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Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke

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Abstract

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09–1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09–1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04–1.68). A positive global genetic correlation was observed (cIMTmax-AS: \({r}_{g}\)=0.23, P=9.44 × 10−5; cIMTmean-AS: \({r}_{g}\)=0.21, P=3.00 × 10−4; cIMTmin-AS: \({r}_{g}\)=0.16, P=6.30 × 10−3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97–1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93–1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90–1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01–0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01–0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01–0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

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Data availability

Data from UK Biobank is available for open access to scientific researcher (www.biobank.ac.uk). The UK Biobank analysis was conducted within the application 50538. The full GWAS summary statistics are available through the MEGASTROKE Consortium (http://megastroke.org/).

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Acknowledgements

We would like to thank Ming Wai Yeung, PhD, University of Groningen, University Medical Center Groningen, Department of Cardiology, for making the complete GWAS summary statistics publicly available. We are grateful to the MEGASTROKE Consortium for making the complete meta-GWAS summary statistics publicly available.

Funding

This study was supported by the National Key R&D Program of China (2022YFC3600600, 2022YFC3600604), the National Natural Science Foundation of China (U22A20359, 81874283, 81673255), the Recruitment Program for Young Professionals of China, the Promotion Plan for Basic Medical Sciences and the Development Plan for Cutting-Edge Disciplines, Sichuan University, and other Projects from West China School of Public Health and West China Fourth Hospital, Sichuan University. The sponsors of this study had no role in study design, data collection, analysis, interpretation, writing of the report, or the decision for submission.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, West China- PUMC C. C. Chen Institute of Health, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China

    Wenqiang Zhang, Jingwei Zhu, Xuan Wu, Tianle Feng, Wei Liao, Xuan Li, Jianci Chen, Li Zhang, Chenghan Xiao, Huijie Cui, Chao Yang, Peijing Yan, Yutong Wang, Mingshuang Tang, Lin Chen, Yunjie Liu, Yanqiu Zou, Xueyao Wu, Ling Zhang, Chunxia Yang, Yuqin Yao, Jiayuan Li, Zhenmi Liu & Xia Jiang

  2. Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Chenghan Xiao & Zhenmi Liu

  3. Department of Iatrical Polymer Material and Artificial Apparatus, School of Polymer Science and Engineering, Sichuan University, Chengdu, China

    Ling Zhang

  4. Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Yuqin Yao

  5. Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Xia Jiang

  6. Department of Clinical Neuroscience, Karolinskaa Institutet, Stockholm, Sweden

    Xia Jiang

  7. Hainan General Hospital and Hainan Affiliated Hospital, Hainan Medical University, Haikou, China; West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Ben Zhang

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B.Z. and X.J. conceived and supervised the study. W.Z., J.Z., X.W., T.F., W.L., X.L., J.C., L.Z., C.X., H.C., C.Y., P.Y., Y.W., M.T., L.C., Y.L., Y.Z., and X.W. did the analyses. W.Z., B.Z., and X.J. drafted the manuscript with significant contributions from L.Z., C.Y., Y.Y., J.L., and Z.L. All authors contributed to the interpretations of the findings, critically revised the paper, and had final responsibility for the decision to submit for publication.

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Correspondence to Xia Jiang or Ben Zhang.

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UK Biobank participants provided written informed consent, and ethical approval was granted by the National Health Service North West Multi-Centre Research Ethics Committee (11/NW/0382). All GWAS summary statistics are publicly available, and the corresponding studies have obtained proper IRB approval and participants’ consent.

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Zhang, W., Zhu, J., Wu, X. et al. Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke. Hum. Genet. (2024). https://doi.org/10.1007/s00439-024-02666-1

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