J Stroke.  2022 May;24(2):236-244. 10.5853/jos.2021.01340.

Causal Relations between Exposome and Stroke: A Mendelian Randomization Study

• Li HQ
• Feng YW
• Yang YX
• Leng XY
• Zhang PC
• Chen SD
• Kuo K
• Huang SY
• Zhang XQ
• Dong Y
• Han X
• Cheng X
• Cui M
• Tan L
• Dong Q
• Yu JT

• KMID: 2530526
• DOI: http://doi.org/10.5853/jos.2021.01340

Abstract

Background and Purpose
To explore the causal relationships of elements of the exposome with ischemic stroke and its subtypes at the omics level and to provide evidence for stroke prevention. Methods We conducted a Mendelian randomization study between exposure and any ischemic stroke (AIS) and its subtypes (large-artery atherosclerotic disease [LAD], cardioembolic stroke [CE], and small vessel disease [SVD]). The exposure dataset was the UK Biobank involving 361,194 subjects, and the outcome dataset was the MEGASTROKE consortium including 52,000 participants.
Results
We found that higher blood pressure (BP) (systolic BP: odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01 to 1.04; diastolic BP: OR, 1.03; 95% CI, 1.01 to 1.05; pulse pressure: OR, 1.03; 95% CI, 1.00 to 1.06), atrial fibrillation (OR, 1.18; 95% CI, 1.13 to 1.25), and diabetes (OR, 1.13; 95% CI, 1.07 to 1.18) were significantly associated with ischemic stroke. Importantly, higher education (OR, 0.69; 95% CI, 0.60 to 0.79) decreased the risk of ischemic stroke. Higher systolic BP (OR, 1.06; 95% CI, 1.02 to 1.10), pulse pressure (OR, 1.08; 95% CI, 1.02 to 1.14), diabetes (OR, 1.28; 95% CI, 1.13 to 1.45), and coronary artery disease (OR, 1.58; 95% CI, 1.25 to 2.00) could cause LAD. Atrial fibrillation could cause CE (OR, 1.90; 95% CI, 1.71 to 2.11). For SVD, higher systolic BP (OR, 1.04; 95% CI, 1.00 to 1.07), diastolic BP (OR, 1.06; 95% CI, 1.01 to 1.12), and diabetes (OR, 1.22; 95% CI, 1.10 to 1.36) were causal factors.
Conclusions
The study revealed elements of the exposome causally linked to ischemic stroke and its subtypes, including conventional causal risk factors and novel protective factors such as higher education.

Keyword

Stroke; Exposome; Mendelian randomization analysis

Figure

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  Figure 1. Flow diagram of the design and analysis process of this study. GWAS, genome-wide association study; AIS, any ischemic stroke; LAD, large-artery atherosclerotic disease; CE, cardiac embolism stroke; SVD, small vessel disease; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

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  Figure 2. Exposome-wide association studies (ExWAS) Manhattan plot highlighting exposures with statistical significance for stroke and stroke subtypes. (A) Any ischemic stroke (AIS), (B) small vessel disease (SVD), (C) large-artery atherosclerotic disease (LAD), and (D) cardiac embolism (CE). The red line indicates the exposome-wide significance threshold of the Bonferroni adjustment. The blue line indicates threshold of P<0.05.

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  Figure 3. Validation of the causal relationships between exposures and any stroke/stroke subtypes. The x-axis corresponds to the odds ratio (OR) for inverse-variance weighted, Mendelian randomization (MR) Egger, and weight median method. SNP, single nucleotide polymorphism; CI, confidence interval; AIS, any ischemic stroke; MTAG, multi-trait analysis of GWAS; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; LAD, large-artery atherosclerotic disease; CE, cardiac embolism; SVD, small vessel disease.

Reference

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