Genetic polymorphisms in uremic secondary hyperparathyroidism: a multicentric Italian Study

Background. The pathophysiology of hyperparathyroidism (HPT) relates to the loss of normal feedback control of parathyroid hormone secretion by extracellular calcium. Why the parathyroid cell loses its normal sensivity to calcium is unknown. Consistent with the essential role of vitamin D in parathyroid cell regulation, restriction fragment length polymorphisms (RFLPs) at the vitamin D receptor (VDR) gene locus have been recently postulated to be responsible for differential VDR transcription and/or mRNA stability, contributing to the parathyroid tumorigenesis. Particularly, common VDR allelic variants have been related to differences in the incidence of both primary and secondary HPT, and in serum PTH levels as well as in calcium regulation of PTH release. However, agreement on these relationships is not universal among different populations. Methods. In this study we investigated the role of VDR and calcium sensing receptor (CaSR) gene RFLPs in 100 uremic secondary HPT patients (mean age 58.2±6.7 yrs; mean dialytic age 7.1±2.0 yrs) compared to 200 age and sex matched controls. Apa I, Bsm I, and Taq I RFLPs at the 3′-end of VDR gene locus as well as Fok I RFLP at the translation initiation codon of the VDR gene were determined after PCR amplification and indicated respectively as A-a, B-b, T-t, and F-f, uppercase letter signifying the absence and lowercase letter the presence of the restriction site. The three polymorphisms in exon 7 of the CaSR gene (T/G at codon 986, A/G at codon 990, and G/C at codon 1011) were evaluated by PCR amplification and direct sequencing. Results. χ2 analysis revealed no significant difference in the distribution of any of the VDR or CaSR genotypes in subjects with secondary HPT compared to controls. Secondary HPT patients were divided into two major groups according to serum PTH levels: group 1 with higher PTH levels, requiring parathyroidectomy, and group 2 with serum PTH levels below 120 pg/ml. Interestingly, a trend for a higher prevalence of VDR genotype aabbTT in group 1, with respect to group 2 was observed (=0.07; χ2 test). Conclusions. Taken together, these results suggest that VDR and CaSR gene RFLPs are not directly involved in parathyroid tumorigenesis and in determining the incidence of secondary HPT. However, VDR gene RFLPs might be useful in predicting the progression of secondary HPT as well as the severity of the disease.