Analysis of the association of polymorphisms CASR and VDR with the development of nephrolithiasis in patients with primary hyperparathyroidism

Pathogenesis of nephrolithiasis (NL) at PHPT is not fully understood. Meanwhile, the detection of NL patients with PHPT is an absolute indication for parathyroidectomy. Conducted various studies aimed at finding a predictor of NL patients with PHPT. Actively study the role of genetic markers, particularly genes that regulate calcium-phosphorus metabolism.

Objective — to assess the relationship of polymorphisms CASR and VDR with the development of the NL at PHPТ.

Material and methods. A study to include 203 patients with confirmed PHPT, out of which 114 patients had the NL and 87 patients without NL. All patients were studied indicators calcium-phosphorus metabolism, the study of the level of PTH, vitamin D, the filtration function of the kidneys. All patients were studied indicators calcium-phosphorus metabolism, the level of PTH, vitamin D, the filtration function of the kidneys. The study of gene polymorphisms VDR (FokI, TaqI, BsmI, ApaI, Cdx2) was performed in 169 patients (113 with NL, 56 without NL) by polymerase chain reaction followed by restriction analysis; Study 3 polymorphisms CASR (A986S, R990G, Q1011E) was performed in 187 patients (110 with NL, 77 without NL), by direct sequencing.

Results. No significant differences in the frequency of genotypes and alleles studied genes between the two groups has been received. According to logistic regression analysis, the only predictor of NL is the level of ionized calcium.

Conclusions. The studied genes can not be used as predictors of the NL. May need to investigate other genes.

1. Bilezikian JP, Silverberg SJ. Clinical spectrum of primary hyperparathyroidism. Rev Endocr Metab Disord. 2000;1(4):237-245. doi: 10.1023/a:1026508829397.

2. Berger AD, Wu W, Eisner BH, et al. Patients With Primary Hyperparathyroidism—Why Do Some Form Stones? The Journal of Urology. 2009;181(5):2141-2145. doi: 10.1016/j.juro.2009.01.028.

3. Pallan S, Rahman MO, Khan AA. Diagnosis and management of primary hyperparathyroidism. BMJ. 2012;344:e1013. doi: 10.1136/bmj.e1013.

4. Yu N, Donnan PT, Leese GP. A record linkage study of outcomes in patients with mild primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf). 2011;75(2):169-176. doi: 10.1111/j.1365-2265.2010.03958.x.

5. Rejnmark L, Vestergaard P, Mosekilde L. Nephrolithiasis and renal calcifications in primary hyperparathyroidism. J Clin Endocrinol Metab. 2011;96(8):2377-2385. doi: 10.1210/jc.2011-0569.

6. Перетокина Е.В., Мокрышева Н.Г. “Нефролитиаз при первичном гиперпаратиреозе, современный взгляд”. // Ожирение и метаболизм. – 2014. – Т. 11. – №3 – С. 3-8. [Peretokina EV, Mokrysheva NG. Nephrolithiasis in primary hyperparathyroidism: a contemporary look. Obesity and metabolism. 2014;11(3):3-8.] doi: 10.14341/omet201433-8.

7. Söreide JA, van Heerden JA, Grant CS, et al. Characteristics of patients surgically treated for primary hyperparathyroidism with and without renal stones. Surgery. 1996;120(6):1033-1038. doi: 10.1016/s0039-6060(96)80051-1.

8. Starup-Linde J, Waldhauer E, Rolighed L, et al. Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables. Eur J Endocrinol. 2012;166(6):1093-1100. doi: 10.1530/EJE-12-0032.

9. Мирная C.C., Пигарова Е.А., Беляева А.В., Мокрышева Н.Г., и др. “Роль кальций-чувствительного рецептора в поддержании системы кальциевого гемостаза”. // Остеопороз и остеопатии. – 2010. – №3 – С. 31-36. [Mirnaya SS, Pigarova EA, Belyaeva AV, Mokrysheva NG, et al. Rol’ kal’tsiy-chuvstvitel’nogo retseptora v podderzhanii sistemy kal’tsievogo gemostaza. Osteoporoz i osteopatii. 2010;3:31-36. (In Russ.)].

10. Han G, Wang O, Nie M, et al. Clinical phenotypes of Chinese primary hyperparathyroidism patients are associated with the calcium-sensing receptor gene R990G polymorphism. Eur J Endocrinol. 2013;169(5):629-638. doi: 10.1530/EJE-13-0441.

11. Vezzoli G, Terranegra A, Arcidiacono T, Soldati L. Genetics and calcium nephrolithiasis. Kidney Int. 2011;80(6):587-593. doi: 10.1038/ki.2010.430.

12. Vezzoli G, Tanini A, Ferrucci L, et al. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol. 2002;13(10):2517-2523.

13. Vezzoli G, Terranegra A, Arcidiacono T, et al. Calcium kidney stones are associated with a haplotype of the calcium-sensing receptor gene regulatory region. Nephrol Dial Transplant. 2010;25(7):2245-2252. doi: 10.1093/ndt/gfp760.

14. Scillitani A, Guarnieri V, Battista C, et al. Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. J Clin Endocrinol Metab. 2007;92(1):277-283. doi: 10.1210/jc.2006-0857.

15. Corbetta S, Baccarelli A, Aroldi A, et al. Risk factors associated to kidney stones in primary hyperparathyroidism. J Endocrinol Invest. 2014;28(4):122-128. doi: 10.1007/bf03345354.

16. Lin Y, Mao Q, Zheng X, et al. Vitamin D receptor genetic polymorphisms and the risk of urolithiasis: a meta-analysis. Urol Int. 2011;86(3):249-255. doi: 10.1159/00032949.

17. Аполихин И.О., Сивков А.В., Константинова О.В., и др. “Поиск полиморфных вариантов кандидатных генов мочекаменной болезни в российской популяции”. // Клиническая и экспериментальная урология. – 2013. – №3 – С. 56-60. [Apolikhin OI, Sivkov AV, Konstantinova OV, et al. The search for the polymorphic variants of the gene candidates of urolithiasis in Russian population. Experimental & clinical urology. 2013;(3):56-60. (in Russ.)].

18. Bilezikian JP, Khan AA, Potts JT, Jr., Third International Workshop on the Management of Asymptomatic Primary H. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335-339. doi: 10.1210/jc.2008-1763.