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ORIGINAL RESEARCH article

Front. Genet.
Sec. Genetics of Aging
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1392061

Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset

Provisionally accepted
Joanna Von Berg Joanna Von Berg 1,2Patrick McArdle Patrick McArdle 3Paavo Häppölä Paavo Häppölä 4Jeffrey Haessler Jeffrey Haessler 5Charles Kooperberg Charles Kooperberg 5Robin Lemmens Robin Lemmens 6Alessandro Pezzini Alessandro Pezzini 7Vincent Thijs Vincent Thijs 8Sara L. Pulit Sara L. Pulit 2Steven Kittner Steven Kittner 9Braxton D. Mitchell Braxton D. Mitchell 3Jeroen de Ridder Jeroen de Ridder 2Sander W. van der Laan Sander W. van der Laan 10*
  • 1 Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands, Netherlands
  • 2 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands, Netherlands
  • 3 Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University Maryland School of Medicine, Baltimore, Maryland, United States
  • 4 Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, Helsinki, Finland
  • 5 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, California, United States
  • 6 Department of Neurology, University Hospitals Leuven, Leuven, Brussels, Belgium
  • 7 Department of Medicine and Surgery, University of Parma, Parma, Emilia-Romagna, Italy
  • 8 Stroke Theme, Florey Neuroscience Institutes, Parkville, Australia
  • 9 Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, United States
  • 10 Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht, Netherlands, Netherlands

The final, formatted version of the article will be published soon.

    Utilizing a case-only genome-wide association study (GWAS) design we identified a significant association between the APOE locus, specifically the rs429358 variant, and age at onset (AAO) of ischemic stroke. This exonic variant in APOE, linked to the APOE-Є4 allele, exhibited a compelling correlation, with each copy of the allele associated with a 1.29 years earlier stroke onset. Notably, our findings, supported by a robust discovery cohort of 10,857 ischemic stroke cases and reinforced through meta-analysis with replication cohorts, shed light on a potential survival bias influencing AAO. While APOE-Є4 has previously been linked to increased mortality and stroke AAO, our simulation study suggests that this association may be independent of ischemic stroke itself, emphasizing the need for nuanced interpretation in understanding the genetic factors influencing age at onset in stroke cases.

    Keywords: GWAS - genome-wide association study, Stroke, age at onset (AAO), APOE, Atherosclerosis

    Received: 26 Feb 2024; Accepted: 18 Jun 2024.

    Copyright: © 2024 Von Berg, McArdle, Häppölä, Haessler, Kooperberg, Lemmens, Pezzini, Thijs, Pulit, Kittner, Mitchell, de Ridder and van der Laan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Sander W. van der Laan, Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht, 3584CX, Netherlands, Netherlands

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.