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Novel Genome-Wide Interactions Mediated via BOLL and EDNRA Polymorphisms in Intracranial Aneurysm

  • Eun Pyo Hong (Institute of New Frontier Research, Hallym University College of Medicine) ;
  • Dong Hyuk Youn (Institute of New Frontier Research, Hallym University College of Medicine) ;
  • Bong Jun Kim (Institute of New Frontier Research, Hallym University College of Medicine) ;
  • Jae Jun Lee (Institute of New Frontier Research, Hallym University College of Medicine) ;
  • Sehyeon Nam (Department of Materials Science and Chemical Engineering, Hanyang University) ;
  • Hyojong Yoo (Department of Materials Science and Chemical Engineering, Hanyang University) ;
  • Heung Cheol Kim (Department of Radiology, Hallym University College of Medicine) ;
  • Jong Kook Rhim (Department of Neurosurgery, Jeju National University College of Medicine) ;
  • Jeong Jin Park (Department of Neurology, Konkuk University Medical Center) ;
  • Jin Pyeong Jeon (Department of Neurosurgery, Hallym University College of Medicine)
  • Received : 2022.02.08
  • Accepted : 2022.10.20
  • Published : 2023.07.01

Abstract

Objective : The association between boule (BOLL) and endothelin receptor type A (EDNRA) loci and intracranial aneurysm (IA) formation has been reported via genome-wide association studies. We sought to identify genome-wide interactions involving BOLL and EDNRA loci for IA in a Korean adult cohort. Methods : Genome-wide pairwise interaction analyses of BOLL and EDNRA involving 250 patients with IA and 296 controls were performed using the additive effect model after adjusting for confounding factors. Results : Among 512575 single-nucleotide polymorphisms (SNPs), 23 and 11 common SNPs suggested a genome-wide interaction threshold (p<1.25×10-8) involving rs700651 (BOLL) and rs6841581 (EDNRA). Rather than singe SNP effect of BOLL or EDNRA on IA development, they showed a synergistic effect on IA formation via multifactorial pair-wise interactions. The rs1105980 of PTCH1 gene showed the most significant interaction with rs700651 (natural log-transformed odds ratio [lnOR], 1.53; p=6.41×10-11). The rs74585958 of RYK gene interacted strongly with rs6841581 (lnOR, -19.91; p=1.64×10-9). Although, there was no direct interaction between BOLL and EDNRA variants, two EDNRA-interacting gene variants of TNIK (rs11925024 and rs1231) and FTO (rs9302654), and one BOLL-interacting METTL4 gene variant (rs549315) exhibited marginal interaction with BOLL gene. Conclusion : BOLL or EDNRA may have a synergistic effect on IA formation via multifactorial pair-wise interactions.

Keywords

Acknowledgement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HR21C0198) and Hallym University Research Fund. All genotype and phenotype resources are managed by "The First Korean Stroke Genetics Association Research" study constructed from the participating hospital stroke database.

References

  1. Bakker MK, van der Spek RAA, van Rheenen W, Morel S, Bourcier R, Hostettler IC, et al. : Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat Genet 52 : 1303-1313, 2020 https://doi.org/10.1038/s41588-020-00725-7
  2. Bilguvar K, Yasuno K, Niemela M, Ruigrok YM, von Und Zu Fraunberg M, van Duijn CM, et al. : Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet 40 : 1472-1477, 2008 https://doi.org/10.1038/ng.240
  3. Boehme AK, Esenwa C, Elkind MS : Stroke risk factors, genetics, and prevention. Circ Res 120 : 472-495, 2017 https://doi.org/10.1161/CIRCRESAHA.116.308398
  4. Brady LK, Wang H, Radens CM, Bi Y, Radovich M, Maity A, et al. : Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation. PLoS Biol 15 : e2002623, 2017
  5. Carlen M, Meletis K, Goritz C, Darsalia V, Evergren E, Tanigaki K, et al. : Forebrain ependymal cells are notch-dependent and generate neuro-blasts and astrocytes after stroke. Nat Neurosci 12 : 259-267, 2009 https://doi.org/10.1038/nn.2268
  6. Ding C, Toll V, Ouyang B, Chen M : Younger age of menopause in women with cerebral aneurysms. J Neurointerv Surg 5 : 327-331, 2013 https://doi.org/10.1136/neurintsurg-2012-010364
  7. Fang G, Wang W, Paunic V, Heydari H, Costanzo M, Liu X, et al. : Discovering genetic interactions bridging pathways in genome-wide association studies. Nat Commun 10 : 4274, 2019
  8. Feldner A, Adam MG, Tetzlaff F, Moll I, Komljenovic D, Sahm F, et al. : Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. EMBO Mol Med 9 : 890-905, 2017 https://doi.org/10.15252/emmm.201606430
  9. Genin E : Missing heritability of complex diseases: case solved? Hum Genet 139 : 103-113, 2020 https://doi.org/10.1007/s00439-019-02034-4
  10. Harrod CG, Batjer HH, Bendok BR : Deficiencies in estrogen-mediated regulation of cerebrovascular homeostasis may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in menopausal and postmenopausal women. Med Hypotheses 66 : 736-756, 2006 https://doi.org/10.1016/j.mehy.2005.09.051
  11. Hong EP, Kim BJ, Cho SS, Yang JS, Choi HJ, Kang SH, et al. : Genomic variations in susceptibility to intracranial aneurysm in the Korean population. J Clin Med 8 : 275, 2019
  12. Hong EP, Kim BJ, Jeon JP : Genome-wide association between the 2q33.1 locus and intracranial aneurysm susceptibility: an updated meta-analysis including 18,019 individuals. J Clin Med 8 : 692, 2019
  13. Hong EP, Kim BJ, Jeon JP, Yang JS, Choi HJ, Kang SH, et al. : Association of endothelin receptor type a with intracranial aneurysm in 20,609 East Asians: an updated meta-analysis. World Neurosurg 130 : e804-e814, 2019 https://doi.org/10.1016/j.wneu.2019.06.228
  14. Hong EP, Youn DH, Kim BJ, Ahn JH, Park JJ, Rhim JK, et al. : Fine-mapping of intracranial aneurysm susceptibility based on a genome-wide association study. Sci Rep 12 : 2717, 2022
  15. Inci S, Spetzler RF : Intracranial aneurysms and arterial hypertension: a review and hypothesis. Surg Neurol 53 : 530-540; discussion 540-542, 2000 https://doi.org/10.1016/S0090-3019(00)00244-5
  16. Jones GT, Tromp G, Kuivaniemi H, Gretarsdottir S, Baas AF, Giusti B, et al. : Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci. Circ Res 120 : 341-353, 2017
  17. Kang KJ, Pyo JH, Ryu KJ, Kim SJ, Ha JM, Choi K, et al. : Oncogenic role of BOLL in colorectal cancer. Dig Dis Sci 60 : 1663-1673, 2015 https://doi.org/10.1007/s10620-015-3533-z
  18. Kim BJ, Kim Y, Youn DH, Park JJ, Rhim JK, Kim HC, et al. : Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage. Sci Rep 10 : 11419, 2020
  19. Lee KY, Leung KS, Ma SL, So HC, Huang D, Tang NL, et al. : Genome-wide search for SNP interactions in GWAS data: algorithm, feasibility, replication using schizophrenia datasets. Front Genet 11 : 1003, 2020
  20. Li P, Guo M, Wang C, Liu X, Zou Q : An overview of SNP interactions in genome-wide association studies. Brief Funct Genomics 14 : 143-155, 2015 https://doi.org/10.1093/bfgp/elu036
  21. Lim KA, Kim KC, Cho MS, Lee BE, Kim HS, Hong YM : Gene expression of endothelin-1 and endothelin receptor a on monocrotaline-induced pulmonary hypertension in rats after bosentan treatment. Korean Circ J 40 : 459-464, 2010 https://doi.org/10.4070/kcj.2010.40.9.459
  22. Luetjens CM, Xu EY, Rejo Pera RA, Kamischke A, Nieschlag E, Gromoll J : Association of meiotic arrest with lack of BOULE protein expression in infertile men. J Clin Endocrinol Metab 89 : 1926-1933, 2004 https://doi.org/10.1210/jc.2003-031178
  23. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. : LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26 : 2336-2337, 2010 https://doi.org/10.1093/bioinformatics/btq419
  24. Tetzlaff F, Adam MG, Feldner A, Moll I, Menuchin A, Rodriguez-Vita J, et al. : MPDZ promotes DLL4-induced Notch signaling during angiogenesis. Elife 7 : e32860, 2018
  25. Vlak MH, Algra A, Brandenburg R, Rinkel GJ : Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 10 : 626-636, 2011 https://doi.org/10.1016/S1474-4422(11)70109-0
  26. Westerveld GH, Repping S, Leschot NJ, van der Veen F, Lombardi MP : Mutations in the human BOULE gene are not a major cause of impaired spermatogenesis. Fertil Steril 83 : 513-515, 2005 https://doi.org/10.1016/j.fertnstert.2004.10.013
  27. Wu X, Dong H, Luo L, Zhu Y, Peng G, Reveille JD, et al. : A novel statistic for genome-wide interaction analysis. PLoS Genet 6 : e1001131, 2010
  28. Xu EY, Moore FL, Pera RA : A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans. Proc Natl Acad Sci U S A 98 : 7414-7419, 2001 https://doi.org/10.1073/pnas.131090498
  29. Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, et al. : Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet 42 : 420-425, 2010 https://doi.org/10.1038/ng.563
  30. Zhang RL, Zhang ZG, Wang Y, LeTourneau Y, Liu XS, Zhang X, et al. : Stroke induces ependymal cell transformation into radial glia in the subventricular zone of the adult rodent brain. J Cereb Blood Flow Metab 27 : 1201-1212, 2007 https://doi.org/10.1038/sj.jcbfm.9600430
  31. Zhou S, Dion PA, Rouleau GA : Genetics of intracranial aneurysms. Stroke 49 : 780-787, 2018 https://doi.org/10.1161/STROKEAHA.117.018152