Analysis of polymorphisms in the MEN 1 gene and Calcium sensing receptor gene in sporadic primary hyperparathyroidism

Primary hyperparathyroidism (pHPT) occurs sporadically and in several hereditary disorders including multiple endocrine neoplasia type 1. It is characterized by hypercalcemia as a result of exessive release of parathyroid hormone (PTH). Candidates for involvement in sporadic parathyroid tumorigenesis are the Calcium-Sensing Receptor Gene (CASR) and the MEN 1 gene. An association of the most common polymorphism (SNP) in the MEN 1 gene, D418D with sporadic pHPT has been recently described (Correa 2002). For the SNPs A986S and G990R in the CASR gene Cole et al. and Yamauchi et al. found an influence on serum calcium and PTH concentration. Therefore, we investigated the frequency of the D418D (MEN 1 gene), A986S and G990R (CASR gene) SNPs in patients with sporadic pHPT and related them to serum calcium and PTH levels. In 66 patients with pHPT D418D, A986S and G990R SNPs and in 50 controls D418D SNP have been analysed by direct sequencing of the PCR amplified genomic DNA. The observed allelic frequency for 418D allele in the MEN 1 gene was 34.8% (46/132) in patients with pHPT and 47% (47/100) in controls. In the pHPT patients the CASR gene allele 986S was found in 21.2% (28/132) and the 990G allele in 7.5% (10/132). For D418D and R990G no association to calcium and PTH could be seen. For A986S a trend to higher calcium in 986AS could be detected (2.82 mmol/L in 986AA vs. 2.87 mmol/L in 986AS). We report an overrepresentation of 418D in MEN 1 gene in patients with pHPT and confirm the results of Correa et al. As reported by Cole et al., we also detect a trend to higher calcium in 986AS in CASR gene, though our differences are not significant. In contrast we could not confirm the results of Yamauchi et al. We did not find an association between PTH levels in G990R. The pathophysiological importance of these results has to be discussed.

References: Correa et al. Surgery 132 (3) 450–455, 2002;

Yamauchi et al. Clin. Endocrinol.55, 373–379, 2001;

Cole et al. Molecular Genetics and Metabolism 72, 168–174, 2001