Association Between Hypoxia-Inducible Factor-1α and Neurological Diseases: A Bidirectional Two-Sample Mendelian Randomization Analysis

Overview

Journal Brain Behav

Specialty Psychology

Date 2025 Feb 28

PMID 40022282

Authors

Jing Liang

Xiaoyan Du

Mengfei Wang

Hongqin Zheng

Yang Sun

Yi Lin

Affiliations

Soon will be listed here.

Abstract

Background: Previous studies have suggested that hypoxia-inducible factor 1-α (HIF-1α) exerted multiple effects on different central nervous system disorders. However, it is still uncertain whether plasma HIF-1α can be a causal indicator for the relevant diseases. This study aimed to test the causality relationship between plasma HIF-1α and neurological diseases, including cerebrovascular diseases, migraines, and neurodegenerative diseases with a Mendelian randomization (MR) method.

Methods: Single-nucleotide polymorphisms (SNPs) genetically representing plasma HIF-1α were screened as instrumental variables (IVs). Summary-level data for neurological disorder from genome-wide association studies (GWAS) were identified as outcomes. The causal effects between the IVs and outcomes were determined via the major analysis of inverse-variance-weighted (IVW) method. The reverse causal direction was also performed to investigate the possibility of reverse causation.

Results: The findings revealed that plasma HIF-1α was identified to be genetically associated with cardioembolic stroke (CES) (OR = 0.885; 95% confidence interval [CI] = 0.796-0.985, p = 0.026), migraine (OR = 0.941, 95% CI = 0.888-0.998, p = 0.041), and drug-induced migraine without aura (MOA) (OR = 0.586, 95% CI = 0.375-0.916, p = 0.019). There was no association identified in plasma HIF-1α with subarachnoid hemorrhage (SAH), other stroke and migraine subtype, and neurodegenerative disorders. The reverse-MR analysis revealed that the above-stated neurological diseases did not have a causal effect on plasma HIF-1α levels. Sensitivity and validation analyses support that the above results are stable.

Conclusions: Our research indicated that plasma HIF-1α may have a causal effect on the risk of CES, migraine and drug-induced MOA, providing new insights for those disease prevention and therapeutic approaches.

References

Alexander C, Li T, Hattori Y, Chiu D, Frost G, Jonas L . Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion. Mol Psychiatry. 2022; 27(10):4264-4273. PMC: 9722522. DOI: 10.1038/s41380-022-01676-7. View

Sun B, Maranville J, Peters J, Stacey D, Staley J, Blackshaw J . Genomic atlas of the human plasma proteome. Nature. 2018; 558(7708):73-79. PMC: 6697541. DOI: 10.1038/s41586-018-0175-2. View

Maciejewska M, Sikora M, Stec A, Zaremba M, Maciejewski C, Pawlik K . Hypoxia-Inducible Factor-1α (HIF-1α) as a Biomarker for Changes in Microcirculation in Individuals with Systemic Sclerosis. Dermatol Ther (Heidelb). 2023; 13(7):1549-1560. PMC: 10307739. DOI: 10.1007/s13555-023-00952-w. View

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

Colgan S, Furuta G, Taylor C . Hypoxia and Innate Immunity: Keeping Up with the HIFsters. Annu Rev Immunol. 2020; 38:341-363. PMC: 7924528. DOI: 10.1146/annurev-immunol-100819-121537. View

Cai Y, Zhuang Y, Wang W, Jiang F, Hu J, Zhang X . Potential role of serum hypoxia-inducible factor 1alpha as a biomarker of delayed cerebral ischemia and poor clinical outcome after human aneurysmal subarachnoid hemorrhage: A prospective, longitudinal, multicenter, and observational study. Front Neurol. 2022; 13:1072351. PMC: 9772017. DOI: 10.3389/fneur.2022.1072351. View

Cooper W, Doty E, Hochstetler H, Hake A, Martin V . The current state of acute treatment for migraine in adults in the United States. Postgrad Med. 2020; 132(7):581-589. DOI: 10.1080/00325481.2020.1767402. View

Jiang Q, Ding Y, Li F, Fayyaz A, Duan H, Geng X . Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke. Redox Biol. 2024; 73:103169. PMC: 11070764. DOI: 10.1016/j.redox.2024.103169. View

Park J, Wacholder S, Gail M, Peters U, Jacobs K, Chanock S . Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet. 2010; 42(7):570-5. PMC: 4615599. DOI: 10.1038/ng.610. View

10.

Goschorska M, Gutowska I, Baranowska-Bosiacka I, Barczak K, Chlubek D . The Use of Antioxidants in the Treatment of Migraine. Antioxidants (Basel). 2020; 9(2). PMC: 7070237. DOI: 10.3390/antiox9020116. View

11.

Haddad J . Science review: redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for hypoxia-inducible factor-1alpha. Crit Care. 2003; 7(1):47-54. PMC: 154109. DOI: 10.1186/cc1840. View

12.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

13.

Wilson 3rd D, Cookson M, Van Den Bosch L, Zetterberg H, Holtzman D, Dewachter I . Hallmarks of neurodegenerative diseases. Cell. 2023; 186(4):693-714. DOI: 10.1016/j.cell.2022.12.032. View

14.

Tannahill G, Curtis A, Adamik J, Palsson-McDermott E, McGettrick A, Goel G . Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013; 496(7444):238-42. PMC: 4031686. DOI: 10.1038/nature11986. View

15.

Lv Q, Zheng Z, Zhang H, Guo M, Shen L . Serum hypoxia-inducible factor 1alpha emerges as a prognostic factor for severe traumatic brain injury. Clin Chim Acta. 2021; 522:77-82. DOI: 10.1016/j.cca.2021.08.017. View

16.

Nicolas A, Kenna K, Renton A, Ticozzi N, Faghri F, Chia R . Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018; 97(6):1267-1288. PMC: 5867896. DOI: 10.1016/j.neuron.2018.02.027. View

17.

Ashok B, Ajith T, Sivanesan S . Hypoxia-inducible factors as neuroprotective agent in Alzheimer's disease. Clin Exp Pharmacol Physiol. 2016; 44(3):327-334. DOI: 10.1111/1440-1681.12717. View

18.

Xue L, Chen H, Lu K, Huang J, Duan H, Zhao Y . Clinical significance of changes in serum neuroglobin and HIF-1α concentrations during the early-phase of acute ischemic stroke. J Neurol Sci. 2017; 375:52-57. DOI: 10.1016/j.jns.2017.01.039. View

19.

Hemani G, Zheng J, Elsworth B, Wade K, Haberland V, Baird D . The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018; 7. PMC: 5976434. DOI: 10.7554/eLife.34408. View

20.

Brion M, Shakhbazov K, Visscher P . Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013; 42(5):1497-501. PMC: 3807619. DOI: 10.1093/ije/dyt179. View