Association between serum anti‑ASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension

Li,Shu‑Yang; Yoshida,Yoichi; Kobayashi,Eiichi; Adachi,Akihiko; Hirono,Seiichiro; Matsutani,Tomoo; Mine,Seiichiro; Machida,Toshio; Ohno,Mikiko; Nishi,Eiichiro; Maezawa,Yoshiro; Takemoto,Minoru; Yokote,Koutaro; Kitamura,Kenichiro; Sumazaki,Makoto; Ito,Masaaki; Shimada,Hideaki; Takizawa,Hirotaka; Kashiwado,Koichi; Tomiyoshi,Go; Shinmen,Natsuko; Nakamura,Rika; Kuroda,Hideyuki; Zhang,Xiao‑Meng; Wang,Hao; Goto,Kenichiro; Iwadate,Yasuo; Hiwasa,Takaki

doi:10.3892/ijmm.2020.4690

Association between serum anti‑ASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension

Authors:
- Shu‑Yang Li
- Yoichi Yoshida
- Eiichi Kobayashi
- Akihiko Adachi
- Seiichiro Hirono
- Tomoo Matsutani
- Seiichiro Mine
- Toshio Machida
- Mikiko Ohno
- Eiichiro Nishi
- Yoshiro Maezawa
- Minoru Takemoto
- Koutaro Yokote
- Kenichiro Kitamura
- Makoto Sumazaki
- Masaaki Ito
- Hideaki Shimada
- Hirotaka Takizawa
- Koichi Kashiwado
- Go Tomiyoshi
- Natsuko Shinmen
- Rika Nakamura
- Hideyuki Kuroda
- Xiao‑Meng Zhang
- Hao Wang
- Kenichiro Goto
- Yasuo Iwadate
- Takaki Hiwasa
View Affiliations

Affiliations: Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan, Department of Neurological Surgery, Chiba Cerebral and Cardiovascular Center, Chiba 290‑0512, Japan, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan, Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan, Department of Internal Medicine 3, University of Yamanashi School of Medicine, Yamanashi 409‑3898, Japan, Department of Gastroenterological Surgery and Clinical Oncology, Toho University Graduate School of Medicine, Tokyo 143‑8541, Japan, Port Square Kashiwado Clinic, Kashiwado Memorial Foundation, Chiba 260‑0025, Japan, Department of Neurology, Kashiwado Hospital, Chiba 260‑8656, Japan, Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan, Medical Project Division, Research Development Center, Fujikura Kasei Co., Saitama 340‑0203, Japan
Published online on: July 29, 2020 https://doi.org/10.3892/ijmm.2020.4690
Pages: 1274-1288
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to identify novel antibody markers for the early diagnosis of atherosclerosis in order to improve the prognosis of patients at risk for acute ischemic stroke (AIS) and acute myocardial infarction (AMI). A first screening involved the serological identification of antigens by recombinant cDNA expression cloning and identified additional sex combs‑like 2 (ASXL2) as a target antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. Antigens, including the recombinant glutathione S‑transferase‑fused ASXL2 protein and its synthetic peptide were then prepared to examine serum antibody levels. Amplified luminescence proximity homogeneous assay‑linked immunosorbent assay, which incorporates glutathione‑donor beads and anti‑human‑IgG‑acceptor beads, revealed significantly higher serum antibody levels against the ASXL2 protein and its peptide in the patients with AIS, diabetes mellitus, AMI, chronic kidney disease, esophageal squamous cell carcinoma, or colorectal carcinoma compared with those in healthy donors. The ASXL2 antibody levels were well associated with hypertension complication, but not with sex, body mass index, habitual smoking, or alcohol intake. These results suggest that the serum ASXL2 antibody marker can discriminate between hypertension‑induced atherosclerotic AIS and AMI, as well as a number of digestive organ cancers.

View Figures

View References

1	Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 380:2095–2128. 2012. View Article : Google Scholar : PubMed/NCBI
2	Meschia JF and Brott T: Ischaemic stroke. Eur J Neurol. 25:35–40. 2018. View Article : Google Scholar
3	Writing Group Members; Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, et al: Executive summary: Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation. 133:447–454. 2016. View Article : Google Scholar : PubMed/NCBI
4	French BR, Boddepalli RS and Govindarajan R: Acute ischemic stroke: Current status and future directions. Mol Med. 113:480–486. 2016.
5	Deb P, Sharma S and Hassan KM: Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology. 17:197–218. 2010. View Article : Google Scholar : PubMed/NCBI
6	Chen YT, Scanlan MJ, Sahin U, Türeci O, Gure AO, Tsang S, Williamson B, Stockert E, Pfreundschuh M and Old LJ: A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA. 94:1914–1918. 1997. View Article : Google Scholar : PubMed/NCBI
7	Gnjatic S, Nishikawa H, Jungbluth AA, Güre AO, Ritter G, Jäger E, Knuth A, Chen YT and Old LJ: NY-ESO-1: Review of an immunogenic tumor antigen. Adv Cancer Res. 95:1–30. 2006. View Article : Google Scholar : PubMed/NCBI
8	Shimada H, Nakajima K, Ochiai T, Koide Y, Okazumi S, Matsubara H, Takeda A, Miyazawa Y, Arima M and Isono K: Detection of serum p53 antibodies in patients with esophageal squamous cell carcinoma: Correlation with clinicopathologic features and tumor markers. Oncol Rep. 5:871–874. 1998.PubMed/NCBI
9	Shimada H: p53 molecular approach to diagnosis and treatment of esophageal squamous cell carcinoma. Ann Gastroenterol Surg. 2:266–273. 2018. View Article : Google Scholar : PubMed/NCBI
10	Qin JJ, Wang XR, Wang P, Ren PF, Shi JX, Zhang HF, Xia JF, Wang KJ, Song CH, Dai LP, et al: Mini-array of multiple tumor-associated antigens (TAAs) in the immunodiagnosis of esophageal cancer. Asian Pac J Cancer Prev. 15:2635–2640. 2014. View Article : Google Scholar : PubMed/NCBI
11	Nakashima K, Shimada H, Ochiai T, Kuboshima M, Kuroiwa N, Okazumi S, Matsubara H, Nomura F, Takiguchi M and Takaki H: Serological identification of TROP2 by recombinant cDNA expression cloning using sera of patients with esophageal squamous cell carcinoma. Int J Cancer. 112:1029–1035. 2004. View Article : Google Scholar : PubMed/NCBI
12	Kuboshima M, Shimada H, Liu TL, Nakashima K, Nomura F, Takiguchi M, Hiwasa T and Ochiai T: Identification of a novel SEREX antigen, SLC2A1/GLUT1, in esophageal squamous cell carcinoma. Int J Oncol. 28:463–468. 2006.PubMed/NCBI
13	Kuboshima M, Shimada H, Liu TL, Nomura F, Takiguchi M, Hiwasa T and Ochiai T: Presence of serum tripartite motif-containing 21 antibodies in patients with esophageal squamous cell carcinoma. Cancer Sci. 97:380–386. 2006. View Article : Google Scholar : PubMed/NCBI
14	Shimada H, Kuboshima M, Shiratori T, Nabeya Y, Takeuchi A, Takagi H, Nomura F, Takiguchi M, Ochiai T and Hiwasa T: Serum anti-myomegalin antibodies in patients with esophageal squamous cell carcinoma. Int J Oncol. 30:97–103. 2007.
15	Shimada H, Shiratori T, Yasuraok M, Kagaya A, Kuboshima M, Nomura F, Takiguchi M, Ochiai T, Matsubara H and Hiwasa T: Identification of Makorin 1 as a novel SEREX antigen of esophageal squamous cell carcinoma. BMC Cancer. 9:2322009. View Article : Google Scholar : PubMed/NCBI
16	Kagaya A, Shimada H, Shiratori T, Kuboshima M, Nakashima-Fujita K, Yasuraoka M, Nishimori T, Kurei S, Hachiya T, Murakami A, et al: Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma. Proteome Sci. 9:312011. View Article : Google Scholar : PubMed/NCBI
17	Shimada H, Ito M, Kagaya A, Shiratori T, Kuboshima M, Suzuki M, Liu TL, Nabeya Y, Matsubara H, Matsushita K, et al: Elevated serum antibody levels against cyclin L2 in patients with esophageal squamous cell carcinoma. J Cancer Sci Ther. 7:60–66. 2015.
18	Kobayashi S, Hoshino T, Hiwasa T, Satoh M, Rahmutulla B, Tsuchida S, Komukai Y, Tanaka T, Matsubara H, Shimada H, et al: Anti-FIRs (PUF60) auto-antibodies are detected in the sera of early-stage colon cancer patients. Oncotarget. 7:82493–82503. 2016. View Article : Google Scholar : PubMed/NCBI
19	Matsutani T, Hiwasa T, Takiguchi M, Oide T, Kunimatsu M, Saeki N and Iwadate Y: Autologous antibody to src-homology 3-domain GRB2-like 1 specifically increases in the sera of patients with low-grade gliomas. J Exp Clin Cancer Res. 31:852012. View Article : Google Scholar : PubMed/NCBI
20	Adachi-Hayama M, Adachi A, Shinozaki N, Matsutani T, Hiwasa T, Takiguchi M, Saeki N and Iwadate Y: Circulating anti-filamin C antibody as a potential serum biomarker for low-grade gliomas. BMC Cancer. 14:4522014. View Article : Google Scholar
21	Hontani K, Tsuchikawa T, Hiwasa T, Nakamura T, Ueno T, Kushibiki T, Takahashi M, Inoko K, Takano H, Takeuchi S, et al: Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors. Oncotarget. 8:106206–106221. 2017. View Article : Google Scholar :
22	Machida T, Kubota M, Kobayashi E, Iwadate Y, Saeki N, Yamaura A, Nomura F, Takiguchi M and Hiwasa T: Identification of stroke-associated-antigens via screening of recombinant proteins from the human expression cDNA library (SEREX). J Translat Med. 13:712015. View Article : Google Scholar
23	Goto KI, Sugiyama T, Matsumura R, Zhang XM, Kimura R, Taira A, Arita E, Iwase K, Kobayashi E, Iwadate Y, et al: Identification of cerebral infarction-specific antibody markers from autoantibodies detected in patients with systemic lupus erythematosus. J Mol Biomark Diagn. 6:2192015.
24	Yoshida Y, Wang H, Hiwasa T, Machida T, Kobayashi E, Mine S, Tomiyoshi G, Nakamura R, Shinmen N, Kuroda H, et al: Elevation of autoantibody level against PDCD11 in patients with transient ischemic attack. Oncotarget. 9:8836–8848. 2017. View Article : Google Scholar
25	Wang H, Zhang XM, Tomiyoshi G, Nakamura R, Shinmen N, Kuroda H, Kimura R, Mine S, Kamitsukasa I, Wada T, et al: Association of serum levels of antibodies against MMP1 CBX1, and CBX5 with transient ischemic attack and cerebral infarction. Oncotarget. 9:5600–5613. 2017. View Article : Google Scholar
26	Linke AT, Marchant B, Marsh P, Frampton G, Murphy J and Rose ML: Screening of a HUVEC cDNA library with transplant-associated coronary artery disease sera identifies RPL7 as a candidate autoantigen associated with this disease. Clin Exp Immunol. 126:173–179. 2001. View Article : Google Scholar : PubMed/NCBI
27	Hiwasa T, Machida T, Zhang XM, Kimura R, Wang H, Iwase K, Ashino H, Taira A, Arita E, Mine S, et al: Elevated levels of autoantibodies against ATP2B4 and BMP-1 in sera of patients with atherosclerosis-related diseases. Immunome Res. 11:0972015.
28	Hiwasa T, Tomiyoshi G, Nakamura R, Shinmen N, Kuroda H, Kunimatsu M, Mine S, Machida T, Sato E, Takemoto M, et al: Serum SH3BP5-specific antibody level is a biomarker of athero-sclerosis. Immunome Res. 13:1322017.
29	Nakamura R, Tomiyoshi G, Shinmen N, Kuroda H, Kudo T, Doi H, Mine S, Machida T, Kamitsukasa I, Wada T, et al: An anti-deoxyhypusine synthase antibody as a marker of atherosclerosis-related cerebral infarction myocardial infarction diabetes mellitus and chronic kidney disease. SM Atheroscler J. 1:10012017.
30	Chen PM, Ohno M, Hiwasa T, Nishi K, Saijo S, Sakamoto J, Morita Y, Matsuda S, Watanabe S, Kuwabara Y, et al: Nardilysin is a promising biomarker for the early diagnosis of acute coro-nary syndrome. Int J Cardiol. 243:1–8. 2017. View Article : Google Scholar : PubMed/NCBI
31	Hiwasa T, Zhang XM, Kimura R, Machida T, Kitamura K, Yamazoe R, Kunimatsu M, Mine S, Kobayashi E, Iwadate Y, et al: Association of serum antibody levels against TUBB2C with diabetes and cerebral infarction. Gratis J Biomed Sci. 1:49–63. 2015.
32	Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK and Paquette TL: Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science. 222:1337–1339. 1983. View Article : Google Scholar : PubMed/NCBI
33	Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H and De Camilli P: Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 347:151–156. 1990. View Article : Google Scholar : PubMed/NCBI
34	Hiwasa T, Zhang XM, Kimura R, Ohno M, Chen PM, Nishi E, Ono K, Kimura T, Kamitsukasa I, Wada T, et al: Elevated adiponectin antibody levels in sera of patients with atherosclerosis-related coronary artery disease cerebral infarction and diabetes mellitus. J Circ Biomark. 5:82016. View Article : Google Scholar
35	Sugimoto K, Tomiyoshi G, Mori M, Kuwabara S, Hirano S, Sawai S, Beppu M, Muto M, Uzawa A, Kitamura K, et al: Identification of serum anti-GADD34 antibody as a common marker of diabetes mellitus and Parkinson disease. J Alzheimers Dis Parkinsonism. 7:3582017. View Article : Google Scholar
36	Zhu H, Li Z, Lv J and Zhao R: Effects of cerebral small vessel disease on the outcome of patients with ischemic stroke caused by large artery atherosclerosis. Neurol Res. 40:381–390. 2018. View Article : Google Scholar : PubMed/NCBI
37	Khyzha N, Alizada A, Wilson MD and Fish JE: Epigenetics of atherosclerosis: Emerging mechanisms and methods. Trends Mol Med. 23:332–347. 2017. View Article : Google Scholar : PubMed/NCBI
38	Valdivielso JM, Rodríguez-Puyol D, Pascual J, Barrios C, Bermúdez-López M, Sánchez-Niño MD, Pérez-Fernández M and Ortiz A: Atherosclerosis in chronic kidney disease: More, less, or just different? Arterioscler Thromb Vasc Biol. 39:1938–1966. 2019. View Article : Google Scholar : PubMed/NCBI
39	Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, et al: Guidelines for the primary prevention of stroke: A guideline for healthcare professionals from the American heart association/American stroke association. Stroke. 42:517–584. 2011. View Article : Google Scholar
40	Alloubani A, Saleh A and Abdelhafiz I: Hypertension and diabetes mellitus as a predictive risk factors for stroke. Diabetes Metab Syndr. 12:577–584. 2018. View Article : Google Scholar : PubMed/NCBI
41	Shao C, Wang J, Tian J and Tang YD: Coronary artery disease: From mechanism to clinical practice. Adv Exp Med Biol. 1177:1–36. 2020. View Article : Google Scholar : PubMed/NCBI
42	Nishiura R, Fujimoto S, Sato Y, Yamada K, Hisanaga S, Hara S, Nakao H and Kitamura K: Elevated osteoprotegerin levels predict cardiovascular events in new hemodialysis patients. Am J Nephrol. 29:257–263. 2009. View Article : Google Scholar
43	Komatsu H, Fujimoto S, Hara S, Fukuda A, Fukudome K, Yamada K, Sato Y and Kitamura K: Recent therapeutic strategies improve renal outcome in patients with IgA nephropathy. Am J Nephrol. 30:19–25. 2009. View Article : Google Scholar : PubMed/NCBI
44	Kanda Y: Investigation of the freely available easy-to-use soft-ware 'EZR' for medical statistics. Bone Marrow Transplant. 48:452–458. 2013. View Article : Google Scholar
45	Katoh M and Katoh M: Identification and characterization of ASXL2 gene in silico. Int J Oncol. 23:845–850. 2003.PubMed/NCBI
46	Park UH, Yoon SK, Park T, Kim EJ and Um SJ: Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor {gamma}. J Biol Chem. 286:1354–1363. 2011. View Article : Google Scholar
47	Della-Morte D, Palmirotta R, Rehni AK, Pastore D, Capuani B, Pacifici F, De Marchis ML, Dave KR, Bellia A, Fogliame G, et al: Pharmacogenomics and pharmacogenetics of thiazolidinediones: Role in diabetes and cardiovascular risk factors. Pharmacogenomics. 15:2063–2082. 2014. View Article : Google Scholar : PubMed/NCBI
48	Lehrke M and Lazar MA: The many faces of PPARgamma. Cell. 123:993–999. 2005. View Article : Google Scholar : PubMed/NCBI
49	Evans RM, Barish GD and Wang YX: PPARs and the complex journey to obesity. Nat Med. 10:355–361. 2004. View Article : Google Scholar : PubMed/NCBI
50	Poulsen LI, Siersbaek M and Mandrup S: PPARs: Fatty acid sensors controlling metabolism. Semin Cell Dev Biol. 23:631–639. 2012. View Article : Google Scholar : PubMed/NCBI
51	Watkins SM, Reifsnyder PR, Pan HJ, German JB and Leiter EH: Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. J Lipid Res. 43:1809–1817. 2002. View Article : Google Scholar : PubMed/NCBI
52	Salomone S and Drago F: Effects of PPARγ ligands on vascular tone. Curr Mol Pharmacol. 5:282–291. 2012. View Article : Google Scholar
53	Marx N, Kehrle B, Kohlhammer K, Grub M, Koenig W, Hombach V, Libby P and Plutzky J: PPAR activators as antiin-flammatory mediators in human T lymphocytes: Implications for atherosclerosis and transplantation-associated arteriosclerosis. Circ Res. 90:703–710. 2002. View Article : Google Scholar : PubMed/NCBI
54	Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 108:171–182. 2002. View Article : Google Scholar : PubMed/NCBI
55	Tarsounas M and Sung P: The antitumorigenic roles of BRCA1-BARD1 in DNA repair and replication. Nat Rev Mol Cell Biol. 21:284–299. 2020. View Article : Google Scholar : PubMed/NCBI
56	Mallery DL, Vandenberg CJ and Hiom K: Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 21:6755–6762. 2002. View Article : Google Scholar : PubMed/NCBI
57	Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M and Ohta T: BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 69:111–119. 2009. View Article : Google Scholar : PubMed/NCBI
58	Greenberg RA, Sobhian B, Pathania S, Cantor SB, Nakatani Y and Livingston DM: Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev. 20:34–46. 2006. View Article : Google Scholar : PubMed/NCBI
59	Peng H, Prokop J, Karar J, Park K, Cao L, Harbour JW, Bowcock AM, Malkowicz SB, Cheung M, Testa JR and Rauscher FJ III: Familial and somatic BAP1 mutations inactivate ASXL1/2-mediated allosteric regulation of BAP1 deubiquitinase by targeting multiple independent domains. Cancer Res. 78:1200–1213. 2018. View Article : Google Scholar :
60	Park UH, Kang MR, Kim EJ, Kwon YS, Hur W, Yoon SK, Song BJ, Park JH, Hwang JT, Jeong JC and Um SJ: ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation. Oncogene. 35:3742–3752. 2016. View Article : Google Scholar
61	Martinet W, Knaapen MW, De Meyer GR, Herman AG and Kockx MM: Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 106:927–932. 2002. View Article : Google Scholar : PubMed/NCBI
62	Andreassi MG and Botto N: DNA damage as a new emerging risk factor in atherosclerosis. Trends Cardiovasc Med. 13:270–275. 2003. View Article : Google Scholar : PubMed/NCBI
63	Shukla PC, Singh KK, Quan A, Al-Omran M, Teoh H, Lovren F, Cao L, Rovira II, Pan Y, Brezden-Masley C, et al: BRCA1 is an essential regulator of heart function and survival following myocardial infarction. Nat Commun. 2:5932011. View Article : Google Scholar : PubMed/NCBI
64	Wold MS: Replication protein A: A heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem. 66:61–92. 1997. View Article : Google Scholar : PubMed/NCBI
65	Erdile LF, Wold MS and Kelly TJ: The primary structure of the 32-kDa subunit of human replication protein A. J Biol Chem. 265:3177–3182. 1990.PubMed/NCBI
66	Atabek ME, Akyürek N, Eklioglu BS and Alp H: Impaired systolic blood dipping and nocturnal hypertension: An independent predictor of carotid intima-media thickness in type 1 diabetic patients. J Diabetes Complicat. 28:51–55. 2014. View Article : Google Scholar
67	Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, et al: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet. 364:937–952. 2004. View Article : Google Scholar : PubMed/NCBI
68	O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, et al: Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): A case-control study. Lancet. 376:112–123. 2010. View Article : Google Scholar
69	Lindgren AM, Nissinen AM, Tuomilehto JO and Pukkala E: Cancer pattern among hypertensive patients in North Karelia, Finland. J Hum Hypertens. 19:373–379. 2005. View Article : Google Scholar : PubMed/NCBI
70	Sanfilippo KM, McTigue KM, Fidler CJ, Neaton JD, Chang Y, Fried LF, Liu S and Kuller LH: Hypertension and obesity and the risk of kidney cancer in 2 large cohorts of US men and women. Hypertension. 63:934–941. 2014. View Article : Google Scholar : PubMed/NCBI
71	Sun LM, Kuo HT, Jeng LB, Lin CL, Liang JA and Kao CH: Hypertension and subsequent genitourinary and gynecologic cancers risk: A population-based cohort study. Medicine (Baltimore). 94:e7532015. View Article : Google Scholar
72	Han H, Guo W, Shi W, Yu Y, Zhang Y, Ye X and He J: Hypertension and breast cancer risk: A systematic review and meta-analysis. Sci Rep. 7:448772017. View Article : Google Scholar
73	Schmid U1, Stopper H, Schweda F, Queisser N and Schupp N: Angiotensin II induces DNA damage in the kidney. Cancer Res. 68:9239–9246. 2008. View Article : Google Scholar : PubMed/NCBI
74	Naito A, Hiwasa T, Tanabe N, Sanada TJ, Sugiura T, Shigeta A, Terada J, Takizawa H, Kashiwado K, Sakao S and Tatsumi K: Elevated levels of autoantibodies against EXD2 and PHAX in the sera of patients with chronic thromboembolic pulmonary hypertension. PLoS One. 14:e02113772019. View Article : Google Scholar : PubMed/NCBI
75	Rothwell PM and Warlow CP: Timing of TIAs preceding stroke: Time window for prevention is very short. Neurology. 64:817–820. 2005. View Article : Google Scholar : PubMed/NCBI
76	Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW and Schopflocher DP: The high risk of stroke immediately after transient ischemic attack: A population-based study. Neurology. 62:2015–2020. 2004. View Article : Google Scholar : PubMed/NCBI