甲状旁腺功能亢进与骨质疏松症之间的因果关系:双向两样本孟德尔随机化研究

The causal relationship between osteoporosis and hyperparathyroidism:a bidirectional two sample Mendelian randomization study

目的:通过双向、两样本孟德尔随机化的方法探讨骨质疏松症与原发性甲状旁腺功能亢进之间的因果关系并判断二者间有无反向因果存在。方法:从英国生物样本数据库(UK Biobank)中获得与骨质疏松症与从芬兰数据库(FinnGen)中获取原发性甲状旁腺功能亢进相关的单核苷酸多态性(SNP),使用随机效应逆方差加权法(Inverse-Variance Weighted,IVW)为主要模型,结合MR-Egger回归、加权中位数法(Weighted Median,WME)、simple mode和基于模式的估计法(weighted mode)四种回归模型评估因果效应,再对其敏感性、异质性、多效性检验以评估结果的稳定性和可靠性。结果:对于筛选后的原发性甲状旁腺功能亢进与骨质疏松症GWAS数据以IVW为主要分析模型,骨质疏松症对原发性甲状旁腺功能亢进IVW结果为OR=0.960,95%CI=0.433~2.13,P=0.551,因果效应无显著性(P>0.05);原发性甲状旁腺功能亢进对骨质疏松症IVW结果为OR=0.998,95%CI=0.996~1.000,P=0.036,因果效应存在统计学意义(P<0.05),多种敏感性分析显示研究不存在敏感性,多效性和异质性,说明结果具有稳健性。结论:利用双向、两样本孟德尔随机化方法从遗传变异角度印证原发性甲状旁腺功能亢进与骨质疏松症之间存在因果关系,且不能从遗传变异角度证明骨质疏松症与原发性甲状旁腺功能亢进的因果关系,贴合临床过程中生理、病理相关机制,二者之间不存在反向因果关系。有助于对骨质疏松症与甲状旁腺功能亢进的临床诊疗,为二者之间发病机制研究提供了参考。

Objective:To explore the causal relationship between osteoporosis and primary hyperparathyroidism,we used a bidirectional,two-sample Mendelian randomization approach and assesses the presence of reverse causality between the two conditions.Methods:Single nucleotide polymorphisms(SNPs)related to osteoporosis were obtained from the UK Biobank,and SNPs related to primary hyperparathyroidism were obtained from the FinnGen database.The main analysis was conducted using the Inverse-Variance Weighted(IVW)method,and additional regression models,including MR-Egger,Weighted Median(WME),simple mode,and weighted mode,were used to evaluate causal effects.Sensitivity,heterogeneity,and pleiotropy tests were performed to assess the stability and reliability of the results.Results:Using the IVW method as the main analysis model for the selected GWAS data for primary hyperparathyroidism and osteoporosis,the IVW result for osteoporosis on primary hyperparathyroidism was OR=0.960,95%CI=0.433 to 2.13,P=0.551,indicating no significant causal effect(P>0.05).The IVW result for primary hyperparathyroidism on osteoporosis was OR=0.998,95%CI=0.996 to 1.000,P=0.036,indicating a statistically significant causal effect(P<0.05).Various sensitivity analyses showed no sensitivity,pleiotropy,or heterogeneity in the study,indicating the results has good robustness.Conclusion:Using a bidirectional,two-sample Mendelian randomization approach,we could not establish a causal relationship between osteoporosis and primary hyperparathyroidism from a genetic variation perspective.However,we confirmed a causal relationship between primary hyperparathyroidism and osteoporosis from a genetic variation perspective,aligning with clinical pathological and physiological mechanisms.There was no evidence of reverse causality between the two conditions.This study contributed to the clinical diagnosis and treatment of osteoporosis and primary hyperparathyroidism and provided a reference for the study of the underlying mechanisms between these two conditions.