Research Article


DOI :10.26650/IstanbulJPharm.2022.1093992   IUP :10.26650/IstanbulJPharm.2022.1093992    Full Text (PDF)

Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking

Özlem Kurnaz GömleksizAyşegül Başak Akadam TekerFatih YanarEzgi I. AslanÖzlem Kurt ŞirinMehmet UyarAyşe CanHülya Yılmaz Aydoğan

Background and Aims: The G protein-coupled calcium-sensing receptor (CaSR) plays an important role in extracellular calcium homeostasis and regulation of parathyroid hormone (PTH) secretion. There are more than 300 activating/inactivating mutations in the CASR gene. However, the effects of both CaSR protein and CASR gene on bone mineral density (BMD) have not been investigated enough. The aim of this study was therefore to determine the effect of rs104893706 (A843E, (Ala to Glu at codon843)), a gain-of-function mutation of the CASR gene, on BMD in postmenopausal women. Methods: We studied the CASR A843E variation using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism methods in 180 postmenopausal women. Statistical analyses were performed using SPSS software package (version 21.0 SPSS Inc.,Chicago,IL,U.S.A.). Results: No minor A allele, homozygous (AA) or heterozygous (CA), was observed in the study population. In other words, the frequency of the CASR A843E common CC genotype was 100%. BMD levels of the lumbar spine (L1-L4), femoral neck, and total hip were 1.03±0.13g/cm2 , 0.87±0.11g/cm2 , and 0.93±0.11g/cm2 , respectively. Although the femoral neck (p=0.017), upper neck (p=0.040), lower neck (p=0.011), and Ward’s triangle BMD values (p=0.005) were found significantly higher in younger postmenopausal women (age<55 years) compared to older postmenopausal women (age>=55 years), there were no significant differences on BMD value of the lumbar spines, trochanter, and total hip between the age groups (p>0.05). Conclusion: Our findings confirm the effects of advanced age in favor of decreased BMD in postmenopausal women. This study suggests that the CASR A843E gain-of-function mutation may not be associated with bone mineral density and osteoporosis risk since we did not detect the A843E variation in Turkish postmenopausal women.


PDF View

References

  • Aida, K., Koishi, S., Tawata, M., & Onaya, T. (1995). Molecular cloning of a putative Ca2+-sensing receptor cDNA from human kidney. Biochemical and Biophysical Research Communications, 214(2), 524-529. google scholar
  • Al-Azzawie, A. F. (2001). Molecular assessment of calcium-sensing receptor gene polymorphism rs1801725 in Iraqi women with os-teoporosis, Asian Journal of Agriculture and Biology, 3, 1-9. https:// doi.org/10.35495/ajab.2020.04.252 google scholar
  • Bjarnason, N. H., & Christiansen, C. (2000). The influence of thin-ness and smoking on bone loss and response to hormone re-placement therapy in early postmenopausal women. Journal of Clinical Endocrinology & Metabolism, 85(2), 590-596. https://doi. org/10.1210/jcem.85.2.6364 google scholar
  • Brown, E. M., Gamba, G., & Riccardi, D. (1993). Cloning and charac-terization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature, 366, 575-580. google scholar
  • Brown, E. M., & Hansen, J. T. (2005). The calcium-sensing recep-tor in normal physiology and pathophysiology: a review. Critical Reviews in Clinical Laboratory Sciences, 42(1), 35-70. google scholar
  • Brown, E. M., & MacLeod, R. J. (2001). Extracellular calcium sens-ing and extracellular calcium signaling. Physiological Reviews, 81(1), 239-297. google scholar
  • Brown, E. M. (1999). Physiology and pathophysiology of the extra-cellular calcium-sensing receptor. American Journal of Medicine, 106(2), 238-253. google scholar
  • Cetani, F., Pardi, E., Borsari, S., Vignali, E., Dipollina, G., Braga, V., ... Marcocci, C. (2003). Calcium-sensing receptor gene poly-morphism is not associated with bone mineral density in Italian postmenopausal women. EuropeanJournal of Endocrinology,148, 603-607. google scholar
  • D’Souza-Li, L. (2006). The calcium-sensing receptor and related diseases. Arquivos Brasileiros de Endocrinologia e Metabologia, 50, 628-636. doi:10.1111/j.1365-2036.2011.04905.x google scholar
  • Donath, J., Speer, G., Poor, G., Gergely, P., Tabak, Jr. A., Lakatos, P (2004). Vitamin D receptor, oestrogen receptor-a and calcium-sensing receptor genotypes, bone mineral density and biochem-ical markers in Paget’s disease of bone. Rheumatology (Oxford), 43 (6), 692-695. doi: 10.1093/rheumatology/keh162 google scholar
  • Egbuna, O. I., & Brown, E. M. (2008). Hypercalcaemic and hypocal-caemic conditions due to calcium-sensing receptor mutations. Best Practice & Research: Clinical Rheumatology, 22(1), 129-148. doi: 10.1016/j.berh.2007.11.006. google scholar
  • Eller-Vainicher, C., Battista, C., Guarnieri, V., Muscarella, S., Palmieri, S., Salcuni, A. S., . Scillitani A. (2014). Factors associated with vertebral fracture risk in patients with primary hyperparathyroidism. European Journal of Endocrinology, 171(3): 399-406. doi: 10.1530/EJE-14-0343. google scholar
  • Garrett, J. E., Capuano, I. V., Hammerland, L. G., Hung, B. C., Brown, E. M., Hebert, S. C., Nemeth, E. F., Fuller, F. (1995). Molecular cloning and functional expression of human parathyroid calcium recep-tor cDNAs. Journal of Biological Chemistry, 270(21), 12919-12925. google scholar
  • Guha, M., Bankura, B., Ghosh, S., Pattanayak, A. K., Ghosh, S., Pal, D.K., . Das M. (2015). Polymorphisms in CaSR and CLDN14 genes associated with increased risk of kidney stone disease in patients from the eastern part of india. PLoS One,10(6): e0130790 google scholar
  • Hannan, F. M., Kallay, E., Chang, W., Brandi, M. L., Thakker, R. V. (2018). The calcium-sensing receptor in physiology and in calci-tropic and noncalcitropic diseases. Nature Reviews Endocrinology, 15(1): 33-51. doi: 10.1038/s41574-018-0115-0. google scholar
  • Hend, G. N., Guarnieri, V., Canaff, L. (2009). Calcium-sensing receptor and associated diseases. Progress in Molecular Biol-ogy and Translational Science, 89, 31-95. doi: 10.1016/S1877-1173(09)89003-0. google scholar
  • Ioannidis, J. P., Stavrou, I., Trikalinos, T. A., Zois, C., Brandi, M. L., Gen-nari, L., . Tsatsoulis, A. (2002). ER-alpha genetics meta-analysis. As-sociation of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-anal-ysis. Journal of Bone and Mineral Research, 17, 2048-2060. google scholar
  • Jeong, S., Kim, I. W., Oh, K. H., Han, N., Joo, K. W., Kim, H. J., Oh, J. M. (2016). Pharmacogenetic analysis of cinacalcet response in sec-ondary hyperparathyroidism patients. Drug Design, Development and Therapy, 10, 2211-2225. doi: 10.2147/DDDT.S103370. google scholar
  • Jung, J., Foroud, T. M., Eckert, G. J., Flury-Wetherill, L., Edenberg, H. J., Xuei, X., .Pratt, J. H. (2009). Association of the calcium-sensing receptor gene with blood pressure and urinary calcium in African-Americans. Journal of Clinical Endocrinology & Metabo-lism,94(3), 1042-1048. doi: 10.1210/jc.2008-1861. google scholar
  • Kinoshita, Y., Hori, M., Taguchi, M., Watanabe, S., Fukumoto, S. (2014). Functional activities of mutant calcium-sensing recep-tors determine clinical presentations in patients with autosomal dominant hypocalcemia. Journal of Clinical Endocrinology & Me-tabolism, 99, 363-368. doi:10.1210/jc.2013-3430 google scholar
  • Kuo, CW., Chang, T. H., Chi, W. L., Chu, T. C. (2008). Effect of Ciga-rette Smoking on Bone Mineral Density in Healthy Taiwanese Middle-Aged Men. Journal of Clinical Densitometry, 11(4), 518-524. doi: 10.1016/j.jocd.2008.07.005. google scholar
  • Kurt, O., Yilmaz-Aydogan, H., Uyar, M., Isbir, T., Seyhan, M., Can, A. (2012). Evaluation of ERa and VDR gene polymorphisms in rela-tion to bone mineral density in Turkish postmenopausal women. MolecularBiologyReports,39(6), 6723-6730. doi: 10.1007/s11033-012-1496-0. google scholar
  • Li, X., Kong, X., Jiang, L., Ma, T., Yan, S., ., Yang, Q. (2014). A ge-netic polymorphism (rs17251221) in the calcium-sensing re-ceptor is associated with breast cancer susceptibility and prog-nosis. Cellular Physiology and Biochemistry, 33(1), 165-172. doi: 10.1159/000356659. google scholar
  • Li, Y., Zhao, Y., Tang, R., Qu, X. (2010). Preventive and therapeutic effects of antlercollagen on osteoporosis in ovariectomized rats. African Journal of Biotechnology, 9(38): 6437-6441. https://doi. org/10.5897/AJB10.251 google scholar
  • Lorentzon, M., Lorentzon, R., Lerner, U. H., Nordstrom, P. (2001). Calcium sensing receptor gene polymorphism, circulating con-centrations and bone mineral density in healthy adolescent girls. European Journal of Endocrinology, 144: 257-261. google scholar
  • Miller, S. A., Dykes, D. D., Poleskey, H. S. (1988). A simple salting out procedure for extracting DNA from human nucleated cells, Nucleic Acids Research, 16: 1215. google scholar
  • NIH consensus development panel on osteoporosis. (2001) Pre-vention diagnosis and therapy osteoporosis prevention, diagno-sis, and therapy. Journal of theAmericanMedicalAssociation, 285, 785-795. doi:10.1001/jama.285.6.785 google scholar
  • North American Menopause Society. (2010). NAMS continuing medical education activity. Menopause, 17(1), 25-54. https://doi. org/10.1097/gme.0b013e3181cdd4a7 google scholar
  • Nuti, R., Brandi, M. L., Checchia, G., Di Munno, O., Dominguez, L., Falaschi, P, ..., Isaia, G. C. (2019). Guidelines for the management of osteoporosis and fragility fractures. Internal and Emergency Medicine, 14(1), 85-102. doi: 10.1007/s11739-018-1874-2. google scholar
  • O’Seaghdha, C. M., Yang, Q., Glazer, N. L., Leak, T. S., Dehghan, A., Smith, A. V., ..., Köttgen, A. (2010). Common variants in the calci-um-sensing receptor gene are associated with total serum calci-um levels. Human Molecular Genetics, 19, 4296-4303. doi:10.1093/ hmg/ddq342 google scholar
  • Pi, M., Garner, S. C., Flannery, P., Spurney, R. F., Quarles, L. D. (2000). Sensing of extracellular cations in CaSR-deficient osteoblasts. Evi-dence for a novel cation sensing mechanism. Journal of Biological Chemistry, 275, 3256-3263. google scholar
  • Rapuri, P. B., Gallagher, J. C., Balhorn, K. E., Ryschon, K. L. (2000). Smoking and bone metabolism in elderly women. Bone, 27, 429436. http://dx.doi.org/10.1016/S8756-3282(00)00341-0 google scholar
  • Regala, J., Cavaco, B., Domingues, R., Limbert, C., Lopes, L. (2015). Novel mutation in the CASR gene (p.Leu123Ser) in a case of auto-somal dominant Hypocalcemia. Journal of Pediatric Genetics, 4(1), 29-33. doi:10.1055/s-0035-1554979 google scholar
  • Sato, K., Hasegawa, Y., Nakae, J., Nanao, K., Takahashi, I., Tajima, T., ., Fujieda, K. (2002). Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. Jour-nal of ClinicalEndocrinology & Metabolism, 87(7), 3068-3073. google scholar
  • Takacs, I., Speer, G., Bajnok, E., Tabak, Â., Nagy, Z., Horvath, C., ..., Lakatos, P. (2002). Lack of association between calcium-sensing receptor gene “A986S” polymorphism and bone mineral den-sity in Hungarian postmenopausal women. Bone, 30(6), 849-852. doi: http://dx.doi.org/10.1016/S8756-3282(02)00741-X google scholar
  • Thakker, R. V. (2004). Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium, 35(3), 275-82 google scholar
  • Wang, Y. B., Guo, J. J., Liu, Y. J., Deng, F. Y., Jiang, D. K., Deng, H. W. (2006). The human calcium-sensing receptor and interleukin-6 genes are associated with bone mineral density in Chinese. Acta Genetica Sinica, 33(10), 870-880. google scholar
  • Watanabe, S., Fukumoto, S., Chang, H., Takeuchi, Y., Hasegawa, Y., Okazaki, R., ., Fujita, T. (2002). Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet, 360(9334), 692-694. google scholar
  • Willing, M., Sowers, M., Aran, D., Clark, M. K., Burns, T., Bunten, C. (1998). Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interac-tion. Journal of Bone and Mineral Research, 13, 695-705. google scholar
  • Xie, P., Liu, B., Zhang, L., Chen, R., Yang, B., Dong, J., Rong, L. (2015). Association of COL1A1 polymorphisms with osteoporosis: a me-ta-analysis of clinical studies. International Journal of Experimen-tal and ClinicalMedicine,8(9), 14764-14781. google scholar
  • Yamauchi, M., Sugimoto, T., Yamaguchi, T., Yano, S., Kanzawa, M., Kobayashi, A., Chihara, K. (2001). Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism. Clinical Endocrinology (Oxford),55, 373-379. google scholar
  • Young, R., Wu, F., Van de Water, N., Ames, R., Gamble, G., Reid, I.R. (2003). Calcium sensing receptor gene A986S polymorphism and responsiveness to calcium supplementation in postmenopausal women. Journal of ClinicalEndocrinology & Metabolism, 88(2), 697700. doi: 10.1210/jc.2002-020355. google scholar
  • Zhang, J., Jameson, K., Sayer, A. A., Robinson, S., Cooper, C., Den-nison, E. (2016). Accumulation of risk factors associated with poor bone health in older adults. Archives of Osteoporosis, 11, 3. doi: 10.1007/s11657-015-0250-3. google scholar
  • Zhao, X. M., Hauache, O., Goldsmith, P. K., Collins, R., Spiegel, A. M. (1999). A missensemutation in the seventh transmembrane domain constitutively activates the human Ca2+receptor. FEBS Letters, 448(1), 180-184. google scholar

Citations

Copy and paste a formatted citation or use one of the options to export in your chosen format


EXPORT



APA

Kurnaz Gömleksiz, Ö., Akadam Teker, A.B., Yanar, F., Aslan, E.I., Kurt Şirin, Ö., Uyar, M., Can, A., & Yılmaz Aydoğan, H. (2022). Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking. İstanbul Journal of Pharmacy, 52(2), 129-135. https://doi.org/10.26650/IstanbulJPharm.2022.1093992


AMA

Kurnaz Gömleksiz Ö, Akadam Teker A B, Yanar F, Aslan E I, Kurt Şirin Ö, Uyar M, Can A, Yılmaz Aydoğan H. Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking. İstanbul Journal of Pharmacy. 2022;52(2):129-135. https://doi.org/10.26650/IstanbulJPharm.2022.1093992


ABNT

Kurnaz Gömleksiz, Ö.; Akadam Teker, A.B.; Yanar, F.; Aslan, E.I.; Kurt Şirin, Ö.; Uyar, M.; Can, A.; Yılmaz Aydoğan, H. Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking. İstanbul Journal of Pharmacy, [Publisher Location], v. 52, n. 2, p. 129-135, 2022.


Chicago: Author-Date Style

Kurnaz Gömleksiz, Özlem, and Ayşegül Başak Akadam Teker and Fatih Yanar and Ezgi I. Aslan and Özlem Kurt Şirin and Mehmet Uyar and Ayşe Can and Hülya Yılmaz Aydoğan. 2022. “Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking.” İstanbul Journal of Pharmacy 52, no. 2: 129-135. https://doi.org/10.26650/IstanbulJPharm.2022.1093992


Chicago: Humanities Style

Kurnaz Gömleksiz, Özlem, and Ayşegül Başak Akadam Teker and Fatih Yanar and Ezgi I. Aslan and Özlem Kurt Şirin and Mehmet Uyar and Ayşe Can and Hülya Yılmaz Aydoğan. Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking.” İstanbul Journal of Pharmacy 52, no. 2 (Oct. 2022): 129-135. https://doi.org/10.26650/IstanbulJPharm.2022.1093992


Harvard: Australian Style

Kurnaz Gömleksiz, Ö & Akadam Teker, AB & Yanar, F & Aslan, EI & Kurt Şirin, Ö & Uyar, M & Can, A & Yılmaz Aydoğan, H 2022, 'Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking', İstanbul Journal of Pharmacy, vol. 52, no. 2, pp. 129-135, viewed 3 Oct. 2022, https://doi.org/10.26650/IstanbulJPharm.2022.1093992


Harvard: Author-Date Style

Kurnaz Gömleksiz, Ö. and Akadam Teker, A.B. and Yanar, F. and Aslan, E.I. and Kurt Şirin, Ö. and Uyar, M. and Can, A. and Yılmaz Aydoğan, H. (2022) ‘Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking’, İstanbul Journal of Pharmacy, 52(2), pp. 129-135. https://doi.org/10.26650/IstanbulJPharm.2022.1093992 (3 Oct. 2022).


MLA

Kurnaz Gömleksiz, Özlem, and Ayşegül Başak Akadam Teker and Fatih Yanar and Ezgi I. Aslan and Özlem Kurt Şirin and Mehmet Uyar and Ayşe Can and Hülya Yılmaz Aydoğan. Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking.” İstanbul Journal of Pharmacy, vol. 52, no. 2, 2022, pp. 129-135. [Database Container], https://doi.org/10.26650/IstanbulJPharm.2022.1093992


Vancouver

Kurnaz Gömleksiz Ö, Akadam Teker AB, Yanar F, Aslan EI, Kurt Şirin Ö, Uyar M, Can A, Yılmaz Aydoğan H. Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking. İstanbul Journal of Pharmacy [Internet]. 3 Oct. 2022 [cited 3 Oct. 2022];52(2):129-135. Available from: https://doi.org/10.26650/IstanbulJPharm.2022.1093992 doi: 10.26650/IstanbulJPharm.2022.1093992


ISNAD

Kurnaz Gömleksiz, Özlem - Akadam Teker, AyşegülBaşak - Yanar, Fatih - Aslan, EzgiI. - Kurt Şirin, Özlem - Uyar, Mehmet - Can, Ayşe - Yılmaz Aydoğan, Hülya. Effects of the CASR rs104893706 (A843E) gainof-function mutation on bone mineral density in postmenopausal women by advanced age and smoking”. İstanbul Journal of Pharmacy 52/2 (Oct. 2022): 129-135. https://doi.org/10.26650/IstanbulJPharm.2022.1093992



TIMELINE


Submitted04.04.2022
Accepted03.05.2022
Published Online29.08.2022

LICENCE


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


SHARE




Istanbul University Press aims to contribute to the dissemination of ever growing scientific knowledge through publication of high quality scientific journals and books in accordance with the international publishing standards and ethics. Istanbul University Press follows an open access, non-commercial, scholarly publishing.