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Article(id=1241522922444092302, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241522919977841545, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202308409, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1692460800000, receivedDateStr=2023-08-20, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773931731090, onlineDateStr=2026-03-19, pubDate=1710000000000, pubDateStr=2024-03-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773931731090, onlineIssueDateStr=2026-03-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773931731090, creator=13701087609, updateTime=1773931731090, updator=13701087609, issue=Issue{id=1241522919977841545, tenantId=1146029695717560320, journalId=1227665162245664772, year='2024', volume='51', issue='5', pageStart='769', pageEnd='960', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773931730503, creator=13701087609, updateTime=1773931880386, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241523548695622547, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241522919977841545, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241523548695622548, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241522919977841545, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=788, endPage=796, ext={EN=ArticleExt(id=1241522922771248021, articleId=1241522922444092302, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=A Mendelian randomized study on the causal relationship between glycemic traits and benign colorectal neoplasm, columnId=1240413921954295836, journalTitle=Modern Preventive Medicine, columnName=Epidemiology and Statistical Methods, runingTitle=null, highlight=null, articleAbstract=
Objective

To explore the causal relationship between the characteristics of glycemic traits (fasting blood glucose, fasting insulin, glycosylated hemoglobin, and insulin resistance) and benign colorectal neoplasm (colorectal adenomas, benign rectal neoplasm, and benign colon neoplasm).

Methods

The instrumental variables of blood glucose characteristics were extracted from MAGIC and GLGCL alliance, and the genome-wide data of colorectal benign tumors came from Finn-Gen alliance. In this study, random effect inverse-variance weighted method (IVW), MR-Egger regression, and weighted median method (WMM) were used to analyze the causal relationship between four glycemic traits and benign colorectal neoplasm.

Results

The results of IVW model showed that there was no causal relationship between fasting blood glucose (OR=0.999, 95%CI: 0.997-1.001), fasting insulin (OR=1.002, 95%CI: 0.998-1.006), glycosylated hemoglobin (OR=1.001, 95%CI: 0.999-1.004), insulin resistance (OR=0.999, 95%CI: 0.997-1.002), and colorectal adenoma. There was no causal relationship between fasting blood glucose (OR=0.909, 95%CI: 0.684-1.209), fasting insulin (OR=1.220, 95%CI: 0.706-2.107), glycosylated hemoglobin (OR=0.678, 95%CI:0.440-1.046), insulin resistance (OR=1.161, 95%CI: 0.810-1.663) and rectal benign tumor. There was no causal relationship between fasting blood glucose (OR=0.966, 95%CI: 0.836-1.116), fasting insulin (OR=1.318, 95%CI: 0.906-1.916), glycosylated hemoglobin (OR=1.124, 95%CI: 0.882-1.431), insulin resistance (OR=1.071, 95%CI: 0.875-1.311) and benign tumors of colon.

Conclusion

There is no evidence of causal relationships of fasting blood glucose, fasting insulin, glycosylated hemoglobin, and insulin resistance with colorectal adenomas, benign rectal neoplasm, and benign colon neoplasm.

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目的

探索血糖特征（空腹血糖、空腹胰岛素、糖化血红蛋白、胰岛素抵抗)与结直肠良性肿瘤（结直肠腺瘤、直肠良性肿瘤、结肠良性肿瘤）发病之间的因果关系。

方法

血糖特征的工具变量数据来自MAGIC和GLGCL联盟，结直肠良性肿瘤的全基因组数据来源于FinnGen联盟。研究采用随机效应逆方差加权法(inverse-variance weighted, IVW)、MR-Egger回归、加权中位数法(weighted median method,WMM)三种回归模型对四项血糖特征与结直肠良性肿瘤的因果关系进行孟德尔随机化分析。

结果

IVW模型计算结果显示空腹血糖（OR=0.999，95%CI：0.997～1.001）、空腹胰岛素（OR=1.002，95%CI：0.998～1.006）、糖化血红蛋白（OR=1.001，95%CI：0.999～1.004）、胰岛素抵抗（OR=0.999，95%CI：0.997～1.002）与结直肠腺瘤之间无因果关系；空腹血糖（OR=0.909，95%CI：0.684～1.209）、空腹胰岛素（OR=1.220，95%CI：0.706～2.107）、糖化血红蛋白（OR=0.678，95%CI：0.440～1.046）、胰岛素抵抗（OR=1.161，95%CI：0.810～1.663）与直肠良性肿瘤之间无因果关系；空腹血糖（OR=0.966，95%CI：0.836～1.116）、空腹胰岛素（OR=1.318，95%CI：0.906～1.916）、糖化血红蛋白（OR=1.124，95%CI：0.882～1.431）、胰岛素抵抗（OR=1.071，95%CI：0.875～1.311）与结肠良性肿瘤之间均无因果关联。

结论

本研究没有发现空腹血糖、空腹胰岛素、糖化血红蛋白、胰岛素抵抗与结直肠腺瘤、直肠良性肿瘤、结肠良性肿瘤发病之间的因果关系的证据。

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杨艳芳，E-mail:
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雷蕾（1998—），女，硕士在读，研究方向：流行病与卫生统计学

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注：图A、B、C暴露为空腹血糖；图D、E、F暴露为空腹胰岛素；图G、H、I暴露为HbA1c；图J、K、L暴露为胰岛素抵抗；图A、D、G、J结局为结直肠腺瘤；图B、E、H、K结局为直肠良性肿瘤；图C、F、I、L结局为结肠良性肿瘤。

, figureFileSmall=hZmHelVmriNbMWhoqWO4rA==, figureFileBig=D1pyycFci6ZNB/FJu5uJSg==, tableContent=null), ArticleFig(id=1241678323324089023, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241522922444092302, language=EN, label=Figure 4, caption=Mendelian randomized scatter diagram of four glycemic traits, figureFileSmall=DJ/NzrxxYrVV9l+nLahtZw==, figureFileBig=imBOIsdaGAxB+L44Vrs2Qg==, tableContent=null), ArticleFig(id=1241678323839988424, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241522922444092302, language=CN, label=图4, caption=血糖四项特征MR散点图

注：图A、B、C暴露为空腹血糖；图D、E、F暴露为空腹胰岛素；图G、H、I暴露为HbA1c；图J、K、L暴露为胰岛素抵抗；图A、D、G、J结局为结直肠腺瘤；图B、E、H、K结局为直肠良性肿瘤；图C、F、I、L结局为结肠良性肿瘤。

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注：图A、B、C暴露为空腹血糖；图D、E、F暴露为空腹胰岛素；图G、H、I暴露为HbA1c；图J、K、L暴露为胰岛素抵抗；图A、D、G、J结局为结直肠腺瘤；图B、E、H、K结局为直肠良性肿瘤；图C、F、I、L结局为结肠良性肿瘤。

, figureFileSmall=UAy4te4a4q4HjUyPZxXi9w==, figureFileBig=GDA58DlNeTJAdxLo1fvNuw==, tableContent=null), ArticleFig(id=1241678324804678361, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241522922444092302, language=EN, label=Table 1, caption=

GWAS summary data used in this study

, figureFileSmall=null, figureFileBig=null, tableContent=
因果方向变量来源PMID人群纳入标准人群排除标准样本量人群年份（年）
正向IRMAGIC22885924全人群（空腹整晚测得的血清血糖指标浓度）医生诊断为糖尿病；正在接受糖尿病治疗；或空腹血糖≥7 mmol/L，个别研究排除了包括怀孕、非禁食个体和1型糖尿病108 557欧洲2017
GLGC24097068全人群（禁食8h后测得血脂水平）已知服用降脂药物的人188 577欧洲
FIMAGIC全人群（禁食8h以上或者一整晚后测得的血清血糖指标浓度）医生诊断为糖尿病；正在接受糖尿病治疗；或FG≥7 mmol/L，或（和）HbA1c≥6.5%151 013欧洲2021
FGMAGIC34059833200 622欧洲2021
HbA1cMAGIC146 806欧洲2021
CRAUKBiobankhttps://gwas.mrcieu.ac.uk/datasets/ukb-b-14210/病例：患有结直肠腺瘤或者结直肠息肉对照：未患结直肠腺瘤或者息肉NA462 933(病例1 391，对照461 542)欧洲2018
BRNFinnGenhttps://finngen.gitbook.io/documentation/病例：经医院诊断为直肠良性肿瘤（例如脂肪瘤、平滑肌瘤等）对照：未患直肠良性肿瘤NA377 277(病例4 776，对照372 501)芬兰2023
BCNFinnGenhttps://finngen.gitbook.io/documentation/病例：经医院诊断为结肠良性肿瘤（例如脂肪瘤、平滑肌瘤等）对照：未患结肠良性肿瘤NA377 277(病例16 445,对照360 832)芬兰2023
反向CRP24084763病例：经镜检，被诊断为任何腺瘤（大小为≥1 cm）、家族性结直肠腺瘤或结直肠癌的受试者；对照：对照组是病例的配偶或伴侣、或经匹配的非结直肠癌、腺瘤人群无结直肠癌病史10 617(病例4 314，对照6 303)欧洲2014
CRATennessee Colorectal Polyp Study2302762740～75岁的人群经镜检，病例：被诊断为任何腺瘤的受试者；对照：无息肉的参与者遗传性结直肠癌综合征（即遗传性非息肉性结直肠癌或家族性腺瘤性息肉病）或炎症性肠病、腺瘤或除黑色素瘤皮肤癌以外的任何癌症的既往病史6 492(病例2 473，对照4 019)欧洲2012
), ArticleFig(id=1241678325152805600, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241522922444092302, language=CN, label=表1, caption=

本研究使用的GWAS汇总数据

, figureFileSmall=null, figureFileBig=null, tableContent=
因果方向变量来源PMID人群纳入标准人群排除标准样本量人群年份（年）
正向IRMAGIC22885924全人群（空腹整晚测得的血清血糖指标浓度）医生诊断为糖尿病；正在接受糖尿病治疗；或空腹血糖≥7 mmol/L，个别研究排除了包括怀孕、非禁食个体和1型糖尿病108 557欧洲2017
GLGC24097068全人群（禁食8h后测得血脂水平）已知服用降脂药物的人188 577欧洲
FIMAGIC全人群（禁食8h以上或者一整晚后测得的血清血糖指标浓度）医生诊断为糖尿病；正在接受糖尿病治疗；或FG≥7 mmol/L，或（和）HbA1c≥6.5%151 013欧洲2021
FGMAGIC34059833200 622欧洲2021
HbA1cMAGIC146 806欧洲2021
CRAUKBiobankhttps://gwas.mrcieu.ac.uk/datasets/ukb-b-14210/病例：患有结直肠腺瘤或者结直肠息肉对照：未患结直肠腺瘤或者息肉NA462 933(病例1 391，对照461 542)欧洲2018
BRNFinnGenhttps://finngen.gitbook.io/documentation/病例：经医院诊断为直肠良性肿瘤（例如脂肪瘤、平滑肌瘤等）对照：未患直肠良性肿瘤NA377 277(病例4 776，对照372 501)芬兰2023
BCNFinnGenhttps://finngen.gitbook.io/documentation/病例：经医院诊断为结肠良性肿瘤（例如脂肪瘤、平滑肌瘤等）对照：未患结肠良性肿瘤NA377 277(病例16 445,对照360 832)芬兰2023
反向CRP24084763病例：经镜检，被诊断为任何腺瘤（大小为≥1 cm）、家族性结直肠腺瘤或结直肠癌的受试者；对照：对照组是病例的配偶或伴侣、或经匹配的非结直肠癌、腺瘤人群无结直肠癌病史10 617(病例4 314，对照6 303)欧洲2014
CRATennessee Colorectal Polyp Study2302762740～75岁的人群经镜检，病例：被诊断为任何腺瘤的受试者；对照：无息肉的参与者遗传性结直肠癌综合征（即遗传性非息肉性结直肠癌或家族性腺瘤性息肉病）或炎症性肠病、腺瘤或除黑色素瘤皮肤癌以外的任何癌症的既往病史6 492(病例2 473，对照4 019)欧洲2012
), ArticleFig(id=1241678325354132198, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241522922444092302, language=EN, label=Table 2, caption=

Results of the sensitivity tests

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暴露结局MR-Egger回归Cochran Q 检验F统计量R2(%)
截距P截距Q值PQ值
IRCRA-0.0010.0517.5370.825>1 0000.38
BRN0.0100.22740.1490.291>1 0000.81
BCN0.0060.38526.8520.803>1 0000.56
FICRA-1.919×10-50.87710.6310.6411870.13
BRN0.0050.75619.4200.8183240.22
BCN-0.0130.17832.4440.1793540.24
FGCRA-7.982×10-50.05246.2670.142>1 0000.96
BRN-0.0010.90958.3820.284>1 0001.15
BCN0.0020.59647.3340.658>1 0001.14
HbA1cCRA-9.032×10-60.84027.0980.7554720.32
BRN0.0080.25478.5760.0649410.64
BCN-0.0010.89574.4290.7199140.62
), ArticleFig(id=1241678326213964521, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241522922444092302, language=CN, label=表2, caption=

敏感性分析结果

, figureFileSmall=null, figureFileBig=null, tableContent=
暴露结局MR-Egger回归Cochran Q 检验F统计量R2(%)
截距P截距Q值PQ值
IRCRA-0.0010.0517.5370.825>1 0000.38
BRN0.0100.22740.1490.291>1 0000.81
BCN0.0060.38526.8520.803>1 0000.56
FICRA-1.919×10-50.87710.6310.6411870.13
BRN0.0050.75619.4200.8183240.22
BCN-0.0130.17832.4440.1793540.24
FGCRA-7.982×10-50.05246.2670.142>1 0000.96
BRN-0.0010.90958.3820.284>1 0001.15
BCN0.0020.59647.3340.658>1 0001.14
HbA1cCRA-9.032×10-60.84027.0980.7554720.32
BRN0.0080.25478.5760.0649410.64
BCN-0.0010.89574.4290.7199140.62
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血糖特征与结直肠良性肿瘤因果关联的孟德尔随机化研究
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雷蕾 1 , 陈玥桥 2 , 马豪 1 , 刘傲男 1 , 杨艳芳 1
现代预防医学 | 流行病与统计方法 2024,51(5): 788-796
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现代预防医学 | 流行病与统计方法 2024, 51(5): 788-796
血糖特征与结直肠良性肿瘤因果关联的孟德尔随机化研究
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雷蕾1, 陈玥桥2, 马豪1, 刘傲男1, 杨艳芳1
作者信息
  • 1.四川大学华西公共卫生学院/华西第四医院流行病与卫生统计学系，四川 成都 610041
  • 2.重庆市江北区疾病预防控制中心

    • 雷蕾（1998—），女，硕士在读，研究方向：流行病与卫生统计学

通讯作者:

杨艳芳，E-mail:
A Mendelian randomized study on the causal relationship between glycemic traits and benign colorectal neoplasm
Lei LEI1, Yue-qiao CHEN2, Hao MA1, Ao-nan LIU1, Yan-fang YANG1
Affiliations
  • Chongqing Jiangbei District Center for Disease Control and Prevention, Chongqing 610041, China
出版时间: 2024-03-10 doi: 10.20043/j.cnki.MPM.202308409
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摘要
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目的

探索血糖特征（空腹血糖、空腹胰岛素、糖化血红蛋白、胰岛素抵抗)与结直肠良性肿瘤（结直肠腺瘤、直肠良性肿瘤、结肠良性肿瘤）发病之间的因果关系。

方法

血糖特征的工具变量数据来自MAGIC和GLGCL联盟，结直肠良性肿瘤的全基因组数据来源于FinnGen联盟。研究采用随机效应逆方差加权法(inverse-variance weighted, IVW)、MR-Egger回归、加权中位数法(weighted median method,WMM)三种回归模型对四项血糖特征与结直肠良性肿瘤的因果关系进行孟德尔随机化分析。

结果

IVW模型计算结果显示空腹血糖（OR=0.999，95%CI：0.997～1.001）、空腹胰岛素（OR=1.002，95%CI：0.998～1.006）、糖化血红蛋白（OR=1.001，95%CI：0.999～1.004）、胰岛素抵抗（OR=0.999，95%CI：0.997～1.002）与结直肠腺瘤之间无因果关系；空腹血糖（OR=0.909，95%CI：0.684～1.209）、空腹胰岛素（OR=1.220，95%CI：0.706～2.107）、糖化血红蛋白（OR=0.678，95%CI：0.440～1.046）、胰岛素抵抗（OR=1.161，95%CI：0.810～1.663）与直肠良性肿瘤之间无因果关系；空腹血糖（OR=0.966，95%CI：0.836～1.116）、空腹胰岛素（OR=1.318，95%CI：0.906～1.916）、糖化血红蛋白（OR=1.124，95%CI：0.882～1.431）、胰岛素抵抗（OR=1.071，95%CI：0.875～1.311）与结肠良性肿瘤之间均无因果关联。

结论

本研究没有发现空腹血糖、空腹胰岛素、糖化血红蛋白、胰岛素抵抗与结直肠腺瘤、直肠良性肿瘤、结肠良性肿瘤发病之间的因果关系的证据。

血糖特征  /  结直肠肿瘤  /  孟德尔随机化  /  因果关系
Objective

To explore the causal relationship between the characteristics of glycemic traits (fasting blood glucose, fasting insulin, glycosylated hemoglobin, and insulin resistance) and benign colorectal neoplasm (colorectal adenomas, benign rectal neoplasm, and benign colon neoplasm).

Methods

The instrumental variables of blood glucose characteristics were extracted from MAGIC and GLGCL alliance, and the genome-wide data of colorectal benign tumors came from Finn-Gen alliance. In this study, random effect inverse-variance weighted method (IVW), MR-Egger regression, and weighted median method (WMM) were used to analyze the causal relationship between four glycemic traits and benign colorectal neoplasm.

Results

The results of IVW model showed that there was no causal relationship between fasting blood glucose (OR=0.999, 95%CI: 0.997-1.001), fasting insulin (OR=1.002, 95%CI: 0.998-1.006), glycosylated hemoglobin (OR=1.001, 95%CI: 0.999-1.004), insulin resistance (OR=0.999, 95%CI: 0.997-1.002), and colorectal adenoma. There was no causal relationship between fasting blood glucose (OR=0.909, 95%CI: 0.684-1.209), fasting insulin (OR=1.220, 95%CI: 0.706-2.107), glycosylated hemoglobin (OR=0.678, 95%CI:0.440-1.046), insulin resistance (OR=1.161, 95%CI: 0.810-1.663) and rectal benign tumor. There was no causal relationship between fasting blood glucose (OR=0.966, 95%CI: 0.836-1.116), fasting insulin (OR=1.318, 95%CI: 0.906-1.916), glycosylated hemoglobin (OR=1.124, 95%CI: 0.882-1.431), insulin resistance (OR=1.071, 95%CI: 0.875-1.311) and benign tumors of colon.

Conclusion

There is no evidence of causal relationships of fasting blood glucose, fasting insulin, glycosylated hemoglobin, and insulin resistance with colorectal adenomas, benign rectal neoplasm, and benign colon neoplasm.

Glycemic traits  /  Colorectal neoplasms  /  Mendelian randomization  /  Causality
雷蕾, 陈玥桥, 马豪, 刘傲男, 杨艳芳. 血糖特征与结直肠良性肿瘤因果关联的孟德尔随机化研究. 现代预防医学, 2024 , 51 (5) : 788 -796 . DOI: 10.20043/j.cnki.MPM.202308409
Lei LEI, Yue-qiao CHEN, Hao MA, Ao-nan LIU, Yan-fang YANG. A Mendelian randomized study on the causal relationship between glycemic traits and benign colorectal neoplasm[J]. Modern Preventive Medicine, 2024 , 51 (5) : 788 -796 . DOI: 10.20043/j.cnki.MPM.202308409
正文
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在全世界范围内的癌症中，结直肠癌（colorectal cancer, CRC）是第三大死亡原因，也是第二大伤残调整寿命年（disability-adjusted life years, DALYs）的原因[1]。仅2020年一年，全球就报告了190万起结直肠癌病例，并造成了90万人的死亡[2]，并且，中、低收入国家的CRC发病率呈现出上升的趋势[3]。因此，CRC预防显得至关重要。CRC大多起源于结直肠腺瘤（colorectal adenomas, CRA），目前的研究表明，结直肠癌主要有两种前体病变途径：传统的腺瘤途径导致70%～90%的CRC，锯齿状肿瘤途径导致10%～20%的CRC[4]。同时CRA已被证明是CRC的主要前兆[5]。在这样的背景下，CRA被认为是CRC发生过程中的可识别和治疗的癌前病变，而这个癌前病变通常需要几年时间才能发展为侵袭性癌症。
先前的流行病学研究表明血糖特征，例如空腹血糖（fasting glucose，FG）、空腹胰岛素（fasting insulin，FI）、糖化血红蛋白（HbA1c）、胰岛素抵抗（insulin resistance, IR）[6-9]是CRA的危险因素之一，这可能是因为胰岛素可以诱导结直肠上皮细胞的增殖和异常隐窝病灶的发展[10]，从而导致了CRA的发生。但是也有流行病学研究得出了不一致的结果，其结果显示FG的升高与CRA风险降低相关[11]以及IR、FI、FG、HbA1c与CRA的发生不存在统计学关联[12-14]。因此，血糖特征与CRA之间的因果关系尚不完全清楚，需要更进一步的研究。
孟德尔随机化（Mendelian redomization,MR）研究使用种系遗传变异作为工具变量来估计暴露和结果的因果效应[15]，不易受到常规混杂和反向因果的影响。迄今为止，缺少MR研究去分析多种血糖特征与CRA、直肠良性肿瘤（benign rectal neoplasm，BRN）、结肠良性肿瘤（benign colon neoplasm，BCN）之间的关联。本研究的目的是利用双样本MR研究去探索血糖特征（FG、FI、HbA1c、IR）与结直肠良性肿瘤（CRA、BRN、BCN）之间的因果关联。
1　资料与方法
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1.1　研究设计
本研究采用双样本MR来评估血糖特征和结直肠良性肿瘤发病风险之间的因果关系，并且结直肠良性肿瘤发病风险与血糖特征之间的反向MR作为孟德尔分析结果的补充。本研究正向MR的暴露为IR、FI、FG、HbA1c，结局为是否患有CRA、BRN以及BCN；反向MR的暴露为CRA和结直肠息肉（colorectal polys，CRP），结局为FI、FG、HbA1c的血清浓度水平，MR研究的工具变量采用的是单核苷酸多态性位点（single nucleotide polymorphisms, SNP）。
1.2　工具变量选择
对于血糖特征的工具变量，IR的SNP信息来自2个不同的队列研究中关于IR特征的meta分析[16]，包括葡萄糖和胰岛素相关性状联盟（meta-analyses of glucose and insulin-related traits consortium，MAGIC）和全球脂质遗传学联盟（global lipids genetics consortium，GLGC），FI、FG、HbA1c的SNP信息则来自MAGIC的GWAS的meta分析[17]，然后对工具变量进行筛选。第一，以P<5×10-8为筛选条件，保证所选择的工具变量暴露强相关（IR：48 SNPs；FG：66 SNPs；FI：38 SNPs；HbA1c：74 SNPs）；第二，设置连锁不平衡系数r2=0.01，区域宽度为10 000 kb，排除连锁不平衡，以保证各SNP之间相互独立；第三，由于肥胖也是CRA的危险因素之一[6]，因此利用phenoscanner（http://www.phenoscanner.medschl.cam.ac.uk/，检查日期为2023年7月，P<5×10-8为筛选条件）排除了与BMI相关的遗传变异（IR：39 SNPs；FG：59 SNPs；FI：29 SNPs；HbA1c：67 SNPs），并在MR的分析中，利用MR-presso排除异常值，最终的数据集为本研究需要的工具变量。CRA相关的SNP来自的GWAS包括4 314名CRA病例和5 036名欧洲血统的对照受试者[18]。与CRP相关的SNP选自美国田纳西州结直肠息肉研究，该研究包括2 473例病例和4 019例对照[19]。去除连锁不平衡的SNP后，获得了19个CRA的SNP和7个CRP的SNP作为工具变量进行MR分析，经MR-presso检验，并未发现异常值。
1.3　结局的选择
结局CRA的SNP信息来自英国生物银行（United Kingdom Biobank，UKB)，CRA的GWAS ID是ukb-b-14210。BRN和BCN的SNP信息来自芬兰基因数据的第九轮数据（FinnGen，Round 9）[20]，结局FI、FG、HbA1c的数据来自MAGIC的GWAS的meta分析[17]。上述研究的信息见表1。本研究所采用的数据均是目前已知的应用广泛、通用度高、可获得的数据，经核实，本研究所选择的暴露和结局的数据来源于不同的样本，因此无样本重叠。
1.4　统计学分析
基于R语言（4.0.3, https://www.r-project.org/）统计软件，运用TwoSampleMR包进行MR分析。使用逆方差加权（inverse variance weighted,IVW）、MR-Egger回归和加权中位数法（weighted median method, WMM）进行MR分析。IVW不考虑截距项的存在并且使用结局方差（SE2）的倒数作为权重来进行拟合，在IVW的假设中，我们认为SNP是没有多效性的；MR-Egger回归考虑截距项的存在，此方法可以检测并矫正潜在的多效性引起的偏差；WMM法计算加权权重大小并行排序，当50%的遗传变异无效时，优先考虑WMM法[21]。因此本研究采用了三种MR分析方法，其中以IVW方法为主，MR-Egger和WMM法作为补充分析。本研究采用Bonferroni进行多重矫正，校正的公式为，其中a为原始检验水准，n为总检验次数，MR的总检验次数为3×4=12次，因此MR分析的结果的矫正检验水准是：a=0.05/12=0.004；反向MR分析的总检验次数为2×3=6次，矫正检验水准是a=0.05/6=0.008；敏感性分析的结果的检验水准是a=0.05。
1.5　敏感性分析
MR-Egger截距分析检验水平多效性[22]；Cochran Q检验判断SNP是否存在异质性[23]；留一法(leave-one-out sensitivity test)进行敏感性分析，逐个剔除每套工具变量中的SNP后计算MR结果,若余下的SNP计算出来的MR结果与未剔除SNP的总结果不存在较大差异，则说明MR结果是稳健的[24]
2　结果
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2.1　MR分析
三种方法的回归结果见图1。使用IVW方法获得的FG、FI、HbA1c、IR与CRA的比值比（OR）以及95%置信区间（95%CI）的结果分别为：0.999（0.997～1.001）、1.002（0.998～1.006）、1.001（0.999～1.004）和0.999（0.997～1.002）；与BNR的结果分别是：0.909（0.684～1.209）、1.220（0.706～2.107）、0.678（0.440～1.046）和1.161（0.810～1.663）；与BCN的结果分别是：0.966（0.836～1.116）、1.318（0.906～1.916）、1.124（0.882～1.431）和1.071（0.875～1.311）。本研究MR分析结果的所有的P值均大于0.004。
2.2　反向MR
三种方法的回归结果见图2。使用IVW方法获得的CRA与FG、FI、HbA1c的OR以及95%CI的结果如下：1.000（0.998～1.002）、1.000（0.999～1.002）和1.002（1.001～1.003）；CRP与FG、FI、HbA1c的OR以及95%CI的结果如下：1.109（1.000～1.038）、0.993（0.969～1.018）和1.009（0.993～1.025）。仅CRA与HbA1c的MR的结果的P值小于0.008。
2.3　敏感性分析
根据本研究工具变量筛选标准，所筛选出的几组工具变量的R2值为0.13%～1.15%，F统计量均大于100，表明MR的结果不太可能受弱工具变量偏倚的影响。MR-Egger截距分析均P>0.05，Cochran Q检验P均>0.05，见表2。本MR研究的漏斗图和散点图见图3、4。漏斗图显示每个SNP的因果效应分布基本对称。
根据leave-one-out检验结果绘制相关森林图，去除任意一个SNP后，其余的SNPs结果都在无效线的同侧，说明本研究MR结果是稳健的，见图5。以上结果显示所选择的工具变量满足三个基本假设，因此MR方法适用本研究。
3　讨论
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本研究使用双样本MR方法研究了血糖特征与结直肠良性肿瘤发病风险之间的关系，使用IVW、MR-Egger和WMM三种方法进行MR分析。结果表明，四种血糖特征（FG、FI、HbA1c、IR）与结局CRA、BRN、BCN的发病风险增加无关。本研究的各种敏感性分析验证结果表示研究结果是稳健和一致的。
本研究结果与之前的某些研究呈现一致性，表明FG、FI、HbA1c、IR与CRA风险之间的因果关系的证据有限[12-14]。一项大型MR研究[9]表明FG与CRC风险无关，结合本研究结果，佐证了FG与CRA、CRC漫长的发生发展过程无因果关联。该研究发现FI与CRC存在因果关联[9]，这表明FI虽然不会影响CRA的发生风险，但是可能会影响CRA后续发展成为CRC的这个过程。实验研究表明胰岛素会通过与同源受体或胰岛素样生长因子受体结合，促进肿瘤细胞中蛋白质的合成[25]，这可能是FI影响CRA后续发展为CRC这个过程的潜在机制，提示我们CRA患者需要关注FI的变化以预防CRA发展成为CRC。该研究[9]的结果也显示HbA1c与仅男性CRC之间存在因果关联，由于本研究并没有对CRA、BRN、BCN进行性别分层分析，因此我们只能猜测HbA1c与CRA的因果联系可能也存在性别差异，未来的研究或许可以进行深入的探索，使用CRA性别分层的数据作更精准地分析。虽然本研究并没有找到足够的证据去证明FG、FI、HbA1c、IR会影响BRN、BCN的发病风险，但是BRN与BCN包含多种良性肿瘤，未来的研究可以对结直肠内的肿瘤作更细致的分类去探索其中的发病机制。反向MR的结果显示CRA会导致HbA1c的升高，这可能是因为结直肠腺瘤会改变胃肠道菌群γ-变形杆菌类和肠杆菌科的丰度[26]，其中肠杆菌科与HbA1c呈负相关[27]，未来需要更多的研究去深入探讨潜在机制。
本研究结果和先前部分研究[6-9]的结果呈现矛盾，对于相互这种矛盾的结果，首先可能是因为一些研究使用了非空腹的血液样本；其次是使用的实验室检测方法存在差异，例如，IR是一种复杂的生理表现，对IR可以使用不同的指标进行评估，例如高胰岛素-正血糖钳夹技术（金标准）、胰岛素敏感性测试、IR的稳态模型评估和空腹胰岛素[28]；最后是先前的研究由于属于观察性研究，残留混杂和反向因果的存在导致结果出现误差。
本研究存在一定的局限性。首先，本研究所选择的GWAS汇总数据仅仅局限在欧洲人群，所以本研究结论可能不能外推到其他人群；其次，受限于原始数据，尽管所使用的工具变量来自现有可获得的最大的GWAS数据库，但是这些研究所获得的工具变量可能不完全包含这个表型的全部工具变量，同时经筛选，纳入的工具变量有限，因此所纳入的工具变量对暴露表型的解释程度也较为有限；再次是结局数据的病例数有限，这导致病例数和对照组的参与者数的比例较低，综合导致了本文的检验效能未达到80%，未来需要更全面的数据对研究结果进行验证；最后，本研究采用的是汇总的GWAS数据，缺乏个体数据，尚未进行分层分析。综上所述，本研究未找到FG、FI、HbA1c、IR与CRA、BRN、BCN之间因果联系的证据，但是FI可能会影响CRA的后续发展，需要更多的大型GWAS和MR研究来证实我们的发现。
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doi: 10.20043/j.cnki.MPM.202308409
  • 接收时间：2023-08-20
  • 首发时间：2026-03-19
  • 出版时间：2024-03-10
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  • 收稿日期：2023-08-20
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    1.四川大学华西公共卫生学院/华西第四医院流行病与卫生统计学系，四川 成都 610041
    2.重庆市江北区疾病预防控制中心

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杨艳芳，E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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