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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2255-2259
Copyright © 1998 by The Endocrine Society

Original Studies

Vitamin D Receptor (VDR) and Parathyroid Hormone Messenger Ribonucleic Acid Levels Correspond to Polymorphic VDR Alleles in Human Parathyroid Tumors1

Tobias Carling, Jonas Rastad, Göran Åkerström and Gunnar Westin

Department of Surgery, Endocrine Unit, Uppsala University Hospital, S-751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Tobias Carling, Ph.D., Department of Surgery, Endocrine Unit, Uppsala University Hospital, S-751 85 Uppsala, Sweden. E-mail: tobias.carling{at}kirurgi.uu.se


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Calcitriol, via its receptor (VDR) is a main regulator of PTH secretion and parathyroid cell proliferation. Recently, marked overrepresentation of the polymorphic VDR alleles b, a, and T was found in patients with primary hyperparathyroidism (pHPT), which suggests pathogenic importance in the disease. Using the ribonuclease protection assay, relative VDR and PTH messenger ribonucleic acid (mRNA) levels of parathyroid adenomas from 42 patients with sporadic pHPT were related to these VDR polymorphisms. The tumors of patients homozygous for the b, a, or T alleles demonstrated significantly lower VDR and higher PTH mRNA levels than those exhibiting the BB, AA, or tt genotypes (P < 0.0001–0.02), whereas heterozygotes had intermediate values. A similar discrepancy was found when comparing the baT and non-baT haplotypes (0.042 ± 0.005 vs. 0.064 ± 0.004 for VDR; 34.4 ± 3.7 vs. 21.6 ± 2.2 for PTH; both P < 0.005). The lower VDR mRNA levels associated with the b, a, and T alleles may affect the calcitriol-mediated control of parathyroid function and thereby contribute to the development of sporadic pHPT.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CALCITRIOL has been shown to be a main inhibitor of both PTH secretion and parathyroid cell proliferation (1, 2, 3). Genetic association studies using polymorphisms in intron 8 (B/b and A/a alleles) and exon 9 (T/t alleles) of the vitamin D receptor (VDR) gene have been conducted in patients with primary hyperparathyroidism (pHPT). The increased prevalence of the VDR alleles b, a, and T in sporadic pHPT indicated that these genetic variants might predispose to parathyroid tumorigenesis (4, 5, 6), although one Japanese study failed to demonstrate any association between VDR alleles and pHPT (7). The VDR baT haplotype has also been related to enhanced abnormality in the calcium regulation of the PTH secretion from adenomatous parathyroid cells of primary HPT (8). These findings could relate to alterations in VDR expression, as the baT haplotype has been coupled to lower expression of a reporter gene as well as lower VDR messenger ribonucleic acid (mRNA) levels from heterozygotic cell lines compared to those of the BAt haplotype (9). Recently, studies on VDR mRNA expression in human peripheral blood mononuclear cells failed to demonstrate correlation to the VDR B/b alleles (10). Possible influences of the VDR polymorphisms on VDR mRNA in human parathyroid tissue have not been elucidated, however.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty-two Caucasian patients (31 females and 11 males; mean age, 69.1 ± 2.0 yr) with primary HPT due to operatively verified parathyroid adenoma were included in the study and randomly selected to create comparable numbers (n = 11–18) of the VDR genotype groups. None of them had a history of familial hypercalcemia, signs of multiple endocrine neoplasia syndromes, or substantially raised serum creatinine values. Preoperative mean values for serum calcium (determined by atomic absorption and corrected for albumin; reference range, 2.20–2.60 mmol/L) and serum PTH (Nichols Institute, San Juan Capistrano, CA; reference range, 12–55 ng/L) were 2.91 ± 0.02 mmol/L and 95 ± 3.8 ng/L, respectively. The weight of the parathyroid adenomas averaged 882 ± 117 mg.

DNA analysis

High mol wt DNA was prepared from leukocytes or parathyroid tissue (4). The PCR and restriction enzymes BsmI, ApaI, and TaqI were used to identify the polymorphic alleles B/b, A/a, and T/t, as previously described (4, 8, 9, 11). The BsmI site in intron 8 of the VDR gene is linked to the presence of the ApaI (intron 8) and absence of the TaqI site (exon 9), concordance between them being approximately 75–80% and 95–99%, respectively (9, 11, 12). No differences in genotype frequencies between males and females have been observed (12). The distribution of the VDR genotypes in the examined primary HPT patients were: BB = 11, Bb = 18, bb = 13; AA = 12, Aa = 15, aa = 15; TT = 11, Tt = 17, and tt = 14.

RNA isolation

Biopsies (50–150 mg) of the parathyroid adenomas, without a macroscopically identified rim of normal tissue, were intraoperatively snap-frozen and stored at -70 C. The tissue was pulverized in liquid nitrogen, and total RNA was isolated by standard procedures (13) .

Riboprobes for VDR, PTH, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)

A PstI/BamHI fragment of the human VDR complementary DNA (cDNA) was subcloned into pBluescript II KS (Stratagene, La Jolla, CA). This region corresponds to bases 1674–2006 of the published sequence and is located downstream of the examined VDR polymorphisms (14). A 253-bp DNA fragment of PTH m124, a prepro-PTH cDNA clone (15) (provided by Dr. H. M. Kronenberg), was amplified by PCR primers (5'-gtagaatggctgcgtaagaagctgc-3' and 5'-catgtattgttgccctacactgtctag-3') and Pfu polymerase (Stratagene). The 206-bp PstI/XbaI fragment was subcloned into pBluescript II KS (Stratagene). Radiolabeled antisense RNA for VDR, PTH, and GAPDH (Ambion, Austin, TX) were produced by in vitro transcription from linearized plasmids using [{alpha}-32P]UTP (Amersham, Aylesbury, UK) and T3 or T7 RNA polymerase (Stratagene). The RNA probes were purified on a 6%/7 mol/L urea polyacrylamide gel and eluted overnight in a buffer containing 0.5 mol/L NaAc (pH 7.0), 1 mmol/L ethylenediamine tetraacetate, and 0.2% SDS. The sizes of the RNA probes and protected fragments were 471 and 332 nucleotides for VDR, 248 and 206 nucleotides for PTH, and 383 and 316 nucleotides for GAPDH. Several protected PTH fragments were obtained due to heterogeneous initiation of the PTH transcription (16).

Ribonuclease (RNase) protection assay

Total RNA from the parathyroid adenomas or HeLa cells were analyzed by RNase protection assay with RNase A (8 µg/mL) and RNase T1 (16 U/mL), essentially as previously described (17). Briefly, excess 32P-labeled VDR and GAPDH or PTH and GAPDH antisense RNA were hybridized overnight to 10 µg total RNA. After RNase digestion, proteinase K treatment, phenol-chloroform extraction, and ethanol precipitation, the samples were run every second slot on a 6%/7 mol/L urea polyacrylamide gel. After overnight exposure, the bands were quantified by PhosphorImager (Molecular Dynamics, Sunnyvale, CA) analysis. All parathyroid tumors were subjected to measurement of VDR mRNA levels, whereas PTH mRNA levels could only be determined in 34 adenomas due to the lack of parathyroid tissue. The individual VDR and PTH mRNA values was corrected by the GAPDH mRNA level, assuming that the amount of GAPDH mRNA in each sample could be used as an internal standard, not influenced by the polymorphic VDR alleles.

Statistical analysis

Differences in mean values were calculated by t test and ANOVA using a P < 0.05 significance level. Regression analysis was performed with StatView 4.0.2 (Abacus, Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
No significant differences in mean values for serum calcium, serum PTH, age, or parathyroid adenoma weight were found among the VDR genotype groups (not shown). The VDR and GAPDH mRNA levels of the 42 parathyroid adenomas were determined by RNase protection assay (Fig. 1aGo). The VDR probe used was located downstream of the examined VDR polymorphisms. PTH mRNA levels adjusted for GAPDH were determined in 34 of the adenomas (Fig. 1bGo). Homozygosity for the b, a, and T alleles were associated with a 41–43% lower VDR/GAPDH mRNA ratio vs. B, A, and t, respectively (Fig. 2aGo). The values were 0.042 ± 0.005 and 0.072 ± 0.005 for bb vs. BB (P < 0.001), 0.043 ± 0.005 and 0.075 ± 0.005 for aa vs. AA (P < 0.0001), and 0.043 ± 0.006 and 0.072 ± 0.005 for TT vs. tt (P < 0.002). The heterozygotes in each allele group demonstrated intermediate values. The same relationships between VDR alleles and VDR mRNA levels could be detected when the analyses were restricted to those parathyroid adenomas available for PTH mRNA measurement. When combining the genotypes, parathyroid adenomas from patients exhibiting the baT haplotype (n = 13) demonstrated a relative VDR mRNA level of 0.042 ± 0.005 vs. 0.064 ± 0.004 for those with non-baT (n = 29; P < 0.005). These associations persisted when using an antisense probe spanning a different portion of the VDR message (not shown). The relative PTH mRNA levels for the bb, aa, and TT genotypes were 41–45% higher than those for BB, AA, and tt (Fig. 2bGo). The levels were 34.4 ± 3.7 vs. 19.1 ± 3.1 for bb vs. BB (P < 0.001), 33.8 ± 3.5 vs. 20.0 ± 2.8 for aa vs. AA (P < 0.01), and 32.8 ± 3.8 vs. 19.1 ± 3.1 for TT vs. tt (P < 0.02). A similar discrepancy was noted between the baT and non-baT haplotypes (34.4 ± 3.7 vs. 21.6 ± 2.2; P < 0.005). Linear regression analysis substantiated inverse correlations between VDR gene expression and serum calcium levels (r2 = -0.13; P < 0.02) and between PTH mRNA levels and adenoma weight (r2 = -0.26; P < 0.002), whereas the VDR and PTH mRNA levels were not related to each other (r2 = -0.02; P > 0.05). No other correlations were seen between VDR mRNA levels and serum PTH, adenoma weight, or age of the patients or between PTH mRNA levels and serum calcium, serum PTH, or age of the patients (data not shown).



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  		Figure 1. The RNase protection assay was used to quantify the VDR (a) and PTH (b) mRNA levels in the parathyroid adenomas. GAPDH was used as an internal standard. Ten micrograms of total RNA from eight representative parathyroid adenomas (PAd 1–8) and HeLa cells (H) were analyzed. V, G, and P are free probes for VDR, GAPDH, and PTH, respectively, and M is a 123-bp DNA ladder marker (Life Technologies, Gaithersburg, MD).

 


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  		Figure 2. Results of the quantification of VDR and PTH mRNA levels in the parathyroid adenomas in relation to VDR genotypes/haplotypes. The data are presented as a ratio of VDR/GAPDH mRNA levels of 42 parathyroid adenomas (a) and as a ratio of PTH/GAPDH mRNA levels of 34 parathyroid adenomas (b). Values are the mean ± SEM for the indicated number of adenomas in each allele group, and P values were calculated using t test and ANOVA.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Calcitriol is known to inhibit both PTH secretion and proliferation of parathyroid cells (1, 3, 18, 19), and reduced parathyroid VDR expression or function has been implicated in the pathogenesis of both primary and secondary HPT (20, 21). Recently described overrepresentation of the polymorphic VDR alleles b, a, and T in Caucasian patients with primary HPT in Sweden and the USA has suggested that these alleles may be important for the development of the disease (4, 5, 6). Such overrepresentation was not found in a Japanese study on limited HPT patient material (7). This discrepancy might be ethnically related, as VDR allelic frequencies differ between populations (4, 7, 22, 23, 24).

The present study demonstrates that homozygosity for the physically related alleles b, a, and T is associated with lower VDR mRNA levels in parathyroid adenomas of patients with primary HPT. This is consistent with studies in which the baT haplotype was associated with lower reporter gene expression and VDR mRNA levels in heterozygotic cell lines (9). It is not known whether the different VDR mRNA levels in the present and previous studies are due to altered VDR transcription or stability of its mRNA, nor is it known whether the effects are direct or dependent on linkage to other polymorphisms in the VDR gene or other genes regulating parathyroid VDR expression.

Reduced VDR expression in human parathyroid tumors could conceivably interfere with the inhibitory actions of calcitriol on PTH synthesis and parathyroid cell proliferation and may thereby contribute to the development of primary HPT. Consistent with this assumption, the baT haplotype seems to be associated with higher PTH mRNA levels and, as previously demonstrated, with a more pronounced functional derangement in the calcium-regulated PTH secretion (8). It is unlikely that the relation of VDR genotypes with VDR and PTH mRNA levels mainly resulted from differences in the clinical expression of HPT, as biochemical variables of HPT were similar in the allelic groups. Circulating calcitriol levels could be regarded as a confounder in this respect, although influences of VDR alleles on these levels are controversial (9, 10, 25, 26, 27).

It seems evident that calcium up-regulates parathyroid VDR in normal rat and avian parathyroids (28, 29). However, in the parathyroid adenomas, VDR mRNA levels were negatively related to serum calcium. Parathyroid tumors consequently may differ from their normal equivalents, as serum calcium is abnormally high and positively correlated to serum PTH and tumor size in HPT (30). The reduced expression of calcium-sensing receptors on the parathyroid cell surface in parathyroid tumors could also impair the effects of calcium on VDR expression (31, 32, 33). Tissue-related heterogeneity exists in the complex regulation of VDR expression and may explain the lack of correlation between VDR alleles and VDR mRNA levels in human peripheral blood mononuclear cells (10). Regulation of VDR is mainly performed by ligand-induced stabilization, which is seen in most target tissues (34, 35), and by increasing VDR mRNA levels, which tends to be more cell type specific (29). In the parathyroid, calcitriol seems to up-regulate VDR mRNA levels (28, 29, 36), whereas one study showed no such effects in the kidney (34). The precise role of the VDR polymorphisms in this complex regulation of VDR expression in the parathyroid and other target organs remains to be elucidated. We conclude that the lower level of parathyroid VDR mRNA expression in patients with the VDR baT haplotype supports the hypothesis that VDR alleles are important for the development of primary HPT.


   Acknowledgments
 
Peter Lillhager is acknowledged for expert technical assistance, and Dr. Steven D. Lucas for linguistic revision of the manuscript.


   Footnotes
 
1 This work was supported by the Swedish Medical Research Council, the Swedish Cancer Society, and the Swedish Society for Medical Research. Back

Received December 11, 1997.

Revised February 18, 1998.

Accepted February 25, 1998.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals