"Single nucleotide polymorphisms of the OPG/RANKL system genes in primary hyperparathyroidism and their relationship with bone mineral density"

Abstract

BackgroundPrimary hyperparathyroidism (PHPT) affects mainly cortical bone. It is thought that parathyroid hormone (PTH) indirectly regulates the activity of osteoclasts by means of the osteoprotegerin/ligand of the receptor activator of nuclear factor-κβ (OPG/RANKL) system. Several studies have confirmed that OPG (osteoprotegerin) and RANKL (ligand of the receptor activator of nuclear factor-κβ) loci are determinants of bone mineral density (BMD) in the general population. The aim of this study is to analyze the relationship between fractures and BMD and the rs3102735 (163 A/G), rs3134070 (245 T/G) and rs2073618 (1181 G/C) SNPs of the OPG and the rs2277438 SNP of the RANKL, in patients with sporadic PHPT.MethodsWe enrolled 298 Caucasian patients with PHPT and 328 healthy volunteers in a cross-sectional study. We analyzed anthropometric data, history of fractures or renal lithiasis, biochemical determinants including markers for bone remodelling, BMD measurements in the lumbar spine, total hip, femoral neck and distal radius, and genotyping for the SNPs to be studied.ResultsRegarding the age of diagnosis, BMI, menopause status, frequency of fractures or renal lithiasis, we found no differences between genotypes in any of the SNPs studied in the PHPT group. Significant lower BMD in the distal radius with similar PTH levels was found in the minor allele homozygotes (GG) compared to heterozygotes and major allele homozygotes in both OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs in those with PHPT compared to control subjects. We found no differences between genotypes of the OPG rs2073618 (1181 G/C) SNP with regard to BMD in the PHPT subjects. In the evaluation of rs2277438 SNP of the RANKL in PHPT patients, we found a non significant trend towards lower BMD in the 1/3 distal radius and at total hip in the minor allele homocygotes (GG) genotype group versus heterocygotes and major allele homocygotes (AA).ConclusionsOur study provides the first evaluation of the relationship between SNPs of the OPG/RANK system and sporadic PHPT. Subjects with PHPT and minor homocygote genotype (GG) for the OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs have lower BMD in the distal radius, and this association does not appear to be mediated by differences in PTH serum levels.

Genetic polymorphism of the OPG gene associated with breast cancer

“…In detail, concerning the rs3102735 SNP the G allele was more common among fracture patients [28,34] and patients with lower BMD at the distal radius [30]. Furthermore, there is an association within a subgroup of postmenopausal patients carrying the minor allele and a lower calcaneal velocity of sound [36].…”

RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus

“…To check the quality of the genotyping, 30 random samples (8.2 %) were analyzed twice [16], and the results showed a 98 % concordance. Discordant samples were analyzed three times, and concordant results are presented.…”

“…The RANKL 290 A>G, OPG 1181 G>C, 245 T>G, and 163 A>G and RANK A>G SNPs were chosen because they are the SNPs most frequently cited in the literature as being associated with decreased BMD and increased fractures [9,[15][16][17].…”

Polymorphisms of the vitamin D receptor and their effect on bone mass density in patients with normocalcemic hyperparathyroidism

“…This is consistent with the high bone turnover observed in our patients. This fact has been observed by other authors [11][12][13]. The key role of RANKL was demonstrated by Nakchbadi et al [14], who found an increase in RANKL in patients with HPT that correlated with resorption markers.…”