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

PurposeOsteopathy/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 methodsFifty 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).ResultsForty-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.ConclusionsWe 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.

Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review

“…Studies on vitamin D receptor (VDR) gene polymorphisms have become popular recently in the general population and in specific groups of patients, including GD1 patients. The AA genotype of the c.1024 + 283G > A (rs1544410) gene variant in the VDR gene seems to be a risk factor for low BMD, osteoporosis and pathological fracture in GD1 patients [98]. VDR Bsml polymorphism was associated with skeletal involvement, including osteonecrosis and/or pathological fractures, in GD1 subjects [99].…”

Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis

“…Moreover, text-mining identified a study indicating that the expression of glucocerebrosidase gene is affected by JUN ( Moran et al, 1997 ), a TF that in our network regulates IL10 , IL1B , CCL2 , TNF , and CXCL12 . Finally, we identified several studies reporting polymorphisms in the VDR gene possibly associated with GD phenotypes ( Vlieger et al, 2002 ; Greenwood et al, 2010a , b ; Lieblich et al, 2011 ; Zhang et al, 2012 ; Mistry et al, 2013 ; Gervas-Arruga et al, 2015 ; Zimmermann et al, 2018 ; Kałużna et al, 2019 ).…”

TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

“…Accumulated findings indicate that OPG-related osteoclast activity is not a major mechanism of bone pathology in GD patients with relatively mild form [33]. However, there is still controversy regarding RANKL/OPG and its effects on GD bone pathology [34]. The genetic variability of OPG and RANK genes in GD may also play a role in the GD bone pathology with its response to treatment.…”