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4 "Mendelian randomization"
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Original Articles
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
  • 2,571 View
  • 71 Download
AbstractAbstract AbstractSummary PDFSupplementary 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
  • 4,868 View
  • 167 Download
  • 1 Crossref
AbstractAbstract AbstractSummary PDFSupplementary 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
  • 4,811 View
  • 193 Download
  • 3 Web of Science
  • 2 Crossref
AbstractAbstract AbstractSummary PDFSupplementary 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  
  • 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
  • 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.2023;[Epub]     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
  • 11,893 View
  • 286 Download
  • 10 Web of Science
  • 10 Crossref
AbstractAbstract AbstractSummary PDFSupplementary 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
  • 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.2023; 24(18): 931.     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
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