Epidemiology and Health

Original Articles

Causal effect of fasting serum glucose on atherosclerotic cardiovascular disease: a multivariable Mendelian randomization: Su Hyun Lee, Heejin Kimm, Byung-Wan Lee, Chung Mo Nam, So Young Kim, Sunmi Lee, Sun Ha Jee; Epidemiol Health. 2024;46:e2024096. Published online December 6, 2024; DOI: https://doi.org/10.4178/epih.e2024096

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Abstract Summary PDF: Abstract
OBJECTIVES
Observational studies have reported that diabetes is a risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD). However, the causal relationship remains a matter of debate. This study aimed to analyze the relationship between fasting serum glucose (FSG) and ASCVD.
METHODS
This study used data from the Korean Cancer Prevention Study-II (KCPS-II) Biobank, consisting of 159,844 people recruited with consent from 18 health examination centers from 2004 to 2013. Outcomes were confirmed based on diagnoses on hospital discharge summaries from National Health Insurance System. We used linear and non-linear Mendelian randomization (MR) methods. The outcome data were obtained from KCPS-II, and the exposure data were derived from the Korean Genome Epidemiology Study.
RESULTS
First, a prospective cohort study estimated that for each 10 mg/dL increase in FSG level, the risk of ASCVD increased by 4% (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03 to 1.05). Second, the 2-sample MR study showed that every 10 mg/dL increase in FSG influenced the risk of ASCVD (odds ratio [OR], 1.11; 95% CI, 1.04 to 1.18). Third, the multivariable MR study showed that the OR per 10 mg/dL increase in FSG on ASCVD was 1.14 (p<0.001). Similar results were found for a 10 mg/dL increase in FSG and ischemic heart disease (IHD), but a significant relationship with stroke was not found. When performing non-linear MR, a linear relationship was observed between fasting blood sugar and ASCVD, including IHD and stroke.
CONCLUSIONS
FSG showed a linear and causal association with IHD, but not with stroke.; Summary

Korean summary
그동안 당뇨병이 심뇌혈관질환 발생에 위험요인이라는 역학적인 관찰연구는 많이 발표되었지만, 이러한 관련성에 대한 인과적 관련성에 대부분 연구는 서양인을 대상으로 발표되었고, 한국인 자료를 통해 발표된 적은 없었다. 이 연구는 관찰연구의 제한점으로 부각되는 혼란변수와 측정오류에 덜 영향을 받는 새로운 방법론으로써 다변수 멘델리언 무작위화 방법을 사용하여 공복혈당과 심뇌혈관질환의 인과성을 분석하였다. 분석결과, 공복혈당은 허혈성 심질환 발생위험에 인과적인을 관련성을 보였고 뇌졸중에 대해서는 인과적이지 않았다.

Key Message
Over the years, numerous epidemiological observational studies have reported that diabetes is a risk factor for cardiovascular and cerebrovascular diseases. However, most of these studies examining this association were conducted on Western populations, and no studies have been published using Korean data. This study employed a new methodology—multivariable Mendelian randomization—which is less affected by confounding factors and measurement errors, often highlighted as limitations of observational studies, to analyze the causal relationship between fasting glucose levels and cardiovascular and cerebrovascular diseases. The analysis revealed a causal relationship between fasting glucose levels and the risk of ischemic heart disease, while no causal association was observed with stroke.

Causal association between serum bilirubin and ischemic stroke: multivariable Mendelian randomization: Jong Won Shin, Keum Ji Jung, Mikyung Ryu, Jungeun Kim, Heejin Kimm, Sun Ha Jee; Epidemiol Health. 2024;46:e2024070. Published online August 19, 2024; DOI: https://doi.org/10.4178/epih.e2024070

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Abstract Summary PDF: Abstract
OBJECTIVES
Previous research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated.
METHODS
Two-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (n=159,844) and the Korean Genome and Epidemiology Study (n=72,299). Data on ischemic stroke were obtained from BioBank Japan (n=201,800). Colocalization analysis was performed, focusing on the <i>UGT1A1, SLCO1B1</i>, and <i>SLCO1B3</i> genes, which are the primary loci associated with serum bilirubin levels.
RESULTS
Crude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke.
CONCLUSIONS
Our study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.; Summary

Korean summary
이 연구는 혈청 빌리루빈의 세 가지 형태(총, 직접, 간접 빌리루빈)와 허혈성 뇌졸중 간의 인과적 연관성을 다루었습니다. 다변수 멘델리안 무작위 분석(MVMR)을 통해 간접 빌리루빈이 허혈성 뇌졸중 위험을 유의미하게 감소시키는 것으로 나타났습니다. 이 결과는 빌리루빈의 항산화 역할과 허혈성 뇌졸중 간의 상관관계를 심화 이해하는 데 기여합니다.

Key Message
This study investigated the causal associations between three forms of serum bilirubin (total, direct, and indirect) and ischemic stroke. Multivariable Mendelian randomization (MVMR) analysis revealed a significant inverse association between indirect bilirubin and the risk of ischemic stroke. These findings contribute to a deeper understanding of the relationship between bilirubin's antioxidant role and ischemic stroke.

Causal effect of serum matrix metalloproteinase levels on venous thromboembolism: a Mendelian randomization study: Deheng Han, Fangcong Yu, Liangrong Zheng; Epidemiol Health. 2024;46:e2024046. Published online April 7, 2024; DOI: https://doi.org/10.4178/epih.e2024046

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Abstract Summary PDF Supplementary Material

Abstract

OBJECTIVES
Serum matrix metalloproteinase (MMP) levels are associated with cardiovascular diseases. However, the causal associations between serum levels of specific MMPs and venous thromboembolism (VTE) remain unclear. The present study sought to explore the causal relationship between serum MMP levels and VTE by using the Mendelian randomization (MR) method.

METHODS

In this study 2-sample MR study, the exposure data on serum MMP levels were derived from genome-wide association studies involving 21,758 individuals from 13 cohorts of European descent. The outcome data on VTE, including deep vein thrombosis and pulmonary embolism, were derived from the FinnGen research project. The primary method used was the inverse-variance weighting method. The MR-Egger intercept test and the Cochran Q test were used to evaluate pleiotropy and heterogeneity.

RESULTS

Using the inverse-variance weighting method, higher serum MMP-12 levels were found to be associated with an increased risk of VTE (odds ratio, 1.04; 95% confidence interval, 1.01 to 1.07; p=0.001). Moreover, there was a weak association between the levels of certain MMPs and VTE. Sensitivity analyses revealed no significant heterogeneity and pleiotropy in our study, and the Steiger directionality test did not reveal a significant reverse causation association.

CONCLUSIONS

There is a causal association between MMP-12 levels and VTE, which may have substantial implications for the diagnostic and therapeutic strategies used for VTE.

Summary

Key Message
We found that there is a causal association between matrix metalloproteinase-12 levels and venous thromboembolism. Serum matrix metalloproteinase may have profound implications on the diagnostic andtherapeutic strategies used for venous thromboembolism.

Citations

Citations to this article as recorded by

Causal relationship between matrix metalloproteinase and pulmonary embolism: a bidirectional two-sample Mendelian randomization study
Xiaowei Gong, Yadong Yuan
Scientific Reports.2025;[Epub] CrossRef

The mediating role of atrial fibrillation in causal associations between risk factors and stroke: a Mendelian randomization study: Shanmei Qin, Mengmeng Wang, Dipender Gill, Zhizhong Zhang, Xinfeng Liu; Epidemiol Health. 2024;46:e2024005. Published online December 6, 2023; DOI: https://doi.org/10.4178/epih.e2024005

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Abstract Summary PDF Supplementary Material: Abstract
OBJECTIVES
Atrial fibrillation (AF) contributes to stroke development and progression. We aimed to quantify the mediating role of AF in the causal associations between a wide range of risk factors and stroke via a Mendelian randomization (MR) framework.
METHODS
We assessed the associations of 108 traits with stroke and its subtypes in a 2-sample univariable MR approach, then conducted a bidirectional MR analysis between these 108 traits and AF to evaluate the presence and direction of their causal associations. Finally, to further investigate the extent to which AF mediated the effects of eligible traits on stroke, we applied multivariable and 2-step MR techniques in a mediation analysis where outcomes were restricted to stroke types causally affected by AF (any stroke [AS], any ischemic stroke [AIS], and cardioembolic stroke [CES]).
RESULTS
Among 108 traits, 42 were putatively causal for at least 1 stroke type; of these 42 traits, 20 that had no bidirectional relationship with AF were retained. Finally, 33 associations of 15 eligible traits were examined in the mediation analysis. The mediation analyses for AS, AIS, and CES each included 11 eligible traits. After AF adjustment, the direct effects of all traits on CES were attenuated to null (all p>0.05), while the associations with AS and AIS persisted for most traits (AF-mediated proportion: from 6.6% [95% confidence interval, 2.7 to 0.6] to 52.0% [95% confidence interval, 39.8 to 64.3]).
CONCLUSIONS
The causal associations between all eligible traits and CES were largely mediated through AF, while most traits affected AS and AIS independently of AF.; Summary

Key Message
Previous studies have not systematically detected and quantified the mediating role of AF in causal associations between a wide range of risk factors and stroke types. This study, using several MR approaches, found that the causal associations between risk factors and stroke, and the role of AF in mediating these associations, varied across stroke types. Although AF largely mediated the trait-CES associations, most traits affected AS and AIS independently of AF, highlighting the need for accurate disease classification in clinical practice and trials.

No association between genetically predicted C-reactive protein levels and colorectal cancer survival in Korean: two-sample Mendelian randomization analysis: Chang Kyun Choi, Jung-Ho Yang, Min-Ho Shin, Sang-Hee Cho, Sun-Seog Kweon; Epidemiol Health. 2023;45:e2023039. Published online March 22, 2023; DOI: https://doi.org/10.4178/epih.e2023039

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Abstract Summary PDF Supplementary Material

Abstract

OBJECTIVES
Elevated C-reactive protein (CRP) levels are associated with an increased risk for colorectal cancer (CRC), as well as a poor prognosis, but it remains unclear whether these associations are causal. This study examined the potential causality between CRP levels and CRC survival using 2-sample Mendelian randomization (MR).

METHODS

From the Korean Genome and Epidemiology Study, a genome-wide association study (n=59,605), 7 single-nucleotide polymorphisms (SNPs) related to log2-transformed CRP levels were extracted as instrumental variables for CRP levels. The associations between the genetically predicted CRP and CRC-specific and overall mortality among CRC patients (n=6,460) were evaluated by Aalen’s additive hazard model. The sensitivity analysis excluded a SNP related to the blood lipid profile.

RESULTS

During a median of 8.5 years of follow-up, among 6,460 CRC patients, 2,676 (41.4%) CRC patients died from all causes and 1,622 (25.1%) died from CRC. Genetically predicted CRP levels were not significantly associated with overall or CRC-specific mortality in CRC patients. The hazard difference per 1,000 person-years for overall and CRC-specific mortality per 2-fold increase in CRP levels was -2.92 (95% confidence interval [CI], -14.05 to 8.21) and -0.76 (95% CI, -9.61 to 8.08), respectively. These associations were consistent in a subgroup analysis according to metastasis and a sensitivity analysis excluding possible pleiotropic SNPs.

CONCLUSIONS

Our findings do not support a causal role for genetically predisposed CRP levels in CRC survival.

Summary

Korean summary
이 연구는 two-sample Mendelian randomization (MR)을 이용하여 대장암에서 C-reactive protein와 사망률 간의 관련성을 평가하였다. Two-sample MR은 한국유전체역학조사사업 (the Korean Genome and Epidemiology Study, KoGES) 참가자 59,605명에서 혈청 C-reactive protein에 대한 전장유전체 분석을 시행하여 7개의 단일염기다형성을 선별하였고, 화순암역학연구-대장암 (thw Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer, HCES-CRC)에 등록된 6,460명 대장암 환자에서 그 7개 단일염기다형성과 사망률 간의 관련성을 평가한 결과를 이용하였다. 그 결과, 높은 혈청 C-reactive protein을 가지는 유전적 성향은 대장암 환자에서 사망률과의 통계적으로 유의한 관련성을 찾을 수 없었다.

Key Message
This study employed a two-sample Mendelian randomization (MR) analysis to investigate the relationship between serum C-reactive protein (CRP) levels and mortality in colorectal cancer. The analysis utilized genome-wide association analysis (GWAS) data from 59,605 participants in the Korean Genome and Epidemiology Study (KoGES) for serum CRP and 6,460 colorectal cancer cases from the Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer for mortality. Our findings suggest that there is no statistically significant association between genetically predisposed serum CRP levels and mortality. Consequently, our study does not support a causal effect of CRP on mortality in colorectal cancer.

Citations

Citations to this article as recorded by

Mortality risk among adult americans living with cancer and elevated CRP
Srikanta Banerjee, Jagdish Khubchandani, Shalika Tisinger, Kavita Batra, Maribeth Greenway
Cancer Epidemiology.2024; 90: 102569. CrossRef

Impaired pulmonary function mediates the impact of preterm birth on later-life stroke: a 2-step, multivariable Mendelian randomization study: Xingzhi Guo, Peng Tang, Chen Hou, Yue Liu, Rui Li; Epidemiol Health. 2023;45:e2023031. Published online March 3, 2023; DOI: https://doi.org/10.4178/epih.e2023031

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Abstract Summary PDF Supplementary Material

Abstract

OBJECTIVES
Observational studies have suggested an association between preterm birth and stroke in late adulthood, but it remains unclear whether the association is causal. The purpose of this study was to evaluate the causal effects of gestational age on stroke and to determine the pathophysiological mechanisms underlying the causal associations.

METHODS

Two-sample Mendelian randomization (MR) was performed to assess the causal effects of fetal gestational duration, early preterm birth (EPB), preterm birth, or postterm birth on stroke and its subtypes. Two-step Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were additionally used to determine the role of common stroke risk factors, including cardiovascular diseases, hypertension, pulmonary impairment, inflammation, and metabolic diseases, in mediating the causal associations between gestational age and stroke and its subtypes.

RESULTS

Genetically predicted EPB increased the risk of cardioembolic stroke (CES; odds ratio [OR], 1.115; 95% confidence interval [CI], 1.036 to 1.200; p=0.004) and large artery stroke (LAS; OR, 1.131; 95% CI, 1.031 to 1.241; p=0.009). The TSMR results showed that EPB was associated with a lower forced expiratory volume in the first second and forced vital capacity ratio (FEV1/FVC) (β=-0.020; 95% CI, -0.035 to -0.005; p=0.009), which increased the risk of CES and LAS. Further MVMR analysis showed that the associations between EPB and stroke disappeared after adjustment for FEV1/FVC.

CONCLUSIONS

Our data demonstrate that EPB is causally associated with an elevated risk of CES and LAS, and that pulmonary dysfunction mediates the causal impact of EPB on CES and LAS.

Summary

Key Message
Genetically predicted early preterm birth (EPB) is significantly associated with an increased risk of cardioembolic stroke (CES) and large artery stroke (LAS). Further multivariable Mendelian randomization analysis demonstrates that pulmonary impairment mediates the causal impact of EPB on CES and LAS in adulthood.

Citations

Citations to this article as recorded by

Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review
Grace M. Power, Eleanor Sanderson, Panagiota Pagoni, Abigail Fraser, Tim Morris, Claire Prince, Timothy M. Frayling, Jon Heron, Tom G. Richardson, Rebecca Richmond, Jessica Tyrrell, Nicole Warrington, George Davey Smith, Laura D. Howe, Kate M. Tilling
European Journal of Epidemiology.2024; 39(5): 501. CrossRef
Tumor necrosis factor mediates the impact of PM2.5 on bone mineral density: Inflammatory proteome Mendelian randomization and colocalization analyses
Mingzheng Li, Peng Shi, Huajie Yang, Suyuan Tong, Nianfeng Qiu, Fan Yao, Yuan Du, Shuhua Xi, Fei Wang
Ecotoxicology and Environmental Safety.2024; 270: 115896. CrossRef
Causal associations of circulating Helicobacter pylori antibodies with stroke and the mediating role of inflammation
Xingzhi Guo, Peng Tang, Xin Zhang, Rui Li
Inflammation Research.2023; 72(6): 1193. CrossRef
Causal relationship between Helicobacter pylori antibodies and gastroesophageal reflux disease (GERD): A mendelian study
Jiaqin Chen, Junning Zhang, Xiaolu Ma, Yuehan Ren, Yi Tang, Zhongmian Zhang, Wangyu Ye, Xiyan Zhang, Zili Lin, Lan Wang, Zhihong Li, Yasin Sahin
PLOS ONE.2023; 18(12): e0294771. CrossRef

Bilirubin and risk of ischemic heart disease in Korea: a two-sample Mendelian randomization study: Christina Jeon, Ji-Young Lee, Sun Ju Lee, Keum Ji Jung, Heejin Kimm, Sun Ha Jee; Epidemiol Health. 2019;41:e2019034. Published online July 12, 2019; DOI: https://doi.org/10.4178/epih.e2019034

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292 Download
10 Web of Science
10 Crossref

Abstract Summary PDF Supplementary Material

Abstract

OBJECTIVES
Bilirubin is an endogenous antioxidant that protects cells against oxidative stress. Increased plasma levels of bilirubin have been associated with a reduced risk of ischemic heart disease (IHD) in previous studies. Nonetheless, whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown. Therefore, we applied two-sample Mendelian randomization to evaluate the causal association between bilirubin levels and IHD risk in a Korean population.

METHODS

A total of 5 genetic variants—TRPM8 (rs10490012), USP40 (rs12993249), ATG16L1 (rs2119503), SLCO1B1 (rs4149014), and SLCO1B3 (rs73233620)—were selected as genetic instruments for serum bilirubin levels using a communitybased cohort, the Korean Genome and Epidemiology Study, comprising 33,598 subjects. We then evaluated their impact on IHD using the Korean Cancer Prevention Study-II cohort.

RESULTS

Among the 5 instrumental variables that showed significant associations with serum bilirubin levels, rs12993249 (USP40) showed the most significant association (p<2.36×10-105). However, we found no significant association between serum bilirubin levels and IHD. Sensitivity analyses demonstrated a consistent association, suggesting that our observations were robust.

CONCLUSIONS

Using two-sample Mendelian randomization, we found no association between serum bilirubin levels and IHD. Further studies that confirm the observed interactions among other ethnicities are warranted.

Summary

Korean summary
이 연구는 대규모 한국인 코호트를 이용하여, 빌리루빈과 허혈성 심장질환의 인과성을 규명한 연구결과이다. 특히 두 가지 자료를 이용한 멘델리안 무작위배정 연구방법을 적용하여, 한국인을 대상으로 빌리루빈과 허혈성 심장질환의 인과성을 처음으로 규명한 점이 큰 시사점을 가진다.

Citations

Citations to this article as recorded by

Association of Different Total Bilirubin Levels with Prognosis of Peritoneal Dialysis-Associated Peritonitis
Yujian He, Jingjing Zhu, Fei Xiao, Qingyun Luo, Pengpeng Wang, Xu Wang, Yan He, Zibo Xiong
Medicina.2023; 59(10): 1837. CrossRef
Novel prognostic score based on the preoperative total bilirubin-albumin ratio and fibrinogen-albumin ratio in ampullary adenocarcinoma
Xiao-Jie Zhang, He Fei, Chong-Yuan Sun, Ze-Feng Li, Zheng Li, Chun-Guang Guo, Dong-Bing Zhao
World Journal of Gastrointestinal Surgery.2023; 15(10): 2247. CrossRef
The Nonlinear Relationship Between Total Bilirubin and Coronary Heart Disease: A Dose-Response Meta-Analysis
Chaoxiu Li, Wenying Wu, Yumeng Song, Shuang Xu, Xiaomei Wu
Frontiers in Cardiovascular Medicine.2022;[Epub] CrossRef
Another Reason to Cut Down on Alcohol?
Hyeon Chang Kim
Korean Circulation Journal.2022; 52(3): 231. CrossRef
Serum bilirubin and kidney function: a Mendelian randomization study
Sehoon Park, Soojin Lee, Yaerim Kim, Yeonhee Lee, Min Woo Kang, Kwangsoo Kim, Yong Chul Kim, Seung Seok Han, Hajeong Lee, Jung Pyo Lee, Kwon Wook Joo, Chun Soo Lim, Yon Su Kim, Dong Ki Kim
Clinical Kidney Journal.2022; 15(9): 1755. CrossRef
Heme Oxygenase-1 and Blood Bilirubin Are Gradually Activated by Oral D-Glyceric Acid
O. Petteri Hirvonen, Maarit Lehti, Heikki Kyröläinen, Heikki Kainulainen
Antioxidants.2022; 11(12): 2319. CrossRef
Exploring the causal pathway from bilirubin to CVD and diabetes in the UK biobank cohort study: Observational findings and Mendelian randomization studies
Lei Hou, Hongkai Li, Shucheng Si, Yuanyuan Yu, Xiaoru Sun, Xinhui Liu, Ran Yan, Yifan Yu, Chuan Wang, Fan Yang, Qing Wang, Fuzhong Xue
Atherosclerosis.2021; 320: 112. CrossRef
The causal association of bilirubin with cardiovascular disease: Are there still any questions?
Claudia Lamina, Florian Kronenberg
Atherosclerosis.2021; 320: 92. CrossRef
Association between Alcohol Consumption and Serum Cortisol Levels: a Mendelian Randomization Study
Jung-Ho Yang, Sun-Seog Kweon, Young-Hoon Lee, Seong-Woo Choi, So-Yeon Ryu, Hae-Sung Nam, Kyeong-Soo Park, Hye-Yeon Kim, Min-Ho Shin
Journal of Korean Medical Science.2021;[Epub] CrossRef
SLCO1B1 Variants and The Risk of Antituberculosis Drug-induced Hepatotoxicity: A Systematic Review and Meta-analysis
Min Zhu, Xinyu Chen, Zhuolu Hao, Yiwen He, Bing Han, Shaowen Tang
Pharmacogenomics.2009; 24(18): 931. CrossRef

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