Association between risk of ischemic stroke and the rs17216473 single nucleotide polymorphism in the 5-lipoxygenase-activating protein gene locus

O.Yu.  Pavlenko; I.G.  Strokina; T.I.  Drevytska; I.M.  Karvatsky; L.M.  Sokurenko; V.E.  Dosenko

doi:10.26641/2307-0404.2025.1.325230

Authors

O.Yu. Pavlenko O.O. Bogomolets Institute of Physiology of the National Academy of Sciences of Ukraine, Akademika Bogomoltsia str, 4, Kyiv, 01024, Ukraine https://orcid.org/0000-0002-4253-1120
I.G. Strokina Bogomolets National Medical University, T. Shevchenko blvd, 13, Kyiv, 01601, Ukraine, Ukraine https://orcid.org/0000-0002-3873-1111
T.I. Drevytska O.O. Bogomolets Institute of Physiology of the National Academy of Sciences of Ukraine, Akademika Bogomoltsia str, 4, Kyiv, 01024, Ukraine https://orcid.org/0000-0002-3192-4682
I.M. Karvatsky Bogomolets National Medical University, T. Shevchenko blvd, 13, Kyiv, 01601, Ukraine https://orcid.org/0000-0002-3117-309X
L.M. Sokurenko Bogomolets National Medical University, T. Shevchenko blvd, 13, Kyiv, 01601, Ukraine; Laboratory of Engineering, Informatics and Imaging (ICube), Integrative multimodal imaging in healthcare (IMIS), CNRS, UMR 7357, University of Strasbourg, Kirschleger str., 4, Strasbourg, 67085, France https://orcid.org/0000-0002-4152-0032
V.E. Dosenko O.O. Bogomolets Institute of Physiology of the National Academy of Sciences of Ukraine, Akademika Bogomoltsia str, 4, Kyiv, 01024, Ukraine https://orcid.org/0000-0002-6919-7724

DOI:

https://doi.org/10.26641/2307-0404.2025.1.325230

Keywords:

single nucleotide polymorphism, genetics, ischemic stroke, ALOX5AP

Abstract

Multiple studies have focused on the genetic basis of stroke, in particular on single nucleotide polymorphisms. However, the contribution of single nucleotide polymorphism rs17216473 in the gene that encodes ALOX5AP to stroke has been researched too little. The purpose of the work is to study the association between the risk of ischemic stroke and the single nucleotide polymorphism rs17216473 of the gene that encodes ALOX5AP, in particular, the G/G and G/A genotypes and alleles A and G, within the Ukrainian population. DNA extracted from leukocytes of venous blood of healthy donors (control group) and patients (stroke group) was studied. The control group consisted of 110 people, including 60 men (54.5%) and 50 women (45.5%), the average age in the group was 58.8±6.2 years, mode (Mo) by group was equal to 64 years. The absence of cardiovascular pathology in the donors was confirmed by anamnesis, electrocardiography and pressure measurement. The stroke group included 109 patients, 58 men (53.2%) and 51 women (46.8%), suffering from an acute violation of cerebral blood circulation (acute ischemic stroke). The focus of brain infarction was localized in the basin of the left middle cerebral artery in 51 patients (46.8%), in the basin of the right middle cerebral artery in 39 (35.8%), in the vertebral-basilar basin in 18 (16.5%) and in the basin of the left anterior cerebral artery in 1 patient (0.9%). 21 of these patients also have a history of ischemic stroke, 15 (13.8%) of them in the same basin and 6 (5.5%) in another vascular basin. The average age of patients at the time of brain infarction was 70.3±10.0 years, mode (Mo) by group was equal to 60 years. In the context of the study of the role of single nucleotide polymorphisms in the occurrence of stroke, the contingent of patients by age and localization of the focus of brain infarction is considered as homogeneous. Healthy donors and stroke patients belonged to the older age group, they are residents of Kyiv, the percentage of men and women in the indicated groups was almost the same, therefore, according to socio-demographic indicators, the group of stroke patients and the control group can be considered homogeneous. Taking into consideration the average age and mode (Mo) in the groups (58.8±6.2 years, Mo was 64 years in the control group and 70.3±10.0 years, Mo was equal to 60 years in the stroke group), the groups are statistically comparable in age. All women in both groups are postmenopausal. Real-time polymerase chain reaction and the analysis to discriminate alleles were used. The statistical analysis was performed using χ2 criteria and by χ2 criteria with Yates correction. We identified two genotypes, G/G and G/A, of the single nucleotide polymorphism rs17216473 of the gene that encodes ALOX5AP. Humans that were homozygotes for the minor allele A (carrying the A/A genotype) were not found in our study. Genotype G/G was the most prevalent in both the control and stroke groups, without significant difference between these groups. The carries of the G/A genotype were not as significantly represented as those of the G/G genotype. Simultaneously, there was no significant difference in the quantity of G/A genotype carries between the control and stroke groups. The distribution of the G allele was not significantly different between the control and stroke groups. The same trend was observed for allele A; its number in the control group was almost identical to that in the stroke group, Neither the G/G nor G/A genotypes were significantly associated with ischemic stroke risk (p>0.05). Neither allele (dominant allele G or minor allele A) of single nucleotide polymorphism rs17216473 were significantly associated with ischemic stroke risk in the Ukrainian population (p>0.05). No contribution of single nucleotide polymorphism rs17216473 (SG13S377) in the gene encoding ALOX5AP to ischemic stroke onset was observed in a Ukrainian population.

References

Liu X, Wang Q, Zhu R. Association of GWAS-susceptibility loci with ischemic stroke recurrence in a Han Chinese population. J Gene Med. 2021;23(1):e3264. doi: https://doi.org/10.1002/jgm.3264

Wang Q, Zhao J, Chang H, Liu X, Zhu R. Association between lncRNA ANRIL genetic variants with the susceptibility to ischemic stroke: From a case-control study to meta-analysis. Medicine (Baltimore). 2021;100(11):e25113. doi: https://doi.org/10.1097/MD.0000000000025113

Chen L, Zhang G, Li Q, Lin R. Variant Rs556621 on Chromosome 6p21.1 and the Risk of Ischemic Stroke in Chinese Populations: A Meta-Analysis. Clin Appl Thromb Hemost. 2022;28:10760296221076479. doi: https://doi.org/10.1177/10760296221076479

Appunni S, Rubens M, Ramamoorthy V, Saxe-na A, McGranaghan P, Veledar E. Stroke Genomics: Cur-rent Knowledge, Clinical Applications and Future Pos-sibilities. Brain Sci. 2022;12(3):302. doi: https://doi.org/10.3390/brainsci12030302

Deng XD, Ke JL, Chen TY, Gao Q, Zhao ZL, Zhang W, et al. ERCC1 polymorphism and its expression associated with ischemic stroke in Chinese population. Front Neurol. 2023;13:998428. doi: https://doi.org/10.3389/fneur.2022.998428

Munshi A, Kaul S. Genetic basis of stroke: an overview. Neurol India. 2010 Mar-Apr;58(2):185-90. doi: https://doi.org/10.4103/0028-3886.63780

Tuttolomondo A, Di Raimondo D, Pecoraro R, Casuccio A, Di Bona D, Aiello A, et al. J Neuroinflam-mation. 2019 Apr 17;16(1):88. doi: https://doi.org/10.1186/s12974-019-1469-5

Ekkert A, Šliachtenko A, Grigaitė J, Burnytė B, Utkus A, Jatužis D. Ischemic stroke genetics: what is new and how to apply it in clinical practice? Genes (Basel). 2021;13(1):48. doi: https://doi.org/10.3390/genes13010048

Helgadottir A, Manolescu A, Thorleifsson G, Gre-tarsdottir S, Jonsdottir H, Thorsteinsdottir U, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004;36(3):233-9. doi: https://doi.org/10.1038/ng1311

Helgadottir A, Gretarsdottir S, St Clair D, Mano-lescu A, Cheung J, Thorleifsson G, et al. Association bet-ween the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet. 2005;76(3):505-9. doi: https://doi.org/10.1086/428066

Jin S, Choi EJ, Choi YJ, Min WK, Park JY, Yoon SZ. Relationship between Arachidonate 5-Lipo-xygenase-Activating Protein Gene and Peripheral Arterial Disease in Elderly Patients Undergoing General Surgery: A Retrospective Observational Study. Int J Environ Res Public Health. 2023;20(2):1027. doi: https://doi.org/10.3390/ijerph20021027

Kajimoto K, Shioji K, Ishida C, Iwanaga Y, Kokubo Y, Tomoike H, et al. Validation of the association between the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a Japanese population. Circ J. 2005;69(9):1029-34. doi: https://doi.org/10.1253/circj.69.1029

Shah SH, Hauser ER, Crosslin D, Wang L, Hay-nes C, Connelly J, et al. ALOX5AP variants are associated with in-stent restenosis after percutaneous corona¬ry intervention. Atherosclerosis. 2008;201(1):148-54. doi: https://doi.org/10.1016/j.atherosclerosis.2008.01.011

Zhang S, Luo W, Pan T, Xie J, Xu Z, Fang Y. ALDH2 rs671 Polymorphism Likely a Risk Factor for Hemorrhagic Stroke: A Hospital-Based Study. Int J Gen Med. 2023;16:1471-8. doi: https://doi.org/10.2147/IJGM.S409183

Cao M, Zhang Y, Chen D, Zhong J, ZhangX, Yang L, et al. Polymorphism in genes encoding two fatty acid binding proteins increases risk of ischemic stroke in a Chinese Han population. Front Genet. 2023;14:1056186. doi: https://doi.org/10.3389/fgene.2023.1056186

Pavlenko OU, Strokina IG, Drevytska TI, Soku-renko LM, Dosenko VE. Association between single polymorphism in the locus RS17216473 of the gene that encodes 5-lipoxygenase-activating protein and risk of myocardial infarction. Wiad Lek. 2020;73(11):2431-7. doi: https://doi.org/10.36740/WLek202011118

Bie X, Zhao H, Zhang Z, Wang X, Luan Y, et al. Epigenetic regulation mechanism of DNA methylation and miRNAs on the expression of the ALOX5AP gene in patients with ischemic stroke. Exp Ther Med. 2021;22(6):1484. doi: https://doi.org/10.3892/etm.2021.10919

Domingues-Montanari S, Fernández-Cadenas I, del Rio-Espinola A, Corbeto N, Krug T, Manso H, et al. Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study. Cerebrovasc Dis. 2010;29(6):528-37. doi: https://doi.org/10.1159/000302738

Lõhmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, et al. ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke. 2005 Apr;36(4):731-6. doi: https://doi.org/10.1161/01.STR.0000157587.59821.87

Zhang SY, Xu ML, Zhang CE, Qu ZY, Zhang BB, Zheng ZY, et al. Association of ALOX5AP gene single nuc¬leotide polymorphisms and cerebral infarction in the Han population of northern China. BMC Med Genet. 2012;13:61. doi: https://doi.org/10.1186/1471-2350-13-61

Burdon KP, Rudock ME, Lehtinen AB, Langefeld CD, Bowden DW, Register TC, et al. Human lipoxygenase pathway gene variation and association with markers of subclinical atherosclerosis in the diabetes heart study. Mediators Inflamm. 2010;2010:170153. doi: https://doi.org/10.1155/2010/170153

Yu X, Zhang G, Tang X, Lin R. PDE4D single nucleotide polymorphism rs918592 is associated with ischemic stroke risk in Chinese populations: a meta-analysis. BMC Cardiovasc Disord. 2024 Jan 3;24(1):17. doi: https://doi.org/10.1186/s12872-023-03681-2

Nath M, Swarnkar P, Misra S, Kumar P. Phospho-diesterase 4 D (PDE4D) gene polymorphisms and risk of ischemic stroke: A systematic review and meta-analysis. Acta Neurol Belg. 2023 Dec;123(6):2085-110. doi: https://doi.org/10.1007/s13760-023-02218-w

Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003 Oct;35(2):131-8. doi: https://doi.org/10.1038/ng1245

Chen W, Zhu X, Hu Y, Hong H, Kuang L, Liang N, et al. Association of C-reactive protein gene polymorphisms with the risk of ischemic stroke: A systematic review and meta-analysis. Brain Behav. 2023 Jun;13(6):e2976. doi: https://doi.org/10.1002/brb3.2976

Li X, Gao Y, Zhao X, Chen Z, Li X, Yang X. Polymorphisms of C-reactive protein and growth arrest-specific gene 6 modulate ischemic stroke susceptibility through gene–gene interactions in Chinese Han population. Biotechnol Biotechnol Equip. 2020;34(1):937-45. doi: https://doi.org/10.1080/13102818.2020.1809518

Zhang X, Wang A, Zhang J, Singh M, Liu D, et al. Association of plasma C-reactive protein with ischemic stroke: a Mendelian randomization study. Eur J Neurol. 2020;27(3):565-71. doi: https://doi.org/10.1111/ene.14113

Kumar A, Sharma R, Misra S, Nath M, Kumar P. Relationship between methylenetetrahydrofolate reductase (MTHFR) gene (A1298C) polymorphism with the risk of stroke: A systematic review and meta-analysis. Neurol Res. 2020 Nov;42(11):913-22. doi: https://doi.org/10.1080/01616412.2020.1798107

Jin M, Wang N, Li X, Zhang H, Zhou J, Cong M, et al. Relationship between MTHFR C677T, homo-cysteine, and ischemic stroke in a large sample of the Han Chinese population. Medicine (Baltimore). 2022;101(38):e30562. doi: https://doi.org/10.1097/MD.0000000000030562

Zheng JH, Ning GL, Xu WH, Wu XC, Ma XC. Lack of association between ALOX5AP genetic polymo-rphisms and risk of ischemic stroke: evidence from meta-analyses. Neuropsychiatr Dis Treat. 2019;15:357-67. doi: https://doi.org/10.2147/NDT.S182674

Huryanov VG, Liakh YuYe, Parii VD, et al. [Handbook of biostatistics. Analysis of the results of medical research in the EZR package (R–statistics)]. Kyiv: Vistka; 2018. 208 p. Ukrainian. Available from: http://ir.librarynmu.com/bitstream/123456789/7398/1/Посібник%20з%20біостатистики.pdf

Ohniev VA, editor. [Social medicine, public health: study guide: in 4 volumes. Vol. 1: Biological statistics]. Kharkiv: KhNMU; 2023. 324 p. Ukrainian. doi: https://doi.org/10.5281/zenodo.10053302

Graffelman J, Weir BS. The transitivity of the Hardy-Weinberg law. Forensic Sci Int Genet. 2022;58:102680. doi: https://doi.org/10.1016/j.fsigen.2022.102680

Tang M, Wang T, Zhang X. A review of SNP heritability estimation methods. Brief Bioinform. 2022;23(3):bbac067. doi: https://doi.org/10.1093/bib/bbac067

Zhu H, Zhou X. Statistical methods for SNP heritability estimation and partition: A review. Comput Struct Biotechnol J. 2020;18:1557-68. doi: https://doi.org/10.1016/j.csbj.2020.06.011

Lemaitre RN, Rice K, Marciante K, Bis JC, Lumley TS, Wiggins KL, et al. Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke. Atherosclerosis. 2009 Jun;204(2):e58-63. doi: https://doi.org/10.1016/j.atherosclerosis.2008.10.011

Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35-41. doi: https://doi.org/10.1161/01.str.24.1.35

Kong P, Cui ZY, Huang XF, et al. Inflammation and atherosclerosis: signaling path¬ways and the¬ra¬peutic intervention. Signal Transduct Target Ther. 2022;7(1):131. doi: https://doi.org/10.1038/s41392-022-00955-7

Kuppa A, Tripathi H, Al-Darraji A, Tarhuni WM, Abdel-Latif A. C-reactive protein levels and risk of cardio¬vascular diseases: a two-sample bidirectional Men-delian ran¬domization study. Int J Mol Sci. 2023 May 23;24(11):9129. doi: https://doi.org/10.3390/ijms24119129

Pashkovskyi VM. [Differential diagnosis of ischemic stroke subtypes]. Practical Angiology [Internet]. 2011 [cited 2024 Sep 17];(2-1). Ukrainian. Available from: https://angiology.com.ua/en/archive/2011/2-1/article-395/diferenciyna-diagnostika-pidtipiv-ishemichnogo-insultu

Nath M, Swarnkar P, Sharma R, Kumar A, Mis-ra S, Kumar P. Association of modifiable risk factors with ischaemic stroke subtypes in Asian versus Caucasian populations: a systematic review and meta-analysis. Eur J Clin Invest. 2022 Nov;52(11):e13849. doi: https://doi.org/10.1111/eci.13849

Korczowska-Łącka I, Hurła M, Banaszek N, Ko-bylarek D, Szymanowicz O, Kozubski W, et al. Selected biomarkers of oxidative stress and energy metabolism disorders in neurological diseases. Mol Neurobiol. 2023 Jul;60(7):4132-49. doi: https://doi.org/10.1007/s12035-023-03329-4

Pinzon RT, Wijaya VO, Veronica V. The role of homocysteine levels as a risk factor of ischemic stroke events: a systematic review and meta-analysis. Front Neurol. 2023;14. doi https://doi.org/10.3389/fneur.2023.1144584

Zhuang Q, Shen C, Chen Y, Zhao X, Wei P, Sun J, et al. Association of high-sensitive C-reactive protein with coronary heart disease: a Mendelian randomization study. BMC Med Genet. 2019;20:170. doi: https://doi.org/10.1186/s12881-019-0910-z

Cao MY, Liu D, Zhang XY, Tian QY, Zhang Q, Wang YX. Association of C-reactive protein with cardio-vascular outcomes: a Mendelian randomization study in the Japanese population. Biomed Environ Sci. 2022;35:126-32. doi: https://doi.org/10.3967/bes2022.017

Mengozzi M, Kirkham FA, Girdwood EER, Bunting E, Drazich E, Timeyin J, et al. C-Reactive Protein Predicts Further Ischemic Events in Patients With Tran-sient Ischemic Attack or Lacunar Stroke. Front Im¬munol. 2020;11:1403. doi: https://doi.org/10.3389/fimmu.2020.01403