4 881/427 1.00 7/4 0.78 (0.16-3.78) 0.75 0/0 NA 0.76 (0.15-3.96) 0.75
Abbreviation: NA, not applicable; FAC, frequency among controls; BMD, bone mineral density.
All models were adjusted for age, menopausal status, BMI, serum ALP, creatinine, UA, LDL, hyperglycemia, and regular exercise.
Table 6. SPP1 SNPs and the risk of low BMD by menopausal status
Pre-menopause
SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density.
All models were adjusted for age, BMI, serum ALP, creatinine, UA, LDL, hyperglycemia, and regular exercise.
Table 7. SPP1 SNPs and the risk of low BMD by BMI
Low BMI (< 18.5 kg/m2)
SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density; BMI, body mass index.
All models were adjusted for age, menopausal status, serum ALP, creatinine, UA, LDL, hyperglycemia, and regular exercise.
Table 8. SPP1 SNPs and the risk of low BMD by serum ALP level (low and high)
Low ALP (
≤
57IU/L)SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density; ALP, alkaline phosphatase.
All models were adjusted for age, menopausal status, BMI, serum creatinine, UA, LDL, hyperglycemia, and regular exercise.
*Association remained significant after controlling for FDR.
Table 9. SPP1 SNPs and the risk of low BMD by serum creatinine level (low and high)
Low creatinine (
≤
0.79IU/L)SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density.
All models were adjusted for age, menopausal status, BMI, serum ALP, UA, LDL, hyperglycemia, and regular exercise.
*Association remained significant after controlling for false FDR.
Table 10. SPP1 SNPs and the risk of low BMD by serum UA level (low and high)
Low UA (
≤
4.5 mg/dl)SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density; UA, uric acid.
All models were adjusted for age, menopausal status, BMI, serum ALP, creatinine, LDL, hyperglycemia, and regular exercise.
*Association remained significant after controlling for FDR.
Table 11. SPP1 SNPs and the risk of low BMD by serum LDL level (low and high)
Low LDL (≤ 106 mg/dl)
SNP
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies Abbreviations: SNP, single nucleotide polymorphism; BMD, bone mineral density; LDL, low-density lipoprotein.
All models were adjusted for age, menopausal status, BMI, serum ALP, creatinine, UA, hyperglycemia, and regular exercise.
Table 12. SPP1 haplotypes and the risk of low BMD by menopausal status
Pre-menopause
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviation: NA, not applicable; BMD, bone mineral density.
All models were adjusted for age, BMI, serum ALP, creatinine, UA, LDL, hyperglycemia, and regular exercise.
Table 13. SPP1 haplotypes and the risk of low BMD by BMI
Low BMI(< 18.5 kg/m2)
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviation: NA, not applicable; BMD, bone mineral density; BMI, body mass index.
All models were adjusted for age, menopausal status, serum ALP, creatinine, UA, LDL, hyperglycemia, and regular exercise.
Table 14. SPP1 haplotypes and the risk of low BMD by ALP level (low and high)
Low ALP (≤ 57 IU/L)
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviation: NA, not applicable BMD, bone mineral density; ALP, alkaline phosphatase.
All models were adjusted for age, menopausal status, BMI, serum creatinine, UA, serum LDL, hyperglycemia and regular exercise.
Table 15. SPP1 haplotypes and the risk of low BMD by creatinine level (low and high)
Low creatinine (≤ 0.79 IU/L)
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
High creatinine (> 0.79 IU/L)
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviation: NA, not applicable BMD, bone mineral density.
All models were adjusted for age, menopausal status, BMI, serum ALP, UA, LDL, hyperglycemia, and regular exercise.
Table 16. SPP1 haplotypes and the risk of low BMD by UA level (low and high)
Low UA (≤ 4.5 mg/dl)
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviation: NA, not applicable BMD, bone mineral density; UA, uric acid.
All models were adjusted for age, menopausal status, BMI, serum ALP, creatinine, LDL, hyperglycemia, and regular exercise.
Table 17. SPP1 haplotypes and the risk of low BMD by serum LDL level (low and high)
Low LDL (≤ 106 mg/dl)
Haplotype
Co-dominant model Additive model
0 copies 1 copy 2 copies
Co-dominant model Additive model
0 copies 1 copy 2 copies
Abbreviation: NA, not applicable BMD, bone mineral density; LDL, low-density lipoproteind.
All models were adjusted for age, menopausal status, BMI, serum ALP, creatinine, UA, hyperglycemia, and regular exercise.
Table 18. Interaction between rs4754 and serum biomarkers on low BMD risk
Serum biomarkers
rs4754 Pinteraction*
0 or 1 copy 2 copies
All models were adjusted for age, menopausal status, BMI, serum creatinine, UA, LDL, hyperglycemia, and regular exercise.
*pinteraction was obtained by using the recessive model.
Table 19. Interaction between HAP1 and serum biomarkers on low BMD risk
Serum biomerkers
HAP1 (TGC) Pinteraction*
0 or 1 copy 2 copies
BMD
Low/High OR BMD
Low/High OR (95% CI) p-value Alkaline phosphatase
Low (≤ 57 IU/L) 392/237 1.00 24/19 0.76 (0.37-1.55) 0.45 0.06 High (> 57 IU/L) 453/158 1.00 19/17 0.30 (0.15-0.62) 0.0012
Uric acid
Low (≤ 4.5 mg/dl) 469/187 1.00 21/20 0.34 (0.17-0.70) 0.0033 0.22 High (> 4.5 mg/dl) 376/208 1.00 22/16 0.73 (0.34-1.55) 0.41
Abbreviation: bone mineral density.
All models were adjusted for age, menopausal status, BMI, serum creatinine, UA, LDL, hyperglycemia, and regular exercise.
*pinteraction was obtained by using the recessive model.
Table 20. Previous studies on SPP1 polymorphisms and BMD
Study Journal Sample Size Outcome (Y) Gene/SNP (X) Results Limitations
Taylor et al.
None significant association when adjusted for smoking status, log homeostatic model assessment, education, systolic blood pressure, total cholesterol, and BMI.
CARDIA
SNPs from ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11 were associated with BMD.
SNPs from the LRP5, SOST, SPP1, and TNFRSF11A were significantly associated