Skip to main content
SpringerLink
Log in

Genetic Risk Factors of Intracranial Atherosclerosis

  • Genetics and Genomics (A. Marian, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Intracranial atherosclerosis (ICAS) is the most common cause of stroke throughout the world. It also increases the risk of recurrent stroke and dementia. As a complex and multifactorial disease, ICAS is influenced by multiple genetic, biological, and environmental factors. This review summarizes the candidate gene and genome-wide studies aimed at discovering genetic risk factors of ICAS.

Recent Findings

Numerous studies have focused on the association between single-nucleotide polymorphisms (SNPs) of atherosclerosis-related genes and the risk of ICAS. Variants in adiponectin Q (ADIPOQ), ring finger protein 213 (RNF213), apolipoprotein E (APOE), phosphodiesterase 4D (PDE4D), methylenetetrahydrofolate reductase (MTHFR), lipoprotein lipase (LPL), α-adducin (ADD1) genes, angiotensin-converting enzyme (ACE), and other genes related to renin-angiotensin-aldosterone system have been associated with ICAS.

Summary

We review the available evidences on the candidate genes and SNPs associated with genetic susceptibility to ICAS, and point out future developments of this field. Genetic discoveries could have clinical implications for intracranial atherosclerotic disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ritz K, Denswil NP, Stam OC, van Lieshout JJ, Daemen MJ. Cause and mechanisms of intracranial atherosclerosis. Circulation. 2014;130(16):1407–14. https://doi.org/10.1161/CIRCULATIONAHA.114.011147.

    Article  PubMed  Google Scholar 

  2. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke. 2008;39(8):2396–9. https://doi.org/10.1161/STROKEAHA.107.505776.

    Article  PubMed  Google Scholar 

  3. Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, Lee EB, et al. Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain. 2012;135(Pt 12):3749–56. https://doi.org/10.1093/brain/aws271.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bos D, van der Rijk MJ, Geeraedts TE, Hofman A, Krestin GP, Witteman JC, et al. Intracranial carotid artery atherosclerosis: prevalence and risk factors in the general population. Stroke. 2012;43(7):1878–84. https://doi.org/10.1161/STROKEAHA.111.648667.

    Article  PubMed  Google Scholar 

  5. Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet (London, England). 2014;383(9921):984–98. https://doi.org/10.1016/s0140-6736(13)61088-0.

    Article  Google Scholar 

  6. Gutierrez J, Elkind MS, Virmani R, Goldman J, Honig L, Morgello S, et al. A pathological perspective on the natural history of cerebral atherosclerosis. Int J Stroke. 2015;10(7):1074–80. https://doi.org/10.1111/ijs.12496.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shapiro SD, Goldman J, Morgello S, Honig L, Elkind MSV, Marshall RS, et al. Pathological correlates of brain arterial calcifications. Cardiovasc Pathol. 2019;38:7–13. https://doi.org/10.1016/j.carpath.2018.09.003.

    Article  PubMed  Google Scholar 

  8. Banerjee C, Chimowitz MI. Stroke caused by atherosclerosis of the major intracranial arteries. Circ Res. 2017;120(3):502–13. https://doi.org/10.1161/CIRCRESAHA.116.308441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993–1003. https://doi.org/10.1056/NEJMoa1105335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hoshino T, Sissani L, Labreuche J, Ducrocq G, Lavallee PC, Meseguer E, et al. Prevalence of systemic atherosclerosis burdens and overlapping stroke etiologies and their associations with long-term vascular prognosis in stroke with intracranial atherosclerotic disease. JAMA neurology. 2018;75(2):203–11. https://doi.org/10.1001/jamaneurol.2017.3960.

    Article  PubMed  Google Scholar 

  11. Rincon F, Sacco RL, Kranwinkel G, Xu Q, Paik MC, Boden-Albala B, et al. Incidence and risk factors of intracranial atherosclerotic stroke: the Northern Manhattan Stroke Study. Cerebrovascular diseases (Basel, Switzerland). 2009;28(1):65–71. https://doi.org/10.1159/000219299.

    Article  Google Scholar 

  12. Bang OY, Kim JW, Lee JH, Lee MA, Lee PH, Joo IS, et al. Association of the metabolic syndrome with intracranial atherosclerotic stroke. Neurology. 2005;65(2):296–8. https://doi.org/10.1212/01.wnl.0000168862.09764.9f.

    Article  CAS  PubMed  Google Scholar 

  13. Sacco RL, Kargman DE, Zamanillo MC. Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction: the Northern Manhattan Stroke Study. Neurology. 1995;45(4):659–63. https://doi.org/10.1212/wnl.45.4.659.

    Article  CAS  PubMed  Google Scholar 

  14. Kim JS, Nah HW, Park SM, Kim SK, Cho KH, Lee J, et al. Risk factors and stroke mechanisms in atherosclerotic stroke: intracranial compared with extracranial and anterior compared with posterior circulation disease. Stroke. 2012;43(12):3313–8. https://doi.org/10.1161/strokeaha.112.658500.

    Article  CAS  PubMed  Google Scholar 

  15. Pu Y, Liu L, Wang Y, Zou X, Pan Y, Soo Y, et al. Geographic and sex difference in the distribution of intracranial atherosclerosis in China. Stroke. 2013;44(8):2109–14. https://doi.org/10.1161/strokeaha.113.001522.

    Article  PubMed  Google Scholar 

  16. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke. 1995;26(1):14–20.

    Article  CAS  Google Scholar 

  17. White H, Boden-Albala B, Wang C, Elkind MS, Rundek T, Wright CB, et al. Ischemic stroke subtype incidence among Whites, Blacks, and Hispanics: the Northern Manhattan Study. Circulation. 2005;111(10):1327–31. https://doi.org/10.1161/01.CIR.0000157736.19739.D0.

    Article  PubMed  Google Scholar 

  18. Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke. 1996;27(11):1974–80.

    Article  CAS  Google Scholar 

  19. • Cai B, Peng B. Intracranial artery stenosis: current status of evaluation and treatment in China. Chronic Dis Transl Med. 2017;3(4):197–206. https://doi.org/10.1016/j.cdtm.2017.09.003Current evaluation and treatment on intracranial artery stenosis.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Feldmann E, Daneault N, Kwan E, Ho KJ, Pessin MS, Langenberg P, et al. Chinese-white differences in the distribution of occlusive cerebrovascular disease. Neurology. 1990;40(10):1541–5. https://doi.org/10.1212/wnl.40.10.1540.

    Article  CAS  PubMed  Google Scholar 

  21. Gorelick P, Wong KS, Liu L. Epidemiology. Front Neurol Neurosci. 2016;40:34–46. https://doi.org/10.1159/000448272.

    Article  PubMed  Google Scholar 

  22. Uehara T, Tabuchi M, Mori E. Frequency and clinical correlates of occlusive lesions of cerebral arteries in Japanese patients without stroke. Evaluation by MR angiography. Cerebrovascular diseases (Basel, Switzerland). 1998;8(5):267–72. https://doi.org/10.1159/000015864.

    Article  CAS  Google Scholar 

  23. Kim JS, Kang DW, Kwon SU. Intracranial atherosclerosis: incidence, diagnosis and treatment. J Clin Neurol. 2005;1(1):1–7. https://doi.org/10.3988/jcn.2005.1.1.1.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Park JH, Hong KS, Lee EJ, Lee J, Kim DE. High levels of apolipoprotein B/AI ratio are associated with intracranial atherosclerotic stenosis. Stroke. 2011;42(11):3040–6. https://doi.org/10.1161/strokeaha.111.620104.

    Article  CAS  PubMed  Google Scholar 

  25. Qian Y, Pu Y, Liu L, Wang DZ, Zhao X, Wang C, et al. Low HDL-C level is associated with the development of intracranial artery stenosis: analysis from the Chinese IntraCranial AtheroSclerosis (CICAS) study. PLoS One. 2013;8(5):e64395. https://doi.org/10.1371/journal.pone.0064395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ingall TJ, Homer D, Baker HL Jr, Kottke BA, O’Fallon WM, Whisnant JP. Predictors of intracranial carotid artery atherosclerosis. Duration of cigarette smoking and hypertension are more powerful than serum lipid levels. Arch Neurol. 1991;48(7):687–91. https://doi.org/10.1001/archneur.1991.00530190033011.

    Article  CAS  PubMed  Google Scholar 

  27. Ji R, Pan Y, Yan H, Zhang R, Liu G, Wang P, et al. Current smoking is associated with extracranial carotid atherosclerotic stenosis but not with intracranial large artery disease. BMC Neurol. 2017;17(1):120–8. https://doi.org/10.1186/s12883-017-0873-7.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jerrard-Dunne P, Sitzer M, Risley P, Buehler A, von Kegler S, Markus HS. Inflammatory gene load is associated with enhanced inflammation and early carotid atherosclerosis in smokers. Stroke. 2004;35(11):2438–43. https://doi.org/10.1161/01.STR.0000144681.46696.b3.

    Article  CAS  PubMed  Google Scholar 

  29. Marteau JB, Zaiou M, Siest G, Visvikis-Siest S. Genetic determinants of blood pressure regulation. J Hypertens. 2005;23(12):2127–43. https://doi.org/10.1097/01.hjh.0000186024.12364.2e.

    Article  CAS  PubMed  Google Scholar 

  30. •• Cui M, Zhou S, Li R, Yin Z, Yu M, Zhou H. Association of ADIPOQ single nucleotide polymorphisms with the risk of intracranial atherosclerosis. Int J Neurosci. 2017;127(5):427–32. https://doi.org/10.1080/00207454.2016.1190716A recently study revealed the association of ADIPOQ SNPs with the risk of intracranial atherosclerosis.

    Article  CAS  PubMed  Google Scholar 

  31. Wassel CL, Pankow JS, Rasmussen-Torvik LJ, Li N, Taylor KD, Guo X, et al. Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the multi-ethnic study of atherosclerosis (MESA). Obesity (Silver Spring). 2011;19(4):840–7. https://doi.org/10.1038/oby.2010.229.

    Article  CAS  Google Scholar 

  32. Du W, Li Q, Lu Y, Yu X, Ye X, Gao Y, et al. Genetic variants in ADIPOQ gene and the risk of type 2 diabetes: a case-control study of Chinese Han population. Endocrine. 2011;40(3):413–22. https://doi.org/10.1007/s12020-011-9488-8.

    Article  CAS  PubMed  Google Scholar 

  33. Hegener HH, Lee IM, Cook NR, Ridker PM, Zee RY. Association of adiponectin gene variations with risk of incident myocardial infarction and ischemic stroke: a nested case-control study. Clin Chem. 2006;52(11):2021–7. https://doi.org/10.1373/clinchem.2006.074476.

    Article  CAS  PubMed  Google Scholar 

  34. Wong HK, Ong KL, Leung RY, Cheung TT, Xu A, Lam TH, et al. Plasma level of adrenomedullin is influenced by a single nucleotide polymorphism in the adiponectin gene. PLoS One. 2013;8(8):e70335. https://doi.org/10.1371/journal.pone.0070335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Miyawaki S, Imai H, Shimizu M, Yagi S, Ono H, Mukasa A, et al. Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion. Stroke. 2013;44(10):2894–7. https://doi.org/10.1161/strokeaha.113.002477.

    Article  CAS  PubMed  Google Scholar 

  36. •• Shinya Y, Miyawaki S, Imai H, Hongo H, Ono H, Takenobu A, et al. Genetic Analysis of Ring Finger Protein 213 (RNF213) c.14576G>A in Intracranial Atherosclerosis of the Anterior and Posterior Circulations. J Stroke Cerebrovasc Dis. 2017;26(11):2638–44. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.06.043A recently study revealed the association between the RNF213 variant and intracranial atherosclerosis.

    Article  PubMed  Google Scholar 

  37. Bang OY, Chung JW, Cha J, Lee MJ, Yeon JY, Ki CS, et al. A polymorphism in RNF213 is a susceptibility gene for intracranial atherosclerosis. PLoS One. 2016;11(6):e0156607. https://doi.org/10.1371/journal.pone.0156607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ilveskoski E, Perola M, Lehtimaki T, Laippala P, Savolainen V, Pajarinen J, et al. Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study. Circulation. 1999;100(6):608–13. https://doi.org/10.1161/01.cir.100.6.608.

    Article  CAS  PubMed  Google Scholar 

  39. Hixson JE, Apolipoprotein E. Polymorphisms affect atherosclerosis in young males. Pathobiological determinants of atherosclerosis in youth (PDAY) research group. Arterioscler Thromb. 1991;11(5):1237–44.

    Article  CAS  Google Scholar 

  40. Abboud S, Viiri LE, Lutjohann D, Goebeler S, Luoto T, Friedrichs S, et al. Associations of apolipoprotein E gene with ischemic stroke and intracranial atherosclerosis. Eur J Hum Genet. 2008;16(8):955–60. https://doi.org/10.1038/ejhg.2008.27.

    Article  CAS  PubMed  Google Scholar 

  41. Chutinet A, Suwanwela NC, Snabboon T, Chaisinanunkul N, Furie KL, Phanthumchinda K. Association between genetic polymorphisms and sites of cervicocerebral artery atherosclerosis. J Stroke Cerebrovasc Dis. 2012;21(5):379–85. https://doi.org/10.1016/j.jstrokecerebrovasdis.2010.10.002.

    Article  PubMed  Google Scholar 

  42. Kalita J, Somarajan BI, Kumar B, Kumar S, Mittal B, Misra UK. Phosphodiesterase 4 D gene polymorphism in relation to intracranial and extracranial atherosclerosis in ischemic stroke. Dis Markers. 2011;31(4):191–7. https://doi.org/10.3233/DMA-2011-0810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang Y, Zhang J, Qian Y, Tang X, Ling H, Chen K, et al. Association of Homocysteine with aysmptomatic intracranial and extracranial arterial stenosis in hypertension patients. Sci Rep. 2018;8(1):595. https://doi.org/10.1038/s41598-017-19125-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Oh SH, Kim NK, Kim HS, Kim WC, Kim OJ. Plasma total homocysteine and the methylenetetrahydrofolate reductase 677C>T polymorphism do not contribute to the distribution of cervico-cerebral atherosclerosis in ischaemic stroke patients. Eur J Neurol. 2011;18(3):491–6. https://doi.org/10.1111/j.1468-1331.2010.03188.x.

    Article  PubMed  Google Scholar 

  45. Munshi A, Babu MS, Kaul S, Rajeshwar K, Balakrishna N, Jyothy A. Association of LPL gene variant and LDL, HDL, VLDL cholesterol and triglyceride levels with ischemic stroke and its subtypes. J Neurol Sci. 2012;318(1–2):51–4. https://doi.org/10.1016/j.jns.2012.04.006.

    Article  CAS  PubMed  Google Scholar 

  46. Shimo-Nakanishi Y, Urabe T, Hattori N, Watanabe Y, Nagao T, Yokochi M, et al. Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese. Stroke. 2001;32(7):1481–6. https://doi.org/10.1161/01.str.32.7.1481.

    Article  CAS  PubMed  Google Scholar 

  47. Xu E, Li W, Zhan L, Guan G, Wang X, Chen S, et al. Polymorphisms of the lipoprotein lipase gene are associated with atherosclerotic cerebral infarction in the Chinese. Neuroscience. 2008;155(2):403–8. https://doi.org/10.1016/j.neuroscience.2008.06.007.

    Article  CAS  PubMed  Google Scholar 

  48. van Rijn MJ, Bos MJ, Yazdanpanah M, Isaacs A, Arias-Vasquez A, Koudstaal PJ, et al. Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk. Stroke. 2006;37(12):2930–4. https://doi.org/10.1161/01.STR.0000248760.67039.2b.

    Article  CAS  PubMed  Google Scholar 

  49. Kalita J, Misra UK, Kumar B, Somarajan BI, Kumar S, Mittal B. ACE and ADD1 gene in extra and intracranial atherosclerosis in ischaemic stroke. Neurol Res. 2013;35(4):429–34. https://doi.org/10.1179/1743132813Y.0000000161.

    Article  CAS  PubMed  Google Scholar 

  50. Rong C, Xing Y, Jiang X, Wang J, Gao B, Zhao J, et al. Angiotensin-converting enzyme gene polymorphism and middle cerebral artery stenosis in a Chinese Han population. Neural Regen Res. 2013;8(15):1410–7. https://doi.org/10.3969/j.issn.1673-5374.2013.15.008.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Thomas GN, Lin JW, Lam WW, Tomlinson B, Yeung V, Chan JC, et al. Middle cerebral artery stenosis in type II diabetic Chinese patients is associated with conventional risk factors but not with polymorphisms of the renin-angiotensin system genes. Cerebrovascular diseases (Basel, Switzerland). 2003;16(3):217–23. https://doi.org/10.1159/000071119.

    Article  CAS  Google Scholar 

  52. Munshi A, Sharma V, Kaul S, Rajeshwar K, Babu MS, Shafi G, et al. Association of the -344C/T aldosterone synthase (CYP11B2) gene variant with hypertension and stroke. J Neurol Sci. 2010;296(1–2):34–8. https://doi.org/10.1016/j.jns.2010.06.013.

    Article  CAS  PubMed  Google Scholar 

  53. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003;46(4):459–69. https://doi.org/10.1007/s00125-003-1074-z.

    Article  CAS  PubMed  Google Scholar 

  54. Zhao T, Zhao J. Genetic effects of adiponectin on blood lipids and blood pressure. Clin Endocrinol. 2011;74(2):214–22. https://doi.org/10.1111/j.1365-2265.2010.03902.x.

    Article  CAS  Google Scholar 

  55. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 2002;277(29):25863–6. https://doi.org/10.1074/jbc.C200251200.

    Article  CAS  PubMed  Google Scholar 

  56. Nawrocki AR, Scherer PE. The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Curr Opin Pharmacol. 2004;4(3):281–9. https://doi.org/10.1016/j.coph.2004.03.003.

    Article  CAS  PubMed  Google Scholar 

  57. Muiya N, Al-Najai M, Tahir AI, Elhawari S, Gueco D, Andres E, et al. The 3′-UTR of the adiponectin Q gene harbours susceptibility loci for atherosclerosis and its metabolic risk traits. BMC Med Genet. 2013;14:127. https://doi.org/10.1186/1471-2350-14-127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tong G, Wang N, Leng J, Tong X, Shen Y, Yang J, et al. Common variants in adiponectin gene are associated with coronary artery disease and angiographical severity of coronary atherosclerosis in type 2 diabetes. Cardiovasc Diabetol. 2013;12:67. https://doi.org/10.1186/1475-2840-12-67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Foucan L, Maimaitiming S, Larifla L, Hedreville S, Deloumeaux J, Joannes MO, et al. Adiponectin gene variants, adiponectin isoforms and cardiometabolic risk in type 2 diabetic patients. J Diabetes Investig. 2014;5(2):192–8. https://doi.org/10.1111/jdi.12133.

    Article  CAS  PubMed  Google Scholar 

  60. Ong KL, Li M, Tso AW, Xu A, Cherny SS, Sham PC, et al. Association of genetic variants in the adiponectin gene with adiponectin level and hypertension in Hong Kong Chinese. Eur J Endocrinol. 2010;163(2):251–7. https://doi.org/10.1530/EJE-10-0251.

    Article  CAS  PubMed  Google Scholar 

  61. Wassel CL, Pankow JS, Jacobs DR Jr, Steffes MW, Li N, Schreiner PJ. Variants in the adiponectin gene and serum adiponectin: the Coronary Artery Development in Young Adults (CARDIA) Study. Obesity (Silver Spring). 2010;18(12):2333–8. https://doi.org/10.1038/oby.2010.85.

    Article  CAS  Google Scholar 

  62. Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet. 2011;56(1):34–40. https://doi.org/10.1038/jhg.2010.132.

    Article  CAS  PubMed  Google Scholar 

  63. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542. https://doi.org/10.1371/journal.pone.0022542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fujimura M, Sonobe S, Nishijima Y, Niizuma K, Sakata H, Kure S, et al. Genetics and biomarkers of moyamoya disease: significance of RNF213 as a susceptibility gene. J Stroke. 2014;16(2):65–72. https://doi.org/10.5853/jos.2014.16.2.65.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Miyawaki S, Imai H, Takayanagi S, Mukasa A, Nakatomi H, Saito N. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke. 2012;43(12):3371–4. https://doi.org/10.1161/STROKEAHA.112.663864.

    Article  PubMed  Google Scholar 

  66. Bang OY, Ryoo S, Kim SJ, Yoon CH, Cha J, Yeon JY, et al. Adult moyamoya disease: a burden of intracranial stenosis in East Asians? PLoS One. 2015;10(6):e0130663. https://doi.org/10.1371/journal.pone.0130663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu W, Hitomi T, Kobayashi H, Harada KH, Koizumi A. Distribution of moyamoya disease susceptibility polymorphism p.R4810K in RNF213 in East and Southeast Asian populations. Neurol Med Chir (Tokyo). 2012;52(5):299–303. https://doi.org/10.2176/nmc.52.299.

    Article  Google Scholar 

  68. Choi EH, Lee H, Chung JW, Seo WK, Kim GM, Ki CS, et al. Ring finger protein 213 variant and plaque characteristics, vascular remodeling, and hemodynamics in patients with intracranial atherosclerotic stroke: a high-resolution magnetic resonance imaging and hemodynamic study. J Am Heart Assoc. 2019;8(20):e011996. https://doi.org/10.1161/JAHA.119.011996.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer′s disease and other neurological disorders. Lancet Neurol. 2011;10(3):241–52. https://doi.org/10.1016/S1474-4422(10)70325-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. https://doi.org/10.1038/nrneurol.2012.263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. Jama. 2007;298(11):1300–11. https://doi.org/10.1001/jama.298.11.1300.

    Article  CAS  PubMed  Google Scholar 

  72. Hogh P, Garde E, Mortensen EL, Jorgensen OS, Krabbe K, Waldemar G. The apolipoprotein E epsilon4-allele and antihypertensive treatment are associated with increased risk of cerebral MRI white matter hyperintensities. Acta Neurol Scand. 2007;115(4):248–53. https://doi.org/10.1111/j.1600-0404.2006.00779.x.

    Article  CAS  PubMed  Google Scholar 

  73. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, et al. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998;279(10):751–5.

    Article  CAS  Google Scholar 

  74. Roher AE, Esh C, Rahman A, Kokjohn TA, Beach TG. Atherosclerosis of cerebral arteries in Alzheimer disease. Stroke. 2004;35(11 Suppl 1):2623–7. https://doi.org/10.1161/01.STR.0000143317.70478.b3.

    Article  PubMed  Google Scholar 

  75. Honig LS, Kukull W, Mayeux R. Atherosclerosis and AD: analysis of data from the US National Alzheimer’s Coordinating Center. Neurology. 2005;64(3):494–500. https://doi.org/10.1212/01.WNL.0000150886.50187.30.

    Article  PubMed  Google Scholar 

  76. Yan Y, Luo X, Zhang J, Su L, Liang W, Huang G, et al. Association between phosphodiesterase 4D polymorphism SNP83 and ischemic stroke. J Neurol Sci. 2014;338(1–2):3–11. https://doi.org/10.1016/j.jns.2013.12.012.

    Article  CAS  PubMed  Google Scholar 

  77. Liao YC, Lin HF, Guo YC, Yu ML, Liu CK, Juo SH. Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis. BMC Med Genet. 2010;11:93. https://doi.org/10.1186/1471-2350-11-93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Munshi A, Kaul S. Stroke genetics--focus on PDE4D gene. Int J Stroke. 2008;3(3):188–92. https://doi.org/10.1111/j.1747-4949.2008.00199.x.

    Article  PubMed  Google Scholar 

  79. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370(Pt 1):1–18. https://doi.org/10.1042/BJ20021698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Smith SA, Newby AC, Bond M. Ending restenosis: inhibition of vascular smooth muscle cell proliferation by cAMP. Cells. 2019;8(11). https://doi.org/10.3390/cells8111447.

    Article  CAS  Google Scholar 

  81. Kim C, Wilcox-Adelman S, Sano Y, Tang WJ, Collier RJ, Park JM. Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus. Proc Natl Acad Sci U S A. 2008;105(16):6150–5. https://doi.org/10.1073/pnas.0800105105.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Yang JX, Hsiung TC, Weng FC, Ding SL, Wu CP, Conti M, et al. Synergistic effect of phosphodiesterase 4 inhibitor and serum on migration of endotoxin-stimulated macrophages. Innate immunity. 2018;24(8):501–12. https://doi.org/10.1177/1753425918809155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim JO, Park HS, Ryu CS, Shin JW, Kim J, Oh SH, et al. Interplay between 3′-UTR polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk of ischemic stroke. Sci Rep. 2017;7(1):12464. https://doi.org/10.1038/s41598-017-12668-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhao M, Wang X, He M, Qin X, Tang G, Huo Y, et al. Homocysteine and stroke risk: modifying effect of methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. Stroke. 2017;48(5):1183–90. https://doi.org/10.1161/STROKEAHA.116.015324.

    Article  CAS  PubMed  Google Scholar 

  85. Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke. 2005;36(7):1581–7. https://doi.org/10.1161/01.STR.0000169946.31639.af.

    Article  CAS  PubMed  Google Scholar 

  86. Rutten-Jacobs LC, Traylor M, Adib-Samii P, Thijs V, Sudlow C, Rothwell PM, et al. Association of MTHFR C677T genotype with ischemic stroke is confined to cerebral small vessel disease subtype. Stroke. 2016;47(3):646–51. https://doi.org/10.1161/strokeaha.115.011545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lin X, Zhang W, Lu Q, Lei X, Wang T, Han X, et al. Effect of MTHFR gene polymorphism impact on atherosclerosis via genome-wide methylation. Med Sci Monit. 2016;22:341–5. https://doi.org/10.12659/msm.895296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang C, Sun T, Li H, Bai J, Li Y. Lipoprotein lipase Ser447Ter polymorphism associated with the risk of ischemic stroke: a meta-analysis. Thromb Res. 2011;128(5):e107–12. https://doi.org/10.1016/j.thromres.2011.07.016.

    Article  CAS  PubMed  Google Scholar 

  89. Bianchi G, Ferrari P, Staessen JA. Adducin polymorphism: detection and impact on hypertension and related disorders. Hypertension. 2005;45(3):331–40. https://doi.org/10.1161/01.HYP.0000156497.39375.37.

    Article  CAS  PubMed  Google Scholar 

  90. Beeks E, Kessels AG, Kroon AA, van der Klauw MM, de Leeuw PW. Genetic predisposition to salt-sensitivity: a systematic review. J Hypertens. 2004;22(7):1243–9. https://doi.org/10.1097/01.hjh.0000125443.28861.0d.

    Article  CAS  PubMed  Google Scholar 

  91. Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet (London, England). 1997;350(9093):1734–7. https://doi.org/10.1016/S0140-6736(97)05189-1.

    Article  CAS  Google Scholar 

  92. Wang R, Zhong B, Liu Y, Wang C. Association between alpha-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity: a meta-analysis. J Appl Genet. 2010;51(1):87–94.

    Article  CAS  Google Scholar 

  93. Lucarini L, Sticchi E, Sofi F, Pratesi G, Pratesi C, Pulli R, et al. ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm. Atherosclerosis. 2009;202(1):205–10. https://doi.org/10.1016/j.atherosclerosis.2008.04.038.

    Article  CAS  PubMed  Google Scholar 

  94. Catto A, Carter AM, Barrett JH, Stickland M, Bamford J, Davies JA, et al. Angiotensin-converting enzyme insertion/deletion polymorphism and cerebrovascular disease. Stroke. 1996;27(3):435–40.

    Article  CAS  Google Scholar 

  95. Sharma P. Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry. 1998;64(2):227–30. https://doi.org/10.1136/jnnp.64.2.227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang Z, Xu G, Liu D, Fan X, Zhu W, Liu X. Angiotensin-converting enzyme insertion/deletion polymorphism contributes to ischemic stroke risk: a meta-analysis of 50 case-control studies. PLoS One. 2012;7(10):e46495. https://doi.org/10.1371/journal.pone.0046495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet (London, England). 2007;369(9568):1208–19. https://doi.org/10.1016/S0140-6736(07)60242-6.

    Article  CAS  Google Scholar 

  98. Roscioni SS, Heerspink HJ, de Zeeuw D. The effect of RAAS blockade on the progression of diabetic nephropathy. Nat Rev Nephrol. 2014;10(2):77–87. https://doi.org/10.1038/nrneph.2013.251.

    Article  CAS  PubMed  Google Scholar 

  99. Yan G, Wang Y. Association of CYP11B2 gene polymorphism with ischemic stroke in the north Chinese Han population. Neurol India. 2012;60(5):504–9. https://doi.org/10.4103/0028-3886.103196.

    Article  PubMed  Google Scholar 

  100. Sharma R, Katz J. Preliminary studies on human aldosterone synthase (CYP11B2) gene polymorphism, matrix metalloprotease-9, apoptosis, and carotid atherosclerosis plaque size by proton magnetic resonance imaging. J Renin-Angiotensin-Aldosterone Syst. 2010;11(3):198–204. https://doi.org/10.1177/1470320309358109.

    Article  CAS  PubMed  Google Scholar 

  101. Ding L, Hong Y, Peng B. Association between large artery atherosclerosis and cerebral microbleeds: a systematic review and meta-analysis. Stroke and vascular neurology. 2017;2(1):7–14. https://doi.org/10.1136/svn-2016-000049.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Klein IF, Lavallee PC, Mazighi M, Schouman-Claeys E, Labreuche J, Amarenco P. Basilar artery atherosclerotic plaques in paramedian and lacunar pontine infarctions: a high-resolution MRI study. Stroke. 2010;41(7):1405–9. https://doi.org/10.1161/strokeaha.110.583534.

    Article  PubMed  Google Scholar 

  103. Romero JR, Beiser A, Seshadri S, Benjamin EJ, Polak JF, Vasan RS, et al. Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke. 2009;40(5):1590–6. https://doi.org/10.1161/strokeaha.108.535245.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–236. https://doi.org/10.1161/STR.0000000000000024.

    Article  Google Scholar 

  105. Holliday EG, Traylor M, Malik R, Bevan S, Falcone G, Hopewell JC, et al. Genetic overlap between diagnostic subtypes of ischemic stroke. Stroke. 2015;46(3):615–9. https://doi.org/10.1161/strokeaha.114.007930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, et al. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project. PLoS Genet. 2011;7(2):e1001300. https://doi.org/10.1371/journal.pgen.1001300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jiang Y, Liu X, Du Y, Zhou S. rs1234313 and rs45454293 are risk factors of cerebral arterial thrombosis, large artery atherosclerosis, and carotid plaque in the Han Chinese population: a case-control study. BMC neurology. 2019;19(1):31. https://doi.org/10.1186/s12883-019-1259-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res. 2001;89(12):1092–103. https://doi.org/10.1161/hh2401.101272.

    Article  CAS  PubMed  Google Scholar 

  109. Ria M, Eriksson P, Boquist S, Ericsson CG, Hamsten A, Lagercrantz J. Human genetic evidence that OX40 is implicated in myocardial infarction. Biochem Biophys Res Commun. 2006;339(3):1001–6. https://doi.org/10.1016/j.bbrc.2005.11.092.

    Article  CAS  PubMed  Google Scholar 

  110. Olofsson PS, Soderstrom LA, Jern C, Sirsjo A, Ria M, Sundler E, et al. Genetic variants of TNFSF4 and risk for carotid artery disease and stroke. Journal of molecular medicine (Berlin, Germany). 2009;87(4):337–46. https://doi.org/10.1007/s00109-008-0412-5.

    Article  CAS  Google Scholar 

  111. Kovacic S, Bakran M. Genetic susceptibility to atherosclerosis. Stroke Res Treat. 2012;2012:362941. https://doi.org/10.1155/2012/362941.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Bersano A, Zuffardi O, Pantoni L, Quaglini S, Ciccone R, Vetro A, et al. Next generation sequencing for systematic assessment of genetics of small-vessel disease and lacunar stroke. J Stroke Cerebrovasc Dis. 2015;24(4):759–65. https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.10.019.

    Article  PubMed  Google Scholar 

  113. Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, et al. A systematic approach to assessing the clinical significance of genetic variants. Clin Genet. 2013;84(5):453–63. https://doi.org/10.1111/cge.12257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, College of Physicians and Surgeons, Columbia University Irving Medical Center, 710 W 168th Street, 6th floor, Suite 639, New York, NY, 10032, USA

    Minghua Liu & Jose Gutierrez

Authors
  1. Minghua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose Gutierrez.

Ethics declarations

Conflict of Interest

Minghua Liu has nothing to disclose. Jose Gutierrez reports grants from the NIA (NIA R01 5R01AG057709-02) during the conduct of the study.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Genetics and Genomics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, M., Gutierrez, J. Genetic Risk Factors of Intracranial Atherosclerosis. Curr Atheroscler Rep 22, 13 (2020). https://doi.org/10.1007/s11883-020-0831-5

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-020-0831-5

Keywords

Search

Navigation