Vitamin D receptor gene polymorphism detected by digestion with Apa I influences the parathyroid response to extracellular calcium in Japanese chronic dialysis patients.
BACKGROUND
To play its physiological role, 1,25(OH)2D3 must bind to a specific vitamin D receptor (VDR) in the nucleus. We have previously reported that VDR gene polymorphism influences the parathyroid function in patients with end-stage renal disease (ESRD). In the present study, we have investigated the relationship between the parathyroid responsiveness and VDR gene polymorphism, as detected by the Apa I restriction enzyme, by changing the concentration of Ca2+ in the dialysate.


METHODS
58 Japanese ESRD patients undergoing renal replacement therapy in our institution were evaluated. Genomic DNA was extracted from peripheral leukocytes and digested at the intron between exon 8 and exon 9 of the VDR gene using Apa I enzyme. Then alleles were classified into genotype A (undigested allele) and genotype a (digested allele). Extracellular ionized calcium ([Ca2+]e), serum phosphate, and intact parathyroid hormone (PTH) were measured before and after each hemodialysis (HD) session with dialysates having different concentrations of Ca2+ (1.5 or 1.25 mmol/l). The significance of differences in statistical analyses was defined within confidence limits of 5.0%.


RESULTS
The AA, Aa, and aa genotypes were observed in 7/58 patients (12.1%), 23/58 patients (39.6%), and 28/58 patients (48.3%), respectively. The PTH reduction after HD with the 1.5-mmol/l Ca dialysate did not differ significantly between group AA+Aa and group aa. On the other hand, the PTH increase was significantly higher in group aa than in group AA+Aa after HD with the 1.25-mmol/l Ca dialysate (p = 0.0107), despite a similar PTH level before HD. Similarly, the percent increase of PTH after HD with the 1.25-mmol/l Ca dialysate was significantly higher (p = 0.0112) in group aa (50.2 +/- 9.4%) than in group AA+Aa (19.7 +/- 7.2%). There were no significant differences between the two groups in [Ca2+]e nor in serum phosphorus (Pi) before and after HD with either dialysate. Group AA+Aa and group aa did not show statistically significant differences in age, female/male ratio, ratio of diabetic nephropathy, or dialysis period.


CONCLUSIONS
The study results showed that the patients in group aa were more sensitive to changes in [Ca2+]e than those in group AA+Aa. Moreover, they suggested that the VDR gene polymorphism may affect parathyroid responsiveness to changes in [Ca2+]e, which in turn may influence onset and progression of hyperparathyroidism in ESRD patients.
Yokoyama
K
K
Division of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, Japan. keitaro@mrj.biglobe.ne.jp
Shigematsu
T
T
Kagami
S
S
Tsukada
T
T
Arai
T
T
Hara
S
S
Yamada
A
A
Kawaguchi
Y
Y
Hosoya
T
T
D000483:Alleles; D002118:Calcium / Q000097:blood / Q000494:pharmacology*; D015314:Dialysis Solutions; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006961:Hyperparathyroidism / Q000150:complications / Q000208:ethnology; D007564:Japan; D007676:Kidney Failure, Chronic / Q000150:complications / Q000208:ethnology; D008875:Middle Aged; D010280:Parathyroid Glands / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism; D010758:Phosphorus / Q000097:blood; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D006435:Renal Dialysis
D015314:Dialysis Solutions; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D010758:Phosphorus; D002118:Calcium