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Unravelling the genetic causality of immunoglobulin G N-glycans in ischemic stroke

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Abstract

Background: Evidence suggests that immunoglobulin G (IgG) N-glycosylation is associated with ischemic stroke (IS). However, the causality of IgG N-glycosylation for IS remains unknown. Methods: Two-sample Mendelian randomization (MR) analyses were performed to investigate the potential causal effects of genetically determined IgG N-glycans on IS using publicly available summarized genetic data from East Asian and European populations. Genetic instruments were used as proxies for IgG N-glycan traits. IgG N-glycans were analysed using ultra-performance liquid chromatography. Four complementary MR methods were performed, including the inverse variance weighted method (IVW), MR‒Egger, weighted median and penalized weighted median. Furthermore, to further test the robustness of the results, MR based on Bayesian model averaging (MR-BMA) was then applied to select and prioritize IgG N-glycan traits as risk factors for IS. Results: After correcting for multiple testing, in two-sample MR analyses, genetically predicted IgG N-glycans were unrelated to IS in both East Asian and European populations, and the results remained consistent and robust in the sensitivity analysis. Moreover, MR-BMA also showed consistent results in both East Asian and European populations. Conclusions: Contrary to observational studies, the study did not provide enough genetic evidence to support the causal associations of genetically predicted IgG N-glycan traits and IS, suggesting that N-glycosylation of IgG might not directly involve in the pathogenesis of IS.

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Data Availability

The data underlying this article will be shared upon reasonable request to the corresponding author. The summary association statistics of IS in East Asian can be found here: http://jenger.riken.jp/en/result/. The summary association statistics of IS in European are available at https://www.megastroke.org/mr.html.

Abbreviations

IgG:

immunoglobulin G

IS:

ischemic stroke

GP:

glycan peak

MR:

Mendelian randomization

MR-BMA:

MR based on Bayesian model averaging

MVMR:

Multivariable MR

UPLC:

Ultra-Performance Liquid Chromatography

IVs:

instrumental variables

IgG N-glycosylation-QTLs:

IgG N-glycan quantitative trait loci

GWAS:

genome-wide association study

SNP:

single-nucleotide polymorphism

MAF:

minor allele frequency

IVW:

inverse variance weighting

WM:

weighted median

PWM:

penalized weighted median

OR:

odds ratio

CI:

confidence interval

PP:

posterior probability

MIP:

marginal inclusion probability

MACE:

model-averaged causal effect

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Acknowledgements

We thank all the research participants, and data on IS-associated single nucleotide polymorphisms were accessed through BioBank Japan. Data on IS have been contributed by MEGASTROKE investigators. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. Data on IgG N-glycosylation-associated single nucleotide polymorphisms have been derived from published articles [29].

Funding

The study was supported by grants from the National Natural Science Foundation of China (81673247 and 81872682). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

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Author notes

  1. Biyan Wang and Lei Gao contributed equally.

Authors and Affiliations

  1. Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China

    Biyan Wang, Jie Zhang, Xiaoni Meng, Wei Wang & Youxin Wang

  2. Department of Health Management, the Second Affiliated Hospital, the Fourth Military Medical University, Xi’an, China

    Biyan Wang

  3. Department of Medical Engineering and Medical Supplies Center, PLA General Hospital, Beijing, China

    Lei Gao

  4. School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China

    Xizhu Xu, Haifeng Hou, Weijia Xing & Wei Wang

  5. Centre for Precision Medicine, Edith Cowan University, Perth, WA, 6027, Australia

    Haifeng Hou, Wei Wang & Youxin Wang

  6. School of Public Health, Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, China

    Youxin Wang

  7. Centre for Precision Medicine, Edith Cowan University, Perth, 60127, Australia

    Wei Wang

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  1. Biyan Wang
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Contributions

Youxin Wang, Wei Wang and Weijia Xing conceptualized the study. Biyan Wang, Lei Gao, Jie Zhang, Xiaoni Meng and Xizhu Xu conducted the IgG N-glycome analysis, analysed the data and drafted the manuscript. Biyan Wang and Haifeng Hou recruited the participants and collected the demographic and clinical information. Youxin Wang, Weijia Xing, Biyan Wang and Lei Gao critically revised the manuscript. All authors reviewed the manuscript.

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Correspondence to Weijia Xing, Wei Wang or Youxin Wang.

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Wang, B., Gao, L., Zhang, J. et al. Unravelling the genetic causality of immunoglobulin G N-glycans in ischemic stroke. Glycoconj J 40, 413–420 (2023). https://doi.org/10.1007/s10719-023-10127-6

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