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Published in: BMC Neurology 1/2020

01-12-2020 | Stroke | Research article

CYP3A4 and CYP11A1 variants are risk factors for ischemic stroke: a case control study

Authors: Ning Gao, Hong Tang, Ling Gao, Guolong Tu, Han Luo, Ying Xia

Published in: BMC Neurology | Issue 1/2020

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Abstract

Background

This study aimed to investigate the roles of CYP3A4 and CYP11A1 variants in ischemic stroke (IS) susceptibility among the Han Chinese population.

Methods

Four hundred seventy-seven patients with IS and 493 healthy controls were enrolled. Seven single-nucleotide polymorphisms (SNPs) of CYP3A4 and CYP11A1 were genotyped by Agena MassARRAY. Odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression adjusted for age and gender.

Results

We found that CYP3A4 rs3735451 (OR = 0.81, p = 0.039) and rs4646440 (OR = 0.72, p = 0.021) polymorphisms decreased the risk of IS. CYP3A4 rs4646440 (OR = 0.74, p = 0.038) and CYP11A1 rs12912592 (OR = 1.58, p = 0.034) polymorphisms were correlated with IS risk in males. CYP3A4 rs3735451 (OR = 0.63, p = 0.031) and rs4646440 (OR = 0.57, p = 0.012) possibly weaken the IS susceptibility at age > 61 years. Besides, CYP3A4 rs4646437 (OR = 0.59, p = 0.029), CYP11A1 rs12912592 (OR = 1.84, p = 0.017) and rs28681535 (OR = 0.66, p = 0.038) were associated with IS risk at age ≤ 61 years. CYP11A1 rs28681535 TT genotype was higher high-density lipoprotein cholesterol level than the GT and GG genotype (p = 0.027).

Conclusions

Our findings indicated that rs3735451, rs4646440, rs4646437 in CYP3A4 and rs28681535 in CYP11A1 might be protective factors for IS, while CYP11A1 rs12912592 polymorphism be a risk factor for IS in Chinese Han population.
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Literature
1.
go back to reference Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, and a national priority. Stroke. 2011;42(12):3651–4.CrossRef Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, and a national priority. Stroke. 2011;42(12):3651–4.CrossRef
2.
go back to reference Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Li Y, Wang Y, Chen Z, Wu S, Zhang Y, Wang D, Wang Y, Feigin VL. Prevalence, incidence, and mortality of stroke in China: results from a Nationwide population-based survey of 480 687 adults. Circulation. 2017;135(8):759–71.CrossRef Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Li Y, Wang Y, Chen Z, Wu S, Zhang Y, Wang D, Wang Y, Feigin VL. Prevalence, incidence, and mortality of stroke in China: results from a Nationwide population-based survey of 480 687 adults. Circulation. 2017;135(8):759–71.CrossRef
3.
go back to reference Loo KW, Gan SH. Burden of stroke in Malaysia. Int J Stroke. 2012;7(2):165–7.CrossRef Loo KW, Gan SH. Burden of stroke in Malaysia. Int J Stroke. 2012;7(2):165–7.CrossRef
4.
go back to reference Bejot Y, Daubail B, Giroud M. Epidemiology of stroke and transient ischemic attacks: current knowledge and perspectives. Rev Neurol. 2016;172(1):59–68.CrossRef Bejot Y, Daubail B, Giroud M. Epidemiology of stroke and transient ischemic attacks: current knowledge and perspectives. Rev Neurol. 2016;172(1):59–68.CrossRef
5.
go back to reference Bevan S, Markus HS. Genetic profiles in ischaemic stroke. Curr Atheroscler Rep. 2013;15(8):342.CrossRef Bevan S, Markus HS. Genetic profiles in ischaemic stroke. Curr Atheroscler Rep. 2013;15(8):342.CrossRef
6.
go back to reference Xue Y, Shi N, Zhang B, Gao X, Gao Y, Zhou X, Du J, Chen P, Ouyang Y, Wang F. Genetic variant in ZFHX3 Geneon 16q22 associated with risk of stroke in Chinese Han population. Int J Clin Exp Pathol. 2016;9:8650–6. Xue Y, Shi N, Zhang B, Gao X, Gao Y, Zhou X, Du J, Chen P, Ouyang Y, Wang F. Genetic variant in ZFHX3 Geneon 16q22 associated with risk of stroke in Chinese Han population. Int J Clin Exp Pathol. 2016;9:8650–6.
7.
go back to reference Yu J, Luo D, Zhou F, Jin T, Liang X, Yu D. Polymorphism of TNIP1 was associated with atherosclerotic ischemic stroke in southern Han Chinese but unrelated with telomere. Int J Clin Exp Pathol. 2017;10(3):3510–6. Yu J, Luo D, Zhou F, Jin T, Liang X, Yu D. Polymorphism of TNIP1 was associated with atherosclerotic ischemic stroke in southern Han Chinese but unrelated with telomere. Int J Clin Exp Pathol. 2017;10(3):3510–6.
8.
go back to reference He J, Sun S, Zhang M, Ouyang Y, Zhang N, Yang M, Jin T, Xia Y. Association analysis of ALOX5 gene polymorphisms with stroke risk: a case-control study in a Chinese Han population. Int J Clin Exp Pathol. 2016;9(4):4432–7. He J, Sun S, Zhang M, Ouyang Y, Zhang N, Yang M, Jin T, Xia Y. Association analysis of ALOX5 gene polymorphisms with stroke risk: a case-control study in a Chinese Han population. Int J Clin Exp Pathol. 2016;9(4):4432–7.
9.
go back to reference Larsen BT, Gutterman DD, Hatoum OA. Emerging role of epoxyeicosatrienoic acids in coronary vascular function. Eur J Clin Investig. 2006;36(5):293–300.CrossRef Larsen BT, Gutterman DD, Hatoum OA. Emerging role of epoxyeicosatrienoic acids in coronary vascular function. Eur J Clin Investig. 2006;36(5):293–300.CrossRef
10.
go back to reference Ward NC, Croft KD, Blacker D, Hankey GJ, Barden A, Mori TA, Puddey IB, Beer CD. Cytochrome P450 metabolites of arachidonic acid are elevated in stroke patients compared with healthy controls. Clin Sci. 2011;121(11):501–7.CrossRef Ward NC, Croft KD, Blacker D, Hankey GJ, Barden A, Mori TA, Puddey IB, Beer CD. Cytochrome P450 metabolites of arachidonic acid are elevated in stroke patients compared with healthy controls. Clin Sci. 2011;121(11):501–7.CrossRef
11.
go back to reference Yi X, Liao D, Wu L, Chen H, Li J, Wang C. CYP genetic variants, CYP metabolite levels, and symptomatic carotid stenosis in ischemic stroke patients. J Atheroscler Thromb. 2016;23(5):621–31.CrossRef Yi X, Liao D, Wu L, Chen H, Li J, Wang C. CYP genetic variants, CYP metabolite levels, and symptomatic carotid stenosis in ischemic stroke patients. J Atheroscler Thromb. 2016;23(5):621–31.CrossRef
12.
go back to reference Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res. 2010;20(8):1020–36.CrossRef Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res. 2010;20(8):1020–36.CrossRef
13.
go back to reference Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, Tuckey RC. Novel activities of CYP11A1 and their potential physiological significance. J Steroid Biochem Mol Biol. 2015;151:25–37.CrossRef Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, Tuckey RC. Novel activities of CYP11A1 and their potential physiological significance. J Steroid Biochem Mol Biol. 2015;151:25–37.CrossRef
14.
go back to reference Vanga SR, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health. Am J Cardiol. 2010;106(6):798–805.CrossRef Vanga SR, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health. Am J Cardiol. 2010;106(6):798–805.CrossRef
15.
go back to reference Oeth P, del Mistro G, Marnellos G, Shi T, van den Boom D. Qualitative and quantitative genotyping using single base primer extension coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MassARRAY). Methods Molec Biol. 2009;578:307–43.CrossRef Oeth P, del Mistro G, Marnellos G, Shi T, van den Boom D. Qualitative and quantitative genotyping using single base primer extension coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MassARRAY). Methods Molec Biol. 2009;578:307–43.CrossRef
16.
go back to reference Ellis JA, Ong B. The MassARRAY((R)) system for targeted SNP genotyping. Methods Molec Biol. 2017;1492:77–94.CrossRef Ellis JA, Ong B. The MassARRAY((R)) system for targeted SNP genotyping. Methods Molec Biol. 2017;1492:77–94.CrossRef
17.
go back to reference Huang H, Al-Shabrawey M, Wang MH. Cyclooxygenase- and cytochrome P450-derived eicosanoids in stroke. Prostaglandins Other Lipid Mediat. 2016;122:45–53.CrossRef Huang H, Al-Shabrawey M, Wang MH. Cyclooxygenase- and cytochrome P450-derived eicosanoids in stroke. Prostaglandins Other Lipid Mediat. 2016;122:45–53.CrossRef
18.
go back to reference Kim SK, Yim SV, Lee BC. Association between cytochrome P450 promoter polymorphisms and ischemic stroke. Exp Ther Med. 2012;3(2):261–8.CrossRef Kim SK, Yim SV, Lee BC. Association between cytochrome P450 promoter polymorphisms and ischemic stroke. Exp Ther Med. 2012;3(2):261–8.CrossRef
19.
go back to reference Honda A, Miyazaki T, Ikegami T, Iwamoto J, Maeda T, Hirayama T, Saito Y, Teramoto T, Matsuzaki Y. Cholesterol 25-hydroxylation activity of CYP3A. J Lipid Res. 2011;52(8):1509–16.CrossRef Honda A, Miyazaki T, Ikegami T, Iwamoto J, Maeda T, Hirayama T, Saito Y, Teramoto T, Matsuzaki Y. Cholesterol 25-hydroxylation activity of CYP3A. J Lipid Res. 2011;52(8):1509–16.CrossRef
20.
go back to reference Ayajiki K, Fujioka H, Toda N, Okada S, Minamiyama Y, Imaoka S, Funae Y, Watanabe S, Nakamura A, Okamura T. Mediation of arachidonic acid metabolite(s) produced by endothelial cytochrome P-450 3A4 in monkey arterial relaxation. Hypertens Res. 2003;26(3):237–43.CrossRef Ayajiki K, Fujioka H, Toda N, Okada S, Minamiyama Y, Imaoka S, Funae Y, Watanabe S, Nakamura A, Okamura T. Mediation of arachidonic acid metabolite(s) produced by endothelial cytochrome P-450 3A4 in monkey arterial relaxation. Hypertens Res. 2003;26(3):237–43.CrossRef
21.
go back to reference Katsumata N. Genetic defects in pregnenolone synthesis. Pediatr Endocrinol Rev. 2012;10(Suppl 1):98–109.PubMed Katsumata N. Genetic defects in pregnenolone synthesis. Pediatr Endocrinol Rev. 2012;10(Suppl 1):98–109.PubMed
22.
go back to reference Wang IK, Liu CH, Yen TH, Jeng JS, Hsu SP, Chen CH, Lien LM, Lin RT, Chen AC, Lin HJ, Chi HY, Lai TC, Sun Y, Lee SP, Sung SF, Chen PL, Lee JT, Chiang TR, Lin SK, Muo CH, Ma H, Wen CP, Sung FC, Hsu CY. Cholesterol levels are associated with 30-day mortality from ischemic stroke in dialysis patients. J Stroke Cerebrovasc Dis. 2017;26(6):1349–56.CrossRef Wang IK, Liu CH, Yen TH, Jeng JS, Hsu SP, Chen CH, Lien LM, Lin RT, Chen AC, Lin HJ, Chi HY, Lai TC, Sun Y, Lee SP, Sung SF, Chen PL, Lee JT, Chiang TR, Lin SK, Muo CH, Ma H, Wen CP, Sung FC, Hsu CY. Cholesterol levels are associated with 30-day mortality from ischemic stroke in dialysis patients. J Stroke Cerebrovasc Dis. 2017;26(6):1349–56.CrossRef
23.
go back to reference Chen CH, Wang SC, Tsou HH, Ho IK, Tian JN, Yu CJ, Hsiao CF, Chou SY, Lin YF, Fang KC, Huang CL, Su LW, Fang YC, Liu ML, Lin KM, Hsu YT, Liu SC, Chen A, Liu YL. Genetic polymorphisms in CYP3A4 are associated with withdrawal symptoms and adverse reactions in methadone maintenance patients. Pharmacogenomics. 2011;12(10):1397–406.CrossRef Chen CH, Wang SC, Tsou HH, Ho IK, Tian JN, Yu CJ, Hsiao CF, Chou SY, Lin YF, Fang KC, Huang CL, Su LW, Fang YC, Liu ML, Lin KM, Hsu YT, Liu SC, Chen A, Liu YL. Genetic polymorphisms in CYP3A4 are associated with withdrawal symptoms and adverse reactions in methadone maintenance patients. Pharmacogenomics. 2011;12(10):1397–406.CrossRef
24.
go back to reference Schirmer M, Rosenberger A, Klein K, Kulle B, Toliat MR, Nurnberg P, Zanger UM, Wojnowski L. Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. Pharmacogenomics. 2007;8(5):443–53.CrossRef Schirmer M, Rosenberger A, Klein K, Kulle B, Toliat MR, Nurnberg P, Zanger UM, Wojnowski L. Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. Pharmacogenomics. 2007;8(5):443–53.CrossRef
25.
go back to reference Seo S, Takayama K, Uno K, Ohi K, Hashimoto R, Nishizawa D, Ikeda K, Ozaki N, Nabeshima T, Miyamoto Y. Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene. PLoS One. 2013;8(10):e76960.CrossRef Seo S, Takayama K, Uno K, Ohi K, Hashimoto R, Nishizawa D, Ikeda K, Ozaki N, Nabeshima T, Miyamoto Y. Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene. PLoS One. 2013;8(10):e76960.CrossRef
26.
go back to reference Wang D, Sadee W. CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing. Pharmacogenet Genomics. 2016;26(1):40–3.CrossRef Wang D, Sadee W. CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing. Pharmacogenet Genomics. 2016;26(1):40–3.CrossRef
27.
go back to reference Zhao H, Yang W, Qiu R, Li J, Xin Q, Wang X, Feng Y, Shan S, Liu Y, Gong Y. An intronic variant associated with systemic lupus erythematosus changes the binding affinity of Yinyang1 to downregulate WDFY4. Genes Immun. 2012;13(7):536.CrossRef Zhao H, Yang W, Qiu R, Li J, Xin Q, Wang X, Feng Y, Shan S, Liu Y, Gong Y. An intronic variant associated with systemic lupus erythematosus changes the binding affinity of Yinyang1 to downregulate WDFY4. Genes Immun. 2012;13(7):536.CrossRef
28.
go back to reference Poorthuis MH, Algra AM, Algra A, Kappelle LJ, Klijn CJ. Female- and male-specific risk factors for stroke: a systematic review and meta-analysis. JAMA Neurol. 2017;74(1):75–81.CrossRef Poorthuis MH, Algra AM, Algra A, Kappelle LJ, Klijn CJ. Female- and male-specific risk factors for stroke: a systematic review and meta-analysis. JAMA Neurol. 2017;74(1):75–81.CrossRef
29.
go back to reference Wang J, Ning X, Yang L, Tu J, Gu H, Zhan C, Zhang W, Su TC. Sex differences in trends of incidence and mortality of first-ever stroke in rural Tianjin, China, from 1992 to 2012. Stroke. 2014;45(6):1626–31.CrossRef Wang J, Ning X, Yang L, Tu J, Gu H, Zhan C, Zhang W, Su TC. Sex differences in trends of incidence and mortality of first-ever stroke in rural Tianjin, China, from 1992 to 2012. Stroke. 2014;45(6):1626–31.CrossRef
30.
go back to reference Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(2):517–84.CrossRef Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(2):517–84.CrossRef
31.
go back to reference O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376(9735):112–23.CrossRef O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376(9735):112–23.CrossRef
Metadata
Title
CYP3A4 and CYP11A1 variants are risk factors for ischemic stroke: a case control study
Authors
Ning Gao
Hong Tang
Ling Gao
Guolong Tu
Han Luo
Ying Xia
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Stroke
Published in
BMC Neurology / Issue 1/2020
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-020-1628-4

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