Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women
Abstract
:1. Introduction
2. Materials and Methods
2.1. Population
2.2. Genotyping
2.3. Statistics and Computation
3. Results
3.1. SNP Association
3.2. Haplotype Mapping
3.3. Genotype–Phenotype Correlation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations and Acronyms
AACE | American Association of Clinical Endocrinologists |
ALP | Alkaline phosphatase |
ATP-III | Adult Treatment Panel-III |
BMD | Bone mineral density |
BMI | Body mass index |
BMSC | Bone marrow mesenchymal stem cells |
CRP | C-reactive protein |
CST | Chair stand test |
DBP | Diastolic blood pressure |
DEXA | Dual X-ray absorptiometry |
ECLIA | Electrochemiluminescent immunoassay |
HBP | High blood pressure |
HDL-C | High-density lipoprotein cholesterol |
HOMA | Homeostasis model assessment |
LDL-C | Low-density lipoprotein cholesterol |
GWAS | Genome-wide association study |
LD | Linkage disequilibrium |
MAF | Minor allele frequency |
MetS | Metabolic syndrome |
m6A | N6-methyladenosine |
NCEP | National Cholesterol Education Program |
NAFLD | Non-alcohol fatty liver disease |
OP | Osteoporosis |
P1NP | Procollagen type I N-terminal propeptide |
PTH | Parathyroid hormone |
SBP | Systolic blood pressure |
SNV | Single nucleotide variation |
T2D | Type 2 diabetes mellitus |
TBS | Trabecular bone score |
TG | Triglycerides |
TUG | Timed up and go test |
WC | Waist circumference |
WHO | World Health Organization |
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SNV or Haplotype ID a | Allele or Sequence | Frequency (Entire Population) | Non-OP b (Ctr) (n = 68) | OP (Cases) (n = 120) | Severe OP (Cases) (n = 54) | p Value Ctr/OP | OR [95%CI] | p Value Ctr/Sev-OP c (Genotypes) | OR [95%CI] |
---|---|---|---|---|---|---|---|---|---|
SNVs (unphased DNA) | |||||||||
rs8057044 | G/A | 0.49 | 0.39 | 0.42 | 0.59 | 0.0548 | 1.52 [0.99–2.33] | 0.0026 (GA) | 2.2 [1.32–3.69] |
rs8050136 | C/A | 0.44 | 0.42 | 0.37 | 0.57 | 0.4514 | 1.18 [0.77–1.49] | 0.0225 (CA) | 1.81 [0.09–3.02] |
rs9939609 | T/A | 0.44 | 0.42 | 0.37 | 0.57 | 0.0514 | 0.85 [0.56–1.29] | 0.0225 (TA) | 0.55 [0.33–0.92] |
rs62033406 | A/G | 0.46 | 0.42 | 0.39 | 0.57 | 0.3636 | 1.22 [0.79–1.86] | 0.0225 (GA) | 1.81 [1.09–3.02] |
rs9930506 | A/G | 0.48 | 0.35 | 0.44 | 0.60 | 0.0035 | 1.89 [1.23–2.92] | 0.0002 (GA) | 2.66 [1.58–4.49] |
Haplotypes (phased DNA) | |||||||||
H1 | GCTAA | 0.46 | 0.43 | 0.49 | 0.46 | 0.3964 | 1.21 [0.79–1.83] | 0.6493 | 1.12 [0.68–1.87] |
H2 | GCTAG | 0.03 | 0.04 | 0.01 | 0.04 | 0.3656 | 0.56 [0.16–1.96] | 0.9911 | 1.00 [0.26–3.84] |
H3 | GCTGA | 0.02 | 0.02 | 0.01 | 0.02 | 0.7132 | 0.75 [0.15–3.41] | 0.8457 | 0.83 [0.14–5.09] |
H4 | GCTGG | 0.01 | 0.00 | 0.01 | 0.00 | 0.1795 | NA | NA | NA |
H5 | ACTAA | 0.03 | 0.02 | 0.02 | 0.05 | 0.5244 | 1.52 [0.39–5.86] | 0.3016 | 2.15 [0.50–9.21] |
H6 | ACTAG | 0.02 | 0.04 | 0.01 | 0.00 | 0.0557 | 0.22 [0.04–1.15] | NA | NA |
H7 | AAAAA | 0.01 | 0.01 | 0.08 | 0.00 | 0.6891 | 0.56 [0.03–9.11] | NA | NA |
H8 | AAAGA | 0.00 | 0.00 | 0.00 | 0.01 | 0.3429 | NA | NA | NA |
H9 | AAAGG | 0.43 | 0.44 | 0.42 | 0.046 | 0.7609 | 0.09 [0.61–1.43] | 0.8113 | 0.94 [0.56–1.56] |
Major haplotype pairs | |||||||||
H1/H1 | GCTAA GCTAA | 0.24 | 0.26 | 0.23 | 0.18 | 0.2143 | 0.73 [0.45–1.19] | 0.1441 | 0.63 [0.34–1.170] |
H9/H9 | AAAGG AAAGG | 0.20 | 0.23 | 0.23 | 0.13 | 0.2316 | 0.73 [0.44–1.22] | 0.0385 | 0.48 [0.24–0.96] |
H1/H9 | GCTAA AAAGG | 0.36 | 0.26 | 0.35 | 0.48 | 0.0047 | 1.92 [1.21–3.06] | 0.0005 | 2.58 [1.51–4.41] |
Parameter | Homozygous H1/H1 | Homozygous H9/H9 | Heterozygous H1/H9 | p-Value a Kruskal–Wallis | p-Value Mann–Whitney | p ANOVA h (α) |
---|---|---|---|---|---|---|
Metabolic parameters | ||||||
Age (years) | 65.5 ± 1.0 | 67.0 ± 1.2 | 65.9 ± 0.9 | NS | NS | NS |
BMI (kg/m2) | 26.5 ± 0.6 | 28.1 ± 0.7 | 24.7 ± 0.5 | 0.0002 | 0.0188 * 0.0001 * | 0.0002 (0.983) |
SBP b (mmHg) | 119.8 ± 2.8 | 130.2 ± 3.0 | 120.7 ± 1.4 | 0.0412 | 0.0017 ** | 0.0057 (0.84) |
DBP (mmHg) | 76.4 ± 1.5 | 79.2 ± 1.9 | 74.1 ± 0.9 | NS | 0.0069 ** | 0.0277 (0.66) |
HDL-C c (mmol/L) | 1.4 ± 0.0 | 1.5 ± 0.0 | 1.5 ± 0.0 | 0.0622 | 0.0184 * 0.0172 * | 0.0313 (0.64) |
Central obesity (%) | 71.42 | 86.04 | 55.10 | 0.0011 | NA | NA |
Low HDL-C (%) | 46.42 | 9.30 | 28.57 | 0.0003 | NA | NA |
MetSATPIII | 39.28 | 18.60 | 28.56 | 0.0789 | NA | NA |
CRP (mmol/L) d | 38.1 ± 9.52 | 38.1 ± 0.0 | 28.6 ± 0.0 | 0.0123 | 0.0298 *** 0.0747 * | 0.0586 (0.54) |
Bone and muscular parameters | ||||||
Severe OP with fractures (%) | 35.71 | 32.55 | 53.06 | 0.0285 | NA | NA |
BMD LS (g/cm2) e | 0.92 ± 0.01 | 0.94 ± 0.01 | 0.89 ± 0.01 | 0.0003 | 0.0001 * 0.0208 * | 0.0002 |
BMD HIP (g/cm2) | 0.97 ± 0.01 | 0.99 ± 0.01 | 0.94 ± 0.01 | 0.0002 | 0.0001 * 0.0188 *** | 0.0002 (0.98) |
BMD FN (g/cm2) | 0.80 ± 0.01 | 0.82 ± 0.01 | 0.79 ± 0.01 | 0.0002 | 0.0001 ** 0.0188 *** | 0.0002 (0.98) |
BMD RA (g/cm2) | 0.64 ± 0.00 | 0.65 ± 0.00 | 0.63 ± 0.00 | <0.0001 | 0.0001 ** 0.0206 * 0.0423 *** | <0.0001 (0.99) |
Beta-crosslaps (ng/mL) | 0.37 ± 0.03 | 0.70 ± 0.03 | 0.35 ± 0.02 | NS | 0.0338 ** 0.0306 * | 0.0739 (0.51) |
TBS L1–L4 (pixels) f | 1.23 ± 0.02 | 1.26 ± 0.02 | 1.22 ± 0.01 | NS | 0.0501 ** | NS |
SUMstat (%) g | 32.14 | 46.31 | 51.02 | 0.0738 | NA | NA |
Grip strength right (kg) | 20.96 ± 0.56 | 22.57 ± 0.83 | 20.56 ± 0.45 | NS | 0.0223 ** | 0.0584 |
FRAX PLUS hip (%) | 2.69 ± 0.36 | 2.23 ± 0.19 | 3.28 ± 0.31 | NS | 0.0326 ** | NS |
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Greere, D.; Haydar, S.; Grigorescu, F.; Manda, D.; Voicu, G.; Lautier, C.; Poiana, C. Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women. Genes 2024, 15, 1152. https://doi.org/10.3390/genes15091152
Greere D, Haydar S, Grigorescu F, Manda D, Voicu G, Lautier C, Poiana C. Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women. Genes. 2024; 15(9):1152. https://doi.org/10.3390/genes15091152
Chicago/Turabian StyleGreere, Daniela, Sara Haydar, Florin Grigorescu, Dana Manda, Gabriela Voicu, Corinne Lautier, and Catalina Poiana. 2024. "Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women" Genes 15, no. 9: 1152. https://doi.org/10.3390/genes15091152