Association Between Vitamin D Receptor Gene Polymorphism and Relative Hypoparathyroidism in Patients with Chronic Renal Failure ELVIRA FERNANDEZ,* JOAN FIBLA,t ANGELS BETRIU, JOSEP M. PIULATS,t JAUME ALMIRALL, AND JESUS MONTOLIU* *Nephrology Service and Department of Medicine, Hospital Universitari de Lleida Arnau de Vilanova; Human Genetics Unit, Department of Basic Medical Sciences, Universitat de Lleida; Sistemes Renals, Lleida, Spain; and Nephrology Unit, Consorci Hospitalari Parc TaulI Sabadell, Spain. Abstract. To study the influence of vitamin D receptor (VDR) gene polymorphism on parathyroid cell function in chronic renal failure, 85 patients who had serum PTH levels <12 pmolfL (the low intact PTH [iPTH] group) and 46 patients who had serum iPTH levels >60 pmoiIL (the high iPTH group) were selected out of a total dialysis population of 170 individ- uais. As a result of subsequent exclusions based on several criteria in both groups (diabetic patients, serum aluminum levels, serum calcium levels, and time on dialysis), the final low iPTH group consisted of 34 patients and the final high iPTH included 32 patients. A healthy control population (n = 120) and 162 of the 170-patient dialysis population served as control groups. VDR gene polymorphism was determined by digestion with the BsmI enzyme and single-strand conforma- tion polymorphism analysis of PCR amplified fragments. Se- rum iPTH levels were lower in patients with the BB genotype than in those with the Bb or bb genotype, both in the total dialysis population and when the various exclusion criteria were applied. No differences in genotypic and allelic frequen- cies were found between the healthy control population and the high iPTH group. However, the genotypic distribution was significantly different in the low iPTH group of patients before and after applying all exclusion criteria (P = 0.037 and P = 0.0 1 8, respectively). In the final selected population, the bb genotype was less frequent in the low iPTH group than in the total dialysis population (14.7% versus 36.4%; odds ratio, 0.3; confidence interval, 0.11 to 0.82; P = 0.01). Conversely, the BB genotype was over-represented in the low iPTH group (23.3% versus 19.7%; odds ratio, 1.9; confidence interval, 0.85 to 4.3; P = 0. i). In addition, the bb genotype and the b allele frequencies were lower in the low iPTH group than in the high iPTH group (14.7% versus 34.4%, P = 0.06, and 41 .2% versus 60.9%, P = 0.02, respectively), and the BB genotype and the B allele were significantly more frequent in the low PTH group than in the high iPTH group (32.3% versus 12.5%, P = 0.05, and 58.8% versus 39.1%, P = 0.02, respectively). Thus, VDR gene polymorphism influences parathyroid function in chronic renal faiiure. (J Am Soc Nephrol 8: 1546-i552, 1997) The BsmI polymorphism identified in the untranslated 3’ re- gion of the vitamin D receptor (VDR) locus defines B and b alleles that may determine differences in the VDR gene ex- pression and ultimately have functional consequences. Recent observations in a large population of healthy adults indicate that osteocalcin serum levels are higher in individuals with the BB genotype (1). This genotype is also associated with low bone density and an increased risk of osteoporosis in post- menopausal women (2,3). Although the molecular basis for this phenomenon is largely unknown, the B allele has been linked to increased transcriptional activity or messenger RNA stability (2). These and other observations (3-6) suggest that the presence of a specific allele can have clinical consequences in bone. Received January 2. 1997. Accepted March 14, 1997. Correspondence to Dr. Elvira Fern#{225}ndezNephrology Service, Hospital Uni- versitari de Lleida Arnau de Vilanova, Rovira Roure 80, 25198 Lleida, Spain. 1046-6673/08010-I 546$03.00/0 Journal of the American Society of Nephrology Copyright 0 1997 by the American Society of Nephrology The interaction of caicitriol with the VDR in the parathyroid cell inhibits pre-pro-PTH synthesis, upregulates VDR expres- sion, and exerts an antiproliferative effect (7,8). Among other factors, resistance of parathyroid cells to calcitriol in uremia piays an important role in the pathogenesis of hyperparathy- roidism secondary to renal failure (9). No definite reason for this resistance has been ascertained, but there is evidence of a lower VDR density in the parathyroid cells of uremic patients (10,1 1). For these reasons, we investigated whether ailelic differences in the VDR gene could determine differences in parathyroid cell function that could be at least partially respon- sible for the wide variation in the degree of secondary hyper- parathyroidism observed in patients with end-stage renal dis- ease (ESRD). Materials and Methods Patients Of a total maintenance hemodialysis population of 170, we selected 131 patients with ESRD because of their extreme serum intact PTH (iPTH) values. On the basis of their average serum iPTH levels (measured on two occasions separated by 3-mo intervals), these 131 patients were divided into two groups: the low iPTH group, repre-