Gene variants of osteoprotegerin, estrogen-, calcitonin- and vitamin D-receptor genes and serum markers of bone metabolism in patients with Gaucher disease type 1

Abstract

Purpose

Osteopathy/osteoporosis in Gaucher disease type 1 (GD1) shows variable responses to enzyme replacement therapy (ERT); the pathogenesis is incompletely understood. We aimed to investigate the effects of several gene variants on bone mineral density (BMD) and serum markers of bone metabolism in GD1.

Patients and methods

Fifty adult Caucasian patients with GD1/117 controls were genotyped for gene variants in the osteoprotegerin (TNFRSF11B; OPG), estrogen receptor alpha, calcitonin receptor (CALCR), and vitamin D receptor (VDR) genes. In patients and 50 matched healthy controls, we assessed clinical data, serum markers of bone metabolism, and subclinical inflammation. BMD was measured for the first time before/during ERT (median 6.7 years).

Results

Forty-two percent of patients were splenectomized. ERT led to variable improvements in BMD. Distribution of gene variants was comparable between patients/controls. The AA genotype (c.1024+283G>A gene variant; VDR gene) was associated with lower Z scores before ERT vs GA (P=0.033), was encountered in 82.3% of patients with osteoporosis and was more frequent in patients with pathological fractures. Z score increases during ERT were higher in patients with the CC genotype (c.9C>G variant, TNFRSF11B; OPG gene; P=0.003) compared with GC (P=0.003). The CC genotype (c.1340T>C variant, CALCR gene) was associated with higher Z scores before ERT than the TT genotype (P=0.041) and was absent in osteoporosis. Osteocalcin and OPG were lower in patients vs controls; beta crosslaps, interleukin-6, and ferritin were higher.

Conclusions

We suggest for the first time a protective role against osteoporosis in GD1 patients for the CC genotype of the c.9C>G gene variant in the TNFRSFB11 (OPG) gene and for the CC genotype of the c.1340T>C gene variant (CALCR gene), while the AA genotype of the c.1024+283G>A gene variant in the VDR gene appears as a risk factor for lower BMDs. Serum markers suggest decreased osteosynthesis, reduced inhibition of osteoclast activation, increased bone resorption, and subclinical inflammation during ERT.

Keywords:

• Gaucher disease
• gene variants
• osteoporosis
• vitamin D receptor
• osteoprotegerin
• calcitonin receptor

Acknowledgments

The manuscript has been checked for spelling and grammar by a professional English editing service. We thank Mrs Adriana Degreif for excellent technical assistance. This work was supported by a research grant from SC Sanofi-Aventis Romania to the Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. The grant covered purchasing chemicals for genotyping and measurement of serum markers of bone metabolism. The project was designed as a scientific cooperation between the Center of Genetic Diseases, 1st Pediatric Clinic of the Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania (PG-S) and the 1st Medical Clinic and Polyclinic, Department of Endocrinology and Metabolic Diseases of the University of Mainz (AZ). The funding source was not involved in study design, data collection, conduct of research, analysis and interpretation of data, writing of the manuscript, and in the decision to submit the article for publication.

Author contributions

AZ designed the study and prepared the first draft of the paper. RAP, HR, SB, IN, and MMW contributed to data acquisition. DL was responsible for statistical analysis of the data. PG-S was also responsible for conception and design and is the guarantor. All authors revised the paper critically for important intellectual content and approved the final version. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors confirm independence from the sponsors. The content of the article has not been influenced by the sponsors. PG-S discloses that she received a research grant designed as cooperation between the University of Medicine and Pharmacy Cluj and the University of Mainz and speaker fees at National Symposia on Lysosomal Diseases sponsored by Sanofi-Genzyme. There is no relationship to any own or company-associated patents and no nonfinancial competing interest. The authors report no other conflicts of interest in this work.