孟德尔随机化研究职业性严寒暴露与冻结肩

doi:10.3877/cma.j.issn.1674-134X.2025.05.001

目的

本研究旨在通过孟德尔随机化方法，评估严寒环境工作暴露与冻结肩风险之间的因果关联，为职业健康防护提供科学依据。

方法

本研究采用两样本孟德尔随机化设计，利用英国生物样本库的暴露数据和芬兰FinnGen数据库的结局数据进行分析。工具变量为与职业性严寒暴露显著相关的遗传变异，主要采用逆方差加权法进行因果效应估计，并通过敏感性分析检验结果的稳健性。

结果

研究结果表明，有时暴露于严寒环境与冻结肩风险显著相关[比值比（OR）=2.78，95%置信区间（CI）（1.17，6.57），P=0.020]，而几乎不暴露和经常暴露未观察到显著关联。敏感性分析结果进一步验证了主要结论的稳健性。

结论

孟德尔随机化方法提示了职业性严寒暴露与冻结肩发病之间的因果关联，有时暴露于严寒环境可能是冻结肩的关键风险因素。

关键词: 职业性暴露, 肩凝症, 孟德尔随机化分析, 因果律

Objective

To evaluate the causal association between occupational severe cold exposure and the risk of frozen shoulder using Mendelian randomization (MR), and to provide evidence for occupational health interventions.

Methods

A two-sample MR design was conducted using exposure data from the UK Biobank and outcome data from the FinnGen database. Genetic variants significantly associated with severe cold exposure were employed as instrumental variables. The inverse variance-weighted method was the primary approach for causal effect estimation, supplemented by sensitivity analyses to ensure robustness.

Results

The results indicated a significant association between occasional severe cold exposure and an increased risk of frozen shoulder [odds ratio (OR) = 2.78, 95% confidence interval (CI) (1.17, 6.57), P=0.020]. No significant associations were observed for rare or frequent severe cold exposure. Sensitivity analyses confirmed the robustness of these findings.

Conclusion

MR study indicates causal evidence linking severe cold exposure to frozen shoulder risk, occasional exposure to severe cold environments may represent a key risk factor for frozen shoulder.

Key words: Occupational exposure, Bursitis, Mendelian randomization analysis, Causality

图1 暴露与结局的MR（孟德尔随机化）分析结果注：SNP-单核苷酸多态性；OR-比值比；CI-置信区间；OR>1提示暴露为结局风险因素；OR<1提示暴露为结局的保护因素；OR（95% CI）上下界均>1或<1、且P<0.05时，为差异有统计学意义

Figure 1 The results of the MR (Mendelian randomization) analysis of exposure and outcomeNote: SNP-single nucleotide polymorphism; OR-odds ratio; CI-confidence interval; OR>1indicates that the exposure is a risk factor for the outcome; OR<1 indicates that the exposure is a protective factor for the outcome; if the upper and lower bounds of OR (95% CI) are both greater than one or less than one, and P<0.05, the difference is statistically significant

图2 暴露与结局的MR（孟德尔随机化）分析散点图

Figure 2 Scatter plot of MR (Mendelian randomization) analysis of exposure and outcome

图3 敏感性分析结果。图A~C为是否暴露于严寒环境与冻结肩MR（孟德尔随机化）分析的漏斗图；图A为几乎不暴露；图B为有时暴露；图C为经常暴露；图D~F为是否暴露于严寒环境"留一法"分析森林图；图D为几乎不暴露；图E为有时暴露；图F为经常暴露注：漏斗图对称性表明无明显异质性；"留一法"分析显示显著因果关系的结果在逐个剔除单核苷酸多态性后结果具有稳定性

Figure 3 Sensitivity analysis results. A to C are the funnel plots for the MR (Mendelian randomization) analysis of whether exposure to extreme cold environment and frozen shoulder; A represents rarely exposure; B represents sometimes exposure; Figure C represents often exposure; D to F are the forest plots for the "leave-one-out" method analysis of whether exposure to extreme cold environment; D represents rarely exposure; E represents sometimes exposure; F represents often exposureNote: The symmetry of the funnel plot indicates the absence of significant heterogeneity; the "leave-one-out" analysis shows that the results with significant causal relationships remain stable after each single nucleotide polymorphism is excluded one by one

表1 暴露于严寒工作环境与冻结肩的敏感性分析

Table 1 Sensitivity analysis on sever cold work environment and frozen shoulder

结局Outcome	暴露Exposure	分析方法Methods	Q	Q_df	Q_pval	Egger截距Egger intercept	SE	P值	MR-PRESSO全局性测试Global test of MR-PRESSO
冻结肩Frozen shoulder	很少/从不会Rarely or never	MR Egger	6.660	9	0.672	0.029	0.017	0.134	0.505
	很少/从不会Rarely or never	IVW	9.376	10	0.497
	有时会Sometimes	MR Egger	4.449	7	0.727	-0.002	0.027	0.949	0.835
	有时会Sometimes	IVW	4.453	8	0.814
	经常Often	MR Egger	10.727	16	0.826	-0.005	0.014	0.709	0.877
	经常Often	IVW	10.872	17	0.863

表1 暴露于严寒工作环境与冻结肩的敏感性分析

Table 1 Sensitivity analysis on sever cold work environment and frozen shoulder

结局Outcome	暴露Exposure	分析方法Methods	Q	Q_df	Q_pval	Egger截距Egger intercept	SE	P值	MR-PRESSO全局性测试Global test of MR-PRESSO
冻结肩Frozen shoulder	很少/从不会Rarely or never	MR Egger	6.660	9	0.672	0.029	0.017	0.134	0.505
	很少/从不会Rarely or never	IVW	9.376	10	0.497
	有时会Sometimes	MR Egger	4.449	7	0.727	-0.002	0.027	0.949	0.835
	有时会Sometimes	IVW	4.453	8	0.814
	经常Often	MR Egger	10.727	16	0.826	-0.005	0.014	0.709	0.877
	经常Often	IVW	10.872	17	0.863

表2 暴露于严寒工作环境与冻结肩的共定位分析

Table 2 Co-location analysis on sever cold work environment and frozen shoulder

暴露序列Trait-exposure	结果序列Trait-outcome	SNP	PPH0	PPH1	PPH2	PPH3	PPH4
很少或从不会暴露Rarely or never	冻结肩frozen shoulder	412	0.0244	0.8813	0.0014	0.0514	0.0415
有时会暴露Sometimes		503	0.0026	0.9688	0.0000	0.0166	0.0119
经常会暴露Often		361	0.0247	0.9239	0.0004	0.0163	0.0347

表2 暴露于严寒工作环境与冻结肩的共定位分析

Table 2 Co-location analysis on sever cold work environment and frozen shoulder

暴露序列Trait-exposure	结果序列Trait-outcome	SNP	PPH0	PPH1	PPH2	PPH3	PPH4
很少或从不会暴露Rarely or never	冻结肩frozen shoulder	412	0.0244	0.8813	0.0014	0.0514	0.0415
有时会暴露Sometimes		503	0.0026	0.9688	0.0000	0.0166	0.0119
经常会暴露Often		361	0.0247	0.9239	0.0004	0.0163	0.0347

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Mendelian randomization study on occupational cold exposure and frozen shoulder

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Mendelian randomization study on occupational cold exposure and frozen shoulder