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Julia Bársony, P. Lakatos, J. Földes and T. Fehér

Abstract. Twelve hypothyroid subjects, 13 healthy and 12 healthy women with a slight deficiency of vitamin D were studied to distinguish seasonal changes from the thyroxine-dependent ones. Serum 25-hydroxyvitamin D levels of hypothyroid patients were lower than those of healthy individuals when the sera were obtained in the autumn. In hypothyroid patients a single oral dose of 100 000 IU vitamin D3 resulted in a smaller increase in 25-hydroxyvitamin D concentration than in controls having subclinical exogenous vitamin D deficiency. Substitution therapy with thyroid hormone, started in our study always in autumn, increased the 25-hydroxyvitamin D concentration in hypothyroid patients, which was opposite to the autumn-to-spring variation of this hormone observed in healthy controls. The increase of 25-hydroxyvitamin D, dehydroepiandrosterone and its sulphate values following substitution therapy in the hypothyroid patients may indicate that thyroid hormone(s) is (are) involved in the regulation of steroid hormone synthesis.

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G Speer, K Cseh, G Winkler, P Vargha, E Braun, I Takacs and P Lakatos

OBJECTIVE: We studied the significance of BsmI restriction enzyme polymorphism of the vitamin D receptor (VDR) gene and the XbaI and PvuII polymorphisms of the estrogen receptor (ER) gene in patients with type 2 diabetes (n=49), android type obesity with normal carbohydrate metabolism (n=29) and healthy controls (n=138). METHODS: The distribution of genotypes in the study groups, as well as their relationship to fasting and 1 h postprandial serum C-peptide levels were analyzed. RESULTS: Postprandial serum C-peptide levels of BB genotypes were significantly higher in the diabetes and obese groups (6.18+/-5.09 ng/ml) compared with other genotypes (2.71+/-2.45 vs. 1.72+/-1.97 ng/ml, respectively, P=0.05). Among patients with type 2 diabetes and obese subjects, the XX allelic variant of the ER gene was more frequent (P=0.00015). Postprandial C-peptide levels of subjects exhibiting XX genotype were significantly lower compared with those with Xx genotype (1.67+/-2.16 vs. 3.8+/-3.72 ng/ml, P=0.021). The BBXx allelic combination of the VDR/ER receptor genes was less frequent in diabetic patients than in healthy subjects or in obese patients. The BBXx genotype was associated with significantly elevated postprandial C-peptide levels in all subjects compared with other combinations (9.65+/-3.14 vs. 1.35+/-2.82 ng/ml, P=0.003). No difference was found in the distribution of the PvuII polymorphism of the ER gene or in the association with the C-peptide levels among study groups. CONCLUSION: Polymorphisms of the VDR/ER receptor genes might play a role in the pathogenesis of type 2 diabetes by influencing the secretory capacity of beta-cells.

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István Takács, Áron Lazáry, János P Kósa, János Kiss, Bernadett Balla, Zsolt Nagy, Krisztián Bácsi, Gabor Speer and Péter Lakatos

Objective

Receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) signaling system plays a crucial role in the regulation of bone resorption. Polymorphic variations in the genes may have an influence on gene expression and bone metabolism. In the present study, we aimed to investigate the influence of RANKL/OPG allelic variations on the in vivo human gene expression of five genes, bone mineral density (BMD), and fracture incidence in Hungarian postmenopausal women.

Methods

Three hundred and sixty postmenopausal women (61.6±7.9 years) were genotyped. All together, five single nucleotide polymorphisms (SNPs) in the two genes have been investigated. In addition, bone samples from 17 examined subjects were acquired for gene expression studies. Bone densities and fracture data have also been collected.

Results

All two SNPs in OPG gene and three SNPs in RANKL gene showed correlation with BMD. Haplotype analysis of these genes gave similar results. The ‘CCT’ haplotype of RANKL promoter region, which was associated with decreased BMD, exhibited a significantly upregulated expression of RANKL mRNA, while the other haplotypes of RANKL or OPG 15 genes did not. No correlation between genetic variations and fracture data was found.

Conclusion

We have demonstrated associations between RANKL and OPG haplotypes and BMD as well as between RANKL haplotypes and in vivo RANKL expression in a Hungarian postmenopausal population. Moreover, we have found a new RANKL haplotype associating with reduced BMD and increased in vivo RANKL expression in human bone tissue.

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Áron Lazáry, János P Kósa, Bálint Tóbiás, Judit Lazáry, Bernadett Balla, Krisztián Bácsi, István Takács, Zsolt Nagy, Tibor Mező, Gábor Speer and Péter Lakatos

Objective

Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of 24 single nucleotide polymorphisms (SNPs) located in five genes – alkaline phosphatase, matrix metalloproteinase-2, tissue inhibitor of metalloproteases-2 (TIMP2), fibroblast growth factor receptor-1 (FGFR1), and fatty acid-binding protein-3 (FABP3) – previously not associated with OP.

Design

We performed a genotype–phenotype association study at a university hospital.

Methods

A total of 360 Hungarian postmenopausal women were involved in the study. Bone mineral density (BMD) was determined at spine, hip, and distal radius. Genomic DNA was extracted from venous blood samples and a high-throughput genotyping method based on single-based primer extension was applied for allelic discrimination. Robust statistical tools were utilized for multiplex data analysis.

Results

SNP rs6996321 in FGFR1 was significantly related to spine BMD (P=0.002) and rs10914367 in FABP3 was associated with hip BMD (P=0.028). Non-vertebral fracture risk was significantly increased in carriers of ‘A’ allele of rs9900972 in TIMP2 (odds ratio=2.06, P=0.0187). We could also identify validated gene–gene interactions significantly affecting BMD and fracture risk.

Conclusions

We identified two previously unreported SNPs in FGFR1 and FABP3 associated with BMD and a third SNP in TIMP2 related to risk for non-vertebral osteoporotic fractures. This is the first report about the association between these allelic variants and the phenotypes of postmenopausal OP. Further studies need to clarify the role of these genes and their polymorphisms in the process of bone loss.