Intracranial large artery stenosis (ILAS) is one of the most common causes of stroke worldwide and is associated with the risk for future vascular events. Asymptomatic ILAS is a frequent finding on neuroimaging and shares many risk factors with atherosclerotic vascular disease. Whether asymptomatic ILAS is driven by genetic variants is not well-understood.
Methods:
This study included 4960 participants from seven geographically diverse population-based cohorts (34% Whites, 16% African Americans, 22% Hispanics, 24% Asians, 5% native Ecuadorians). We defined asymptomatic ILAS as luminal stenosis >50% in any large brain artery using time-of-flight magnetic resonance angiography.
Results:
A genome-wide association study revealed one variant in RP11-552D8.1 (rs75615271; odds ratio (OR), 1.22 (1.11–1.33); p = 4.85×10−8) associated with global ILAS at genome-wide significance (p < 5×10−8). Gene-based association analysis identified a gene-set enriched in chr1q32 region, including NEK2, LPGAT1, INTS7, DTL, and TMEM206, in global ILAS (p = 1.34 ×10−7) and anterior ILAS (p = 1.77 ×10−8).
Discussion and conclusion:
This study reveals one variant rs75615271 and a gene-set enriched in chr1q32 region associated with asymptomatic ILAS in a multi-population. Further functional studies may help elucidate the role that this variant plays in the pathophysiology of asymptomatic ILAS.
GorelickPBWongKSBaeHJ, et al. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke2008; 39: 2396–2399.
2.
KasnerSEChimowitzMILynnMJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation2006; 113: 555–563.
3.
HilalSXuXIkramMK, et al. Intracranial stenosis in cognitive impairment and dementia. J Cereb Blood Flow Metab2017; 37: 2262–2269.
4.
HongoHMiyawakiSImaiH, et al. Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis. Sci Rep2020; 10: 11942.
5.
QiaoYSuriFKZhangY, et al. Racial differences in prevalence and risk for intracranial atherosclerosis in a US community-based population. JAMA Cardiol2017; 2: 1341–1348.
6.
BangOY.Intracranial atherosclerosis: current understanding and perspectives. J Stroke2014; 16: 27–35.
7.
MiyawakiSImaiHShimizuM, et al. Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion. Stroke2013; 44: 2894–2897.
8.
OkazakiSMorimotoTKamataniY, et al. Moyamoya disease susceptibility variant RNF213 p. R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation2019; 139: 295–298.
9.
LiuMSariyaSKhasiyevF, et al. Genetic determinants of intracranial large artery stenosis in the northern Manhattan study. J Neurol Sci2022; 436: 120218.
10.
CuiMZhouSLiR, et al. Association of ADIPOQ single nucleotide polymorphisms with the risk of intracranial atherosclerosis. Int J Neurosci2017; 127: 427–432.
11.
KalitaJSomarajanBIKumarB, et al. Phosphodiesterase 4 D gene polymorphism in relation to intracranial and extracranial atherosclerosis in ischemic stroke. Dis Markers2011; 31: 191–197.
12.
MunshiASharmaVKaulS, et al. Association of the -344C/T aldosterone synthase (CYP11B2) gene variant with hypertension and stroke. J Neurol Sci2010; 296: 34–38.
13.
HurfordRWoltersFJLiL, et al. Prognosis of asymptomatic intracranial stenosis in patients with transient ischemic attack and minor stroke. JAMA Neurol2020; 77: 947–954.
14.
GutierrezJKhasiyevFLiuM, et al. Determinants and outcomes of asymptomatic intracranial atherosclerotic stenosis. J Am Coll Cardiol2021; 78: 562–571.
15.
von ElmEAltmanDGEggerM, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol2008; 61: 344–349.
16.
LiaoKPSunJCaiTA, et al. High-throughput multimodal automated phenotyping (MAP) with application to PheWAS. J Am Med Inform Assoc2019; 26: 1255–1262.
17.
WillerCJLiYAbecasisGR.METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics2010; 26: 2190–2191.
18.
WatanabeKTaskesenEvan BochovenA, et al. Functional mapping and annotation of genetic associations with FUMA. Nat Commun2017; 8: 1826.
19.
MalikRChauhanGTraylorM, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet2018; 50: 524–537.
20.
MiyazawaKItoKItoM, et al. Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction. Nat Genet2023; 55: 187–197.
21.
AragamKGJiangTGoelA, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet2022; 54: 1803–1815.
22.
SohJIqbalJQueirozJ, et al. MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat Med2013; 19: 892–900.
23.
WeiZZhaoJNieblerJ, et al. Quantitative proteomic profiling of mitochondrial toxicants in a human cardiomyocyte cell line. Front Genet2020; 11: 719.
24.
TraurigMTOrczewskaJIOrtizDJ, et al. Evidence for a role of LPGAT1 in influencing BMI and percent body fat in Native Americans. Obesity2013; 21: 193–202.
25.
HouJAertsJden HamerB, et al. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS ONE2010; 5: e10312.
26.
GongHMaCLiX, et al. Upregulation of LPGAT1 enhances lung adenocarcinoma proliferation. Front Biosci2023; 28: 89.
27.
WeiRNgoBWuG, et al. Phosphorylation of the Ndc80 complex protein, HEC1, by Nek2 kinase modulates chromosome alignment and signaling of the spindle assembly checkpoint. Mol Biol Cell2011; 22: 3584–3594.
28.
FengXJiangYCuiY, et al. NEK2 is associated with poor prognosis of clear cell renal cell carcinoma and promotes tumor cell growth and metastasis. Gene2023; 851: 147040.
29.
ZhangXHuangXXuJ, et al. NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1. Nat Commun2021; 12: 4536.
30.
FangYZhangX.Targeting NEK2 as a promising therapeutic approach for cancer treatment. Cell Cycle2016; 15: 895–907.
31.
LiXYaoYQianJ, et al. Overexpression and diagnostic significance of INTS7 in lung adenocarcinoma and its effects on tumor microenvironment. Int Immunopharmacol2021; 101: 108346.
32.
FedericoARienzoMAbbondanzaC, et al. Pan-cancer mutational and transcriptional analysis of the integrator complex. Int J Mol Sci2017; 18: 936.
33.
GreenwoodTAAkiskalHSAkiskalKK, et al. Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel Loci. Biol Psychiatry2012; 72: 303–310.
34.
LiZWangRQiuC, et al. Role of DTL in hepatocellular carcinoma and its impact on the tumor microenvironment. Front Immunol2022; 13: 834606.
35.
TeraiKAbbasTJazaeriAA, et al. CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol Cell2010; 37: 143–149.
36.
EvansDLZhangHHamH, et al. MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication. Cell Cycle2016; 15: 95–105.
37.
VanderdysVAllakAGuessousF, et al. The neddylation inhibitor pevonedistat (MLN4924) suppresses and radiosensitizes head and neck squamous carcinoma cells and tumors. Mol Cancer Ther2018; 17: 368–380.
38.
KiranSDarASinghSK, et al. The deubiquitinase USP46 is essential for proliferation and tumor growth of HPV-transformed cancers. Mol Cell2018; 72: 823–835.e825.
39.
PissasKPGründerSTianY.Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BK(Ca) channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells. Pflugers Arch2024; 476: 923–937.
40.
UllrichFBlinSLazarowK, et al. Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels. eLife2019; 8: e49187.
41.
Osei-OwusuJYangJLeungKH, et al. Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor-mediated endocytosis. Cell Rep2021; 34: 108683.
42.
ZeziuliaMBlinSSchmittFW, et al. Proton-gated anion transport governs macropinosome shrinkage. Nat Cell Biol2022; 24: 885–895.
43.
SongSZhangYDingT, et al. The dual role of macropinocytosis in cancers: promoting growth and inducing methuosis to participate in anticancer therapies as targets. Front Oncol2020; 10: 570108.
44.
KotnisSBinghamBVasilyevDV, et al. Genetic and functional analysis of human P2X5 reveals a distinct pattern of exon 10 polymorphism with predominant expression of the nonfunctional receptor isoform. Mol Pharmacol2010; 77: 953–960.
45.
AbramowskiPOgrodowczykCMartinR, et al. A truncation variant of the cation channel P2RX5 is upregulated during T cell activation. PLoS ONE2014; 9: e104692.
46.
KingBF.Rehabilitation of the P2X5 receptor: a re-evaluation of structure and function. Purinergic Signal2023; 19: 421–439.
47.
YapCXVoDDHeffelMG, et al. Brain cell-type shifts in Alzheimer’s disease, autism, and schizophrenia interrogated using methylomics and genetics. Sci Adv2024; 10: eadn7655.
48.
HooperJDClementsJAQuigleyJP, et al. Type II transmembrane serine proteases. Insights into an emerging class of cell surface proteolytic enzymes. J Biol Chem2001; 276: 857–860.
49.
AntalisTMBuzzaMSHodgeKM, et al. The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment. Biochem J2010; 428: 325–346.
50.
LuostariKHartikainenJMTengstromM, et al. Type II transmembrane serine protease gene variants associate with breast cancer. PLoS ONE2014; 9: e102519.
51.
YamadaYSakumaJTakeuchiI, et al. Identification of six polymorphisms as novel susceptibility loci for ischemic or hemorrhagic stroke by exome-wide association studies. Int J Mol Med2017; 39: 1477–1491.
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