BMI与肩关节撞击综合征的因果关系：来自孟德尔随机化的证据

doi:10.3877/cma.j.issn.2095-5790.2025.04.005

目的

应用孟德尔随机化（Mendelian randomization, MR）研究方法联合生物信息分析及全球疾病负担（global burden of disease, GBD）数据库分析，探究体重指数（body mass index, BMI）与肩关节撞击综合征之间的因果关系。

方法

基于欧洲人群全基因组关联研究（genome-wide association studies, GWAS）数据筛选BMI相关单核苷酸多态性（single nucleotide polymorphisms, SNP）作为工具变量，通过逆方差加权法（inverse-variance weighted, IVW）等五种方法结合基因富集分析及GBD数据库验证人群负担并构建回归模型。

结果

共纳入390例SNP患者，IVW等五种方法分析显示：BMI每增加1个单位，肩关节撞击综合征风险提升0.2%（OR=1.002，95% CI: 1.001~1.003），基因富集分析提示BMI可能通过离子通道调控、突触信号传导及Rap1信号通路影响肩关节撞击综合征。药物预测发现劳拉西泮及匹立尼酸等潜在治疗药物。GBD数据分析显示高BMI可增加肌肉骨骼疾病伤残调整寿命年。

结论

研究从遗传因果和人群负担双重角度证实高BMI是肩关节撞击综合征的重要危险因素，为靶向干预提供理论依据，但需进一步验证种族普适性及分子机制。

关键词: 体重指数, 肩关节撞击综合征, 孟德尔随机化, 富集分析, 人群负担分析

Background

Shoulder impingement syndrome is a common shoulder disorder characterized by a structural narrowing of the subacromial space, which causes pain when patients raise their arms or lie on the affected side. Current research suggests that preventing obesity can reduce the incidence of shoulder joint-related diseases, and obesity is positively correlated with rotator cuff ligament injury. Moreover, body mass index (BMI) can serve as a simple method to measure the degree of obesity, as it is easy to obtain and has clear categories. However, some studies suggest that a high BMI can have a specific protective effect on the shoulder joint. Therefore, the causal relationship between BMI and shoulder impingement syndrome awaits further study.

Objective

To explore the causal relationship between BMI and shoulder impingement syndrome by combining Mendelian randomization (MR) research method with bioinformatics analysis and analysis of the global burden of disease (GBD) database.

Methods

Based on the data of genome-wide association studies (GWAS) in European populations, BMI-related single-nucleotide polymorphisms (SNP) were screened as instrumental variables. The population burden was verified, and a regression model was constructed by combining five methods, including inverse variance weighted (IVW) with gene enrichment analysis and the GBD database.

Results

A total of 390 cases of SNP were included. The analysis by five methods, including the inverse variance weighting method, showed that: For every 1-unit increase in BMI, the risk of shoulder impingement syndrome increases by 0.2% (OR=1.002, 95% CI: 1.001-1.003). Gene enrichment analysis suggests that BMI may influence shoulder impingement syndrome through the regulation of ion channels, synaptic signal transduction, and the Rap1 signaling pathway. Drug prediction has identified potential therapeutic drugs such as lorazepam and pilocarpine acid. GBD data analysis shows that a high BMI can increase the disability-adjusted life years for musculoskeletal diseases.

Conclusion

The research, from both genetic causality and population burden perspectives, confirmed that high BMI is an important risk factor for shoulder impaction syndrome, providing a theoretical basis for targeted intervention. However, further verification of racial universality and molecular mechanisms is needed.

Key words: Body mass index, Shoulder impingement syndrome, Mendelian randomization, Enrichment analysis, Population burden analysis

图1 两样本MR设计思路注：MR为孟德尔随机化；BMI为体重指数

表1 BMI与肩关节撞击综合征GWAS数据来源特征

特征描述	GWAS ID	样本量	SNP个数	人种	性别	数据下载地址
BMI	ukb-b-19953	461 460	9 851 867	欧洲	男性+女性	https://gwas.mrcieu.ac.uk/datasets/
肩关节撞击综合征	ukb-b-1418	463 010（2 901:460 109）	9 851 867	欧洲	男性+女性	https://gwas.mrcieu.ac.uk/datasets/

表1 BMI与肩关节撞击综合征GWAS数据来源特征

特征描述	GWAS ID	样本量	SNP个数	人种	性别	数据下载地址
BMI	ukb-b-19953	461 460	9 851 867	欧洲	男性+女性	https://gwas.mrcieu.ac.uk/datasets/
肩关节撞击综合征	ukb-b-1418	463 010（2 901:460 109）	9 851 867	欧洲	男性+女性	https://gwas.mrcieu.ac.uk/datasets/

图2 MR分析的散点图注：MR为孟德尔随机化；SNP为单核苷酸多态性；BMI为体重指数；IVW为逆方差加权法

图3 MR分析结果的漏斗图注：MR为孟德尔随机化；IVW为逆方差加权法

表2 BMI与肩关节撞击综合征MR分析结果

分析方法	OR（95% CI）	P值	Cochran's Q（P值）	MR-Egger回归截距（P值）
MR-Egger回归法	1.00（0.997~1.003）	0.989	417.711（0.144）	2.161×10^-5（0.712）
加权中位数	1.002（1.00~1.004）	0.016 8
IVW	1.002（1.001~1.003）	<0.001	419.722（0.136）
加权模型	1.00（0.996~1.003）	0.918
简单模型	1.001（0.996~1.007）	0.651

表2 BMI与肩关节撞击综合征MR分析结果

分析方法	OR（95% CI）	P值	Cochran's Q（P值）	MR-Egger回归截距（P值）
MR-Egger回归法	1.00（0.997~1.003）	0.989	417.711（0.144）	2.161×10^-5（0.712）
加权中位数	1.002（1.00~1.004）	0.016 8
IVW	1.002（1.001~1.003）	<0.001	419.722（0.136）
加权模型	1.00（0.996~1.003）	0.918
简单模型	1.001（0.996~1.007）	0.651

图4 GO与KEGG富集分析结果（柱状图）注：GO为基因本体；KEGG为京都基因与基因组百科全书

图5 GO与KEGG富集分析结果（气泡图）注：GO为基因本体；KEGG为京都基因与基因组百科全书

图6 EBF1基因与劳拉西泮结合能-4.811 kcal/mol

图7 TENM2与匹立尼酸结合能-6.199 kcal/mol

图8 EBF1基因与匹立尼酸结合能-5.322 kcal/mol

图9 全球高BMI归因负担（X）与肌肉骨骼肉骨疾病DALYs率（Y）关联散点图注：DALYs为伤残调整生命年

图10 1990~2021年全球BMI均值与肌疾病DALYs率变化趋势图注：BMI为体重指数；DALYs为伤残调整生命年

图11 肌肉骨骼疾病DALYs率实际观测值与理论预测值对比图注：DALYs为伤残调整寿命年；MR为孟德尔随机化

表3 肩关节撞击综合征在肌肉骨骼疾病的DALYs中占比的推算过程

序号	参数项描述	数据值	数据来源	推算公式/说明	中间结果
1	全球肌肉骨骼疾病总DALYs	150 000 000 DALYs	GBD 2021年^[7]	作为基准总量
2	颈部疼痛占肌肉骨骼疾病比例	14.3%	GBD 2021年^[8]	150 000 000 × 14.3%	21 450 000 DALYs
3	肩部疾病占颈肩合并病中的比例	40%~60%	系统综述^[9]	21 450 000 × 40%~60%	8 580 000~12 870 000 DALYs
4	推算肩部占肌肉骨骼疾病总DALYs比例	—	计算所得	（8.58~12.87） / 150 ≈ 5.7%~8.6%	≈5%~10%（四舍五入）
5	上肢肌肉骨骼疾病疾病中肩部占比	26.9%	上肢研究综述^[10]	辅助支持，非直接参与计算	提示肩部疾病负担居前
6	Δ肩关节撞击综合征DALYs率	5%~10%	计算所得	β1（20.52）×（5%~10%）×（44%~65%）	0.410 4~1.231 2/100 000 高BMI归因百分比每增加1%，肩关节撞击综合征DALYs上升：0.410 4~1.231 2/100 000
7	公共卫生意义量化示例	0.410 4~1.231 2/100 000	计算所得	按中国14亿人 0.410 4~1.231 2/100 000×14亿÷100 000	5 797~17 388 即每降低1%的高BMI归因负担，可避免5 797~17 388例肩关节撞击综合征相关健康寿命损失

表3 肩关节撞击综合征在肌肉骨骼疾病的DALYs中占比的推算过程

序号	参数项描述	数据值	数据来源	推算公式/说明	中间结果
1	全球肌肉骨骼疾病总DALYs	150 000 000 DALYs	GBD 2021年^[7]	作为基准总量
2	颈部疼痛占肌肉骨骼疾病比例	14.3%	GBD 2021年^[8]	150 000 000 × 14.3%	21 450 000 DALYs
3	肩部疾病占颈肩合并病中的比例	40%~60%	系统综述^[9]	21 450 000 × 40%~60%	8 580 000~12 870 000 DALYs
4	推算肩部占肌肉骨骼疾病总DALYs比例	—	计算所得	（8.58~12.87） / 150 ≈ 5.7%~8.6%	≈5%~10%（四舍五入）
5	上肢肌肉骨骼疾病疾病中肩部占比	26.9%	上肢研究综述^[10]	辅助支持，非直接参与计算	提示肩部疾病负担居前
6	Δ肩关节撞击综合征DALYs率	5%~10%	计算所得	β1（20.52）×（5%~10%）×（44%~65%）	0.410 4~1.231 2/100 000 高BMI归因百分比每增加1%，肩关节撞击综合征DALYs上升：0.410 4~1.231 2/100 000
7	公共卫生意义量化示例	0.410 4~1.231 2/100 000	计算所得	按中国14亿人 0.410 4~1.231 2/100 000×14亿÷100 000	5 797~17 388 即每降低1%的高BMI归因负担，可避免5 797~17 388例肩关节撞击综合征相关健康寿命损失

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Causal relationship between BMI and impingement syndrome of shoulder: evidence from Mendelian randomization

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Causal relationship between BMI and impingement syndrome of shoulder: evidence from Mendelian randomization