C950T and C1181G Osteoprotegerin Gene Polymorphisms In Myeloma Bone Disease

Bone disease is one of the hallmarks of multiple myeloma (MM). The role of osteoprotegerin (OPG) in the RANK/RANKL/OPG signaling system is well defined in the myeloma bone disease. Polymorphisms of the TNFRSF11B gene encoding OPG have been studied in various bone diseases. However, relationship between the levels of OPG and development of bone lesions regardless of RANKL is yet unknown. In this study, the effects of OPG gene polymorphism on the development of bone lesions in MM were investigated.

52 MM patients, admitted to Karadeniz Technical University, Medical Faculty, Department of Internal Medicine, Division of Hematology between March 2011 and March 2012, were included into the study. Pathologic fracture and/or destructive bone lesions were confirmed in 36 MM patients using X-ray, computed tomography (CT), or magnetic resonance imaging (MRI). No bone lesions were noted in 16 patients. The control group consisted of 20 age and gender matched volunteers.

Exon 1 of OPG gene was sequenced using DNA samples obtained from peripheral blood samples of 52 MM patients and 20 healthy control subjects. OPG gene C950T and C1181G polymorphisms were identified in 45 (33 with bone lesions) MM patients and in 16 control subjects. Polymorphic allele 1181G was higher in MM patients with bone lesions compared to MM patients without bone lesions and control group (χ²=8.629, p=0.013). Other polymorphic allele 950T was also overrepresented (73%; p=0.042) in MM patients with bone lesions compared to MM patients without bone lesions and the control group. The most frequent genotype observed in patients with myeloma bone lesions was 950 TT homozygous variant (56%, p=0.08) followed by 1181 CC homozygous wild type with 50% frequency (p=0.09). The frequency of 950 CT heterozygous genotype was higher in MM patients without bone lesions (50%, p=0.604). 1181 GG genotype showed higher frequency in MM patients with bone lesions compared to patients without bone lesions and control group (χ²=3.853, p=0.145). Of the combined haplotypes, 950 TT/1181 GG haplotype frequency is higher in patients with myeloma bone lesions (36%) compared to MM patients without bone lesions (13%) and controls (15%) (χ²=4.77, p=0.09). The frequency of TT/GG combined haplotype carriers in bone disease patients is higher than of those who do not have either polymorphic homozygous alleles (CT/CC and CC/CC haplotypes) (χ²=6.057, p=0.048). Additionally, 950 CC/1181CC wild type haplotype frequency was reasonably low in patients with myeloma bone lesions (8.3%, p=0.240).

This is the first study searching for the relationship between OPG gene variants C950T (promoter), C1181G (exon 1) and myeloma bone disease. It was concluded that the presence of polymorphic 1181 G/950 T alleles and 950 TT/1181 GG genotypes may play a role in the development of bone disease.