Polymorphism of LRP4 Gene (rs9667108) among Post Menopause Women with Osteoporosis
-
Saeid Kavoosian
,
Alimohammad Asgharian
,
Mohsen Asouri
,
Sadegh Fattahi
,
Galia Amirbozorgi
,
Ali Kheirandish
,
Sajad Abolfazli
,
Maryam Lotfi
,
Nima Ebrahimi
,
Ramin Ataee
Abstract
Background: Many studies have been done to identify the factors that influence the development and progression of osteoporosis. One genetic factor is polymorphisms of LRP4 gene. Regarding the lack of comprehensive study on polymorphisms of LRP4 gene in the north of Iran, mainly Mazandaran Province, we decided to investigate the polymorphism of this gene in postmenopausal women with osteoporosis.
Methods: This case-control study has been conducted at GhaemShahr Valiasr Hospital on 100 female patients with osteoporosis (average age of 58.1) and 90 healthy females without osteoporosis (average age of 55.2). After sampling and extraction of genomic DNA via of the salt deposition method, the genotype and SNP (rs9667108) polymorphism of LRP4 gene were evaluated with the PCR-RFLP method. Restriction enzymes cut the PCR products. In order to identify patients, their bone mineral density was tested by the DEXA method .The results of digestion (digestion enzyme) were analyzed by MedCalc, SPSS software, Hardy-Weinberg equilibrium, and Chi2.
Results: The statistical analysis has shown the significant relationship between SNP (rs9667108) polymorphism and the risk of osteoporosis disease in patients and control groups (P<0.05). In SNP (rs9667108), the GC genotype, compared to GG, increased the risk of disease significantly (1.556 time). Similarly, CC genotype, compared to GG genotype, increased the risk of this disease by 2.091 time.
Conclusion: The existence of mutation in the LRP4 gene could increase susceptibility to osteoporosis disease. Moreover, determining this patient's genotype in SNP (rs9667108) can be used to identify individuals who are in endanger osteoporosis.
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2. Watts NB, Adler RA, Bilezikian JP, et al (2012). Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 97(6):1802-22.
3. Buckley L, Guyatt G, Fink H, et al (2017) American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. 2017; 69 (8): 1521–1537.
4. JAMA N (2001). Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. J Am Med Assoc, 85:785-95.
5. Pai MV (2017). Osteoporosis prevention and management. The Journal of Obstetrics and Gynecology of India, 67:237-242.
6. Nguyen VH (2017). Osteoporosis prevention and osteoporosis exercise in community-based public health programs. Osteoporos Sarcopenia, 3(1):18-31.
7. Loh K, Shong H (2007). Osteoporosis: primary prevention in the community. Med J Malaysia, 62(4):355-7.
8. Morris CA, Cabral D, Cheng H, et al (2004). Patterns of bone mineral density testing: current guidelines, testing rates, and interventions. J Gen Intern Med, 19(7):783-90.
9. Golchin MM, Heidari L, Ghaderian SMH, et al (2016). Osteoporosis: a silent disease with complex genetic contribution. J Genet Genomics, 43(2):49-61.
10. Fattahi S, Yousefi GA, Amirbozorgi G, et al (2015). Lack of association of CYP2E1 and CYP1A1 polymorphisms with osteoporosis in postmenauposal women. International Biological and Biomedical Journal, 1:72-80.
11. Raisz LG (2005). Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest, 115(12):3318-25.
12. Leupin O, Piters E, Halleux C, et al (2011). Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem, 286(22):19489-500.
13. Roversi G, Pfundt R, Moroni R, Magnani I, et al (2006). Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines. Oncogene, 25(10):1571-83.
14. Li Y, Pawlik B, Elcioglu N, et al (2010). LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. Am J Hum Genet, 86(5):696-706.
15. Johnson EB, Hammer RE, Herz J (2005). Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet, 14(22):3523-38.
16. Weatherbee SD, Anderson KV, Niswander LA (2006). LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development, 133(24):4993-5000.
17. Ilesanmi-Oyelere BL, Kruger MC (2020). Nutrient and Dietary Patterns in Relation to the Pathogenesis of Postmenopausal Osteoporosis—A Literature Review. Life (Basel), 10(10):220.
18. Lara-Castillo N, Johnson M (2015). LRP receptor family member associated bone disease. Rev Endocr Metab Disord, 16(2):141-148.
19. Kavoosian S, Asgharian A, Ataei R (2016) .Association of Polymorphism of LRP4 Gene (rs 4752947) among Post Meno-pause Women with Osteoporosis in North of Iran. J Arak Uni Med Sci; 19(8): 79-87
20. Robling AG, Niziolek PJ, Baldridge LA, et al (2008). Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem, 283(9):5866-75.
21. Spatz JM, Wein MN, Gooi JH, et al (2015). The Wnt inhibitor sclerostin is up-regulated by mechanical unloading in osteocytes in vitro. J Biol Chem, 290(27):16744-58.
22. Frings-Meuthen P, Boehme G, Liphardt A-M, et al (2013). Sclerostin and DKK1 levels during 14 and 21 days of bed rest in healthy young men. Journal of Musculoskeletal and Neuronal Interactions, 13(1):45-52.
23. Nordberg RC, Mellor LF, Krause AR, et al (2019). LRP receptors in chondrocytes are modulated by simulated microgravity and cyclic hydrostatic pressure. PLoS One, 14(10):e0223245.
24. Spatz J, Fields E, Yu E, et al (2012). Serum sclerostin increases in healthy adult men during bed rest. J Clin Endocrinol Metab, 97(9):E1736-40.
25. Chang M-K, Kramer I, Huber T, et al (2014). Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proc Natl Acad Sci U S A, 111:E5187-95.
26. Kim SP, Da H, Li Z, et al (2019). Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin’s endocrine effects on body composition and glucose metabolism. J Biol Chem, 294(1):6899-6911.
27. Rivadeneira F, Styrkársdottir U, Estrada K, et al (2009). Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet, 41(11):1199-206.
28. Boudin E, Steenackers E, de Freitas F, et al (2013). A common LRP4 haplotype is associated with bone mineral density and hip geometry in men—Data from the Odense Androgen Study (OAS). Bone, 53(2):414-20.
29. Kumar J, Swanberg M, McGuigan F, et al (2011). LRP4 association to bone properties and fracture and interaction with genes in the Wnt-and BMP signaling pathways. Bone, 49(3):343-8.
30. Wang C, Zhang Z, Zhang H, et al (2012). Susceptibility genes for osteoporotic fracture in postmenopausal Chinese women. J Bone Miner Res, 27(12):2582-91.
31. Richards JB, Kavvoura FK, Rivadeneira F, et al (2009). Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med, 151(8):528-37.
32. Sims AM, Shephard N, Carter K, et al (2008). Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res, 23(4):499-506.
33. Vazquez-Villegas ML, Rodriguez-Jimenez NA, Contreras-Haro B, et al (2021). Genotypic Analyses of the Sclerostin rs851056 and Dickkopf rs1569198 Polymorphisms in Mexican-Mestizo Postmenopausal Osteoporosis: A Case–Control Study. Genetic Testing and Molecular Biomarkers, 25(3):211-217.
34. Zheng H-F, Tobias JH, Duncan E, et al (2012). WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genetics, 8(7):e1002745.
35. Yang T-L, Shen H, Liu A, et al (2020). A road map for understanding molecular and genetic determinants of osteoporosis. Nature Reviews Endocrinology, 16(2):91-103.
2. Watts NB, Adler RA, Bilezikian JP, et al (2012). Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 97(6):1802-22.
3. Buckley L, Guyatt G, Fink H, et al (2017) American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. 2017; 69 (8): 1521–1537.
4. JAMA N (2001). Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. J Am Med Assoc, 85:785-95.
5. Pai MV (2017). Osteoporosis prevention and management. The Journal of Obstetrics and Gynecology of India, 67:237-242.
6. Nguyen VH (2017). Osteoporosis prevention and osteoporosis exercise in community-based public health programs. Osteoporos Sarcopenia, 3(1):18-31.
7. Loh K, Shong H (2007). Osteoporosis: primary prevention in the community. Med J Malaysia, 62(4):355-7.
8. Morris CA, Cabral D, Cheng H, et al (2004). Patterns of bone mineral density testing: current guidelines, testing rates, and interventions. J Gen Intern Med, 19(7):783-90.
9. Golchin MM, Heidari L, Ghaderian SMH, et al (2016). Osteoporosis: a silent disease with complex genetic contribution. J Genet Genomics, 43(2):49-61.
10. Fattahi S, Yousefi GA, Amirbozorgi G, et al (2015). Lack of association of CYP2E1 and CYP1A1 polymorphisms with osteoporosis in postmenauposal women. International Biological and Biomedical Journal, 1:72-80.
11. Raisz LG (2005). Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest, 115(12):3318-25.
12. Leupin O, Piters E, Halleux C, et al (2011). Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem, 286(22):19489-500.
13. Roversi G, Pfundt R, Moroni R, Magnani I, et al (2006). Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines. Oncogene, 25(10):1571-83.
14. Li Y, Pawlik B, Elcioglu N, et al (2010). LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. Am J Hum Genet, 86(5):696-706.
15. Johnson EB, Hammer RE, Herz J (2005). Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet, 14(22):3523-38.
16. Weatherbee SD, Anderson KV, Niswander LA (2006). LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development, 133(24):4993-5000.
17. Ilesanmi-Oyelere BL, Kruger MC (2020). Nutrient and Dietary Patterns in Relation to the Pathogenesis of Postmenopausal Osteoporosis—A Literature Review. Life (Basel), 10(10):220.
18. Lara-Castillo N, Johnson M (2015). LRP receptor family member associated bone disease. Rev Endocr Metab Disord, 16(2):141-148.
19. Kavoosian S, Asgharian A, Ataei R (2016) .Association of Polymorphism of LRP4 Gene (rs 4752947) among Post Meno-pause Women with Osteoporosis in North of Iran. J Arak Uni Med Sci; 19(8): 79-87
20. Robling AG, Niziolek PJ, Baldridge LA, et al (2008). Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem, 283(9):5866-75.
21. Spatz JM, Wein MN, Gooi JH, et al (2015). The Wnt inhibitor sclerostin is up-regulated by mechanical unloading in osteocytes in vitro. J Biol Chem, 290(27):16744-58.
22. Frings-Meuthen P, Boehme G, Liphardt A-M, et al (2013). Sclerostin and DKK1 levels during 14 and 21 days of bed rest in healthy young men. Journal of Musculoskeletal and Neuronal Interactions, 13(1):45-52.
23. Nordberg RC, Mellor LF, Krause AR, et al (2019). LRP receptors in chondrocytes are modulated by simulated microgravity and cyclic hydrostatic pressure. PLoS One, 14(10):e0223245.
24. Spatz J, Fields E, Yu E, et al (2012). Serum sclerostin increases in healthy adult men during bed rest. J Clin Endocrinol Metab, 97(9):E1736-40.
25. Chang M-K, Kramer I, Huber T, et al (2014). Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proc Natl Acad Sci U S A, 111:E5187-95.
26. Kim SP, Da H, Li Z, et al (2019). Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin’s endocrine effects on body composition and glucose metabolism. J Biol Chem, 294(1):6899-6911.
27. Rivadeneira F, Styrkársdottir U, Estrada K, et al (2009). Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet, 41(11):1199-206.
28. Boudin E, Steenackers E, de Freitas F, et al (2013). A common LRP4 haplotype is associated with bone mineral density and hip geometry in men—Data from the Odense Androgen Study (OAS). Bone, 53(2):414-20.
29. Kumar J, Swanberg M, McGuigan F, et al (2011). LRP4 association to bone properties and fracture and interaction with genes in the Wnt-and BMP signaling pathways. Bone, 49(3):343-8.
30. Wang C, Zhang Z, Zhang H, et al (2012). Susceptibility genes for osteoporotic fracture in postmenopausal Chinese women. J Bone Miner Res, 27(12):2582-91.
31. Richards JB, Kavvoura FK, Rivadeneira F, et al (2009). Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med, 151(8):528-37.
32. Sims AM, Shephard N, Carter K, et al (2008). Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res, 23(4):499-506.
33. Vazquez-Villegas ML, Rodriguez-Jimenez NA, Contreras-Haro B, et al (2021). Genotypic Analyses of the Sclerostin rs851056 and Dickkopf rs1569198 Polymorphisms in Mexican-Mestizo Postmenopausal Osteoporosis: A Case–Control Study. Genetic Testing and Molecular Biomarkers, 25(3):211-217.
34. Zheng H-F, Tobias JH, Duncan E, et al (2012). WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genetics, 8(7):e1002745.
35. Yang T-L, Shen H, Liu A, et al (2020). A road map for understanding molecular and genetic determinants of osteoporosis. Nature Reviews Endocrinology, 16(2):91-103.
| Files | ||
| Issue | Vol 52 No 4 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i4.12457 | |
| Keywords | ||
| Osteoporosis PCR Polymorphism genetics Single nucleotide polymorphisms (SNPs) | ||
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How to Cite
1.
Kavoosian S, Asgharian A, Asouri M, Fattahi S, Amirbozorgi G, Kheirandish A, Abolfazli S, Lotfi M, Ebrahimi N, Ataee R. Polymorphism of LRP4 Gene (rs9667108) among Post Menopause Women with Osteoporosis. Iran J Public Health. 2023;52(4):840-847.
