Causal Association Between Anemia and Cardiovascular Disease: A 2‐Sample Bidirectional Mendelian Randomization Study

Author:

Gan Ting123,Hu Jing4,Liu Wenhu123,Li Cui123,Xu Qian123,Wang Ya123,Lu Shuai5,Aledan Anwer Khalid Okab123,Wang Yan123,Wang Zhaohui123ORCID

Affiliation:

1. Department of Cardiology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China

2. Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China

3. Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China

4. Department of Infectious Diseases, Union Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China

5. Department of Cardiac Surgery, Union Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China

Abstract

Background Although previous observational studies have shown an association between anemia and cardiovascular disease (CVD), the underlying causal relationship between anemia and CVD remains uncertain. Methods and Results We conducted a 2‐sample bidirectional Mendelian randomization (MR) study to assess the causal association between anemia and CVD. We extracted summary statistics data for anemia, heart failure (HF), coronary artery disease (CAD), atrial fibrillation, any stroke, and any ischemic stroke (AIS) from relevant published genome‐wide association studies. After rigorous quality control steps, independent single‐nucleotide polymorphisms for each disease were selected as instrumental variables. Inverse‐variance weighting was used as the primary method to estimate the causal association between anemia and CVD in the 2‐sample MR analysis. Simultaneously, we performed a series of multiple methods analyses (median weighting, maximum likelihood [MR robust adjusted profile score]), sensitivity analyses (Cochran's Q test and MR‐Egger intercept, leave‐one‐out test [MR pleiotropy residual sum and outlier]), instrumental variable strength evaluations ( F statistic), and statistic power estimates to verify the robustness and reliability of our results. Furthermore, the associations between anemia and CVD from different studies, including the UK Biobank and FinnGen studies, were combined by meta‐analysis. The MR analysis showed that genetically predicted anemia was significantly associated with HF risk at the Bonferroni‐corrected significance level (odds ratio [OR], 1.11 [95% CI, 1.04–1.18]; P =0.002) and was suggestively associated with CAD risk (OR, 1.11 [95% CI, 1.02–1.22]; P =0.020). However, the associations between anemia and atrial fibrillation, any stroke, or AIS were not statistically significant. In the reverse MR analysis, we found that genetic susceptibility to HF, CAD, and AIS was significantly associated with anemia risk. The ORs of HF, CAD, and AIS were 1.64 (95% CI, 1.39–1.94; P =7.60E‐09), 1.16 (95% CI, 1.08–1.24; P =2.32E‐05), and 1.30 (95% CI, 1.11–1.52; P =0.001), respectively. Genetically predicted atrial fibrillation was suggestively associated with anemia (OR, 1.06 [95% CI, 1.01–1.12]; P =0.015). Sensitivity analyses found weak evidence of horizontal pleiotropy and heterogeneity, which ensured the robustness and reliability of the results. Meta‐analysis also showed the statistically significant association between anemia and HF risk. Conclusions Our study supports bidirectional causality between anemia and HF and significant associations between genetic predisposition to CAD and AIS with anemia, which contributes to the clinical management of both diseases.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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