中国绝经后低骨密度女性中NF-κB信号通路相关基因多态性与阿仑膦酸盐治疗反应的关联
Association between NF-B Signal Pathway-Related Gene Polymorphisms and Response to Alendronate Treatment in Postmenopausal Chinese Women with Low Bone Mineral Density.
作者信息
Shen Xiaoyi, Tan Sasa, Feng Xianzhen, Fu Wenzhen, Hu Yunqiu, Li Miao, Wang Wenjie, Yuan Hu, Liu Li, Wang Chun, Hua Fei
机构信息
Department of Endocrinology, The Third Affiliated Hospital of Soochow University, 185, Juqian Street, Changzhou 213003, China.
Shanghai Clinical Research Center of Bone Disease, Department of Osteoporosis and Bone Disease, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China.
出版信息
Evid Based Complement Alternat Med. 2022 Mar 24;2022:2461716. doi: 10.1155/2022/2461716. eCollection 2022.
BACKGROUND
Osteoporosis is a systemic bone disease characterized by reduction of bone content. Bisphosphonates are first-line treatments for osteoporosis, but they have variable effectiveness. Genetic factors may explain these differences. The NF-B signaling pathway plays a key role in the regulation of bone metabolism. We aimed to determine whether genetic variations in the NF-B signaling pathway affect the effectiveness of alendronate in postmenopausal Chinese women with low bone mass.
METHODS
We recruited 455 postmenopausal Han Chinese women with primary osteoporosis or osteopenia aged 48-90 yrs who had experienced no spontaneous menses for at least 1 yr. All participants had dual X-ray absorptiometry (DEXA) bone mineral density (BMD) measurement at baseline and 1 yr after treatment. Treatment involved 1 yr administration of 70 mg oral alendronate weekly and 600 mg calcium and 125 IU of vitamin D daily. Thirteen tagSNPs in NF-B1 (rs28362491, rs3774937, rs230521, rs230510, and rs4648068), RELA (rs7119750, rs11820062), and NLRC5 (rs289747, rs1566439, rs1684575, rs289726, rs289723, and rs41383) were chosen from the NCBI Locus Link and HapMap and genotyped individually. Genetic variation in these genes and the corresponding therapeutic response to alendronate treatment were analyzed.
RESULTS
Among the 13 tagSNPs, rs289747 was significantly correlated with the BMD change rate at the femoral neck (=0.048). This significance no longer existed after Bonferroni correction. We then performed principal component analysis (PCA) and found NLRC5 (rs289747 and rs1566439) were strongly correlated with alendronate efficacy in femoral phenotypes and were major components of BMD change values, particularly total hip and intertrochanteric phenotypes. Furthermore, the PLINK linear regression GLM model revealed that haplotype TT of RELA (rs7119750 and rs11820062) and ICCTA of NF-B1 (rs28362491, rs3774937, rs230521, rs230510, and rs4648068) were associated with BMD of the total hip among each haplotype after 1 yr of treatment.
CONCLUSION
The NFB1, RELA, and NLRC5 genetic variations affect the therapeutic response of alendronate treatment for postmenopausal osteoporosis.
背景
骨质疏松症是一种以骨量减少为特征的全身性骨病。双膦酸盐类药物是骨质疏松症的一线治疗药物，但它们的疗效存在差异。遗传因素可能解释这些差异。核因子-κB（NF-κB）信号通路在骨代谢调节中起关键作用。我们旨在确定NF-κB信号通路中的基因变异是否会影响阿仑膦酸钠对绝经后低骨量中国女性的疗效。
方法
我们招募了455名年龄在48 - 90岁的绝经后汉族女性，她们患有原发性骨质疏松症或骨量减少，且至少1年无自然月经。所有参与者在基线和治疗1年后均进行了双能X线吸收法（DEXA）骨密度（BMD）测量。治疗包括每周口服70mg阿仑膦酸钠1年，每日补充600mg钙和125IU维生素D。从美国国立生物技术信息中心（NCBI）的基因座链接和国际人类基因组单体型图（HapMap）中选择了NF-κB1（rs28362491、rs3774937、rs230521、rs230510和rs4648068）、RELA（rs7119750、rs11820062）和NLRC5（rs289747、rs1566439、rs1684575、rs289726、rs289723和rs41383）中的13个标签单核苷酸多态性（tagSNP），并分别进行基因分型。分析这些基因的遗传变异与阿仑膦酸钠治疗相应的治疗反应。
结果
在这13个标签单核苷酸多态性中，rs289747与股骨颈骨密度变化率显著相关（P = 0.048）。经Bonferroni校正后，这种显著性不再存在。然后我们进行了主成分分析（PCA），发现NLRC5（rs289747和rs1566439）与股骨表型的阿仑膦酸钠疗效密切相关，并且是骨密度变化值的主要组成部分，特别是全髋和转子间表型。此外，PLINK线性回归广义线性模型（GLM）显示，治疗1年后，RELA（rs7119750和rs11820062）的单倍型TT以及NF-κB1（rs28362491、rs3774937、rs230521、rs230510和rs4648068）的ICCTA与各单倍型的全髋骨密度相关。
结论
NF-κB1、RELA和NLRC5基因变异影响阿仑膦酸钠治疗绝经后骨质疏松症的治疗反应。
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