Effect of <i>ELOVL6</i> gene on large artery atherosclerosis stroke risk in Han Chinese population in Chengdu_West China Medical Journal

Authors：

 LIU Hua ^1,2 , CHEN Xiaoling ^1,3 , LIU Xindong ⁴ , LUO Danyang ⁴ , GAO Li ¹ , LIU Wei ²

1. Department of Neurology, the Third People’s Hospital of Chengdu & the Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan 610031, P. R. China;
2. Department of Neurology, Nanchong Central Hospital & North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
3. Department of Neurology, Yanting County People’s Hospital, Yanting, Sichuan 621600, P. R. China;
4. Department of Neurology, the Second Affiliated Hospital of Chengdu Medical College & Nuclear Industry 416 Hospital, Chengdu, Sichuan 610057, P. R. China;

Corresponding author：

LIU Hua, Email: hxliumedidoctor@163.com

Keywords：

Ischemic stroke; Large-artery atherosclerosis stroke; ELOVL6 gene; Single nucleotides polymorphism; Interaction; Gene expression

DOI：

10.7507/1002-0179.201907154

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Objective To explore the association of elongase of very long chain fatty acids family member 6 (ELOVL6) gene with increased risk of large-artery atherosclerosis stroke (LAA) in Han Chinese population in Chengdu.Methods Han Chinese populations in Chengdu, Sichuan were chosen for this study using the case-control design between January 2015 and December 2017. The genotypes and haplotypes of six single nucleotides polymorphisms (SNPs) of ELOVL6 gene (rs3813825, rs17041272, rs4141123, rs9997926, rs6824447, and rs12504538) were analyzed in different genetic models in entire samples, and gene-enviromental interaction analyses were also carried out to get an insight of the risk factors for LAA. At the same time, we also analyzed the gene expression profile in peripheral blood mononuclear cells between groups.Results A total of 240 LAA cases and 211 healthy controls were enrolled in this study. All the enrolled subjects presented CC genotype of rs9997926, while the other five SNPs (rs3813825, rs17041272, rs4141123, rs6824447, and rs12504538) were genotyped successfully in all the enrolled subjects. rs17041272 polymorphism and TGTTG haplotype were significantly associated with LAA risk in studied population [CC/(CG+GG): odds ratio (OR)=0.640, 95% confidence interval (CI) (0.423, 0.968), P=0.034; TGTTG: OR=1.776, 95%CI (1.069, 2.951), P=0.024], and the interaction among rs17041272, rs6824447 SNPs and dyslipidemia increased susceptibility to LAA [OR=2.737, 95%CI (1.715, 4.368), P<0.001]. The ELOVL6 gene expression level was higher in LAA subjects (t=−3.167, P=0.003).Conclusions ELOVL6 gene is associated with LAA risk in Han nationality of Chinese population in Chengdu, and the interaction of gene-environmental risk factors could be of great importance in pathophysiology of LAA.

Citation： LIU Hua, CHEN Xiaoling, LIU Xindong, LUO Danyang, GAO Li, LIU Wei. Effect of ELOVL6 gene on large artery atherosclerosis stroke risk in Han Chinese population in Chengdu. West China Medical Journal, 2019, 34(10): 1148-1153. doi: 10.7507/1002-0179.201907154 Copy

1.	Zhou M, Wang H, Zhu J, et al. Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. Lancet, 2016, 387(115): 251-272.
2.	陈伟伟, 高润霖, 刘力生, 等. 《中国心血管病报告 2016》概要. 中国循环杂志, 2017, 32(6): 521-530.
3.	Wu S, Wu B, Liu M, et al. Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol, 2019, 18(4): 394-405.
4.	Dichgans M, Pulit SL, Rosand J. Stroke genetics: discovery, biology, and clinical applications. Lancet Neurol, 2019, 18(6): 587-599.
5.	Humphries SE, Morgan L. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol, 2004, 3(4): 227-236.
6.	Moon YA, Shah NA, Mohapatra S, et al. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem, 2001, 276(48): 45358-45366.
7.	Matsuzaka T, Shimano H, Yahagi N, et al. Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs. J Lipid Res, 2002, 43: 911-920.
8.	Saito R, Matsuzaka T, Karasawa T, et al. Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol, 2011, 31(9): 1973-1979.
9.	WHO MONICA Project Principal Investigators. The World Health Organization MONICA project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. J Clin Epidemiol, 1988, 41(2): 105-114.
10.	Zhou BF. Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases─report for meta-analysis of prospective studies on optimal cut-off points of body mass index in Chinese adults. Biomed Environ Sci, 2002, 15(3): 245-252.
11.	Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998, 15(7): 539-553.
12.	Chalmers J, MacMahon S, Mancia G, et al. 1999 World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. Guidelines sub-committee of the World Health Organization. Clin Exp Hypertens, 1999, 21(5/6): 1009-1060.
13.	Kelly TN, Gu DF, Chen J, et al. Cigarette smoking and risk of stroke in the Chinese adult population. Stroke, 2008, 39(6): 1688-1693.
14.	中国成人血脂异常防治指南制定联合委员会. 中国成人血脂异常防治指南. 中华心血管病杂志, 2007, 35(5): 390-419.
15.	Morcillo S, Martín-Núñez GM, Rojo-Martínez G, et al. ELOVL6 genetic variation is related to insulin sensitivity: a new candidate gene in energy metabolism. PLoS One, 2011, 6(6): e21198.
16.	Liu Y, Wang F, Yu XL, et al. Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus. Braz J Med Biol Res, 2013, 46(7): 623-628.
17.	Jakobsson A, Westerberg R, Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res, 2006, 45(3): 237-249.
18.	邢华苑, 王颜刚. ELOVL6 基因 rs9997926 位点多态性与 2 型糖尿病病人胰岛素抵抗的相关性. 青岛大学医学院学报, 2017, 53(1): 84-86, 90.
19.	Sunaga H, Matsui H, Anjo S, et al. Elongation of long-chain fatty acid family member 6 (Elovl6)-driven fatty acid metabolism regulates vascular smooth muscle cell phenotype through AMP-activated protein kinase/Krüppel-like factor 4 (AMPK/KLF4) signaling. J Am Heart Assoc, 2016, 5(12): e004014.
20.	Takamura TA, Tsuchiya T, Oda M, et al. Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) as a novel predictor of clinical outcome after endovascular therapy in patients with peripheral artery disease (PAD). Atherosclerosis, 2017, 263: 192-197.
21.	Kuba M, Matsuzaka T, Matsumori R, et al. Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model. Sci Rep, 2015, 5: 17604.
22.	Matsuzaka T, Atsumi A, Matsumori R, et al. Elovl6 promotes nonalcoholic steatohepatitis. Hepatology, 2012, 56(6): 2199-2208.
23.	Shimano H. SREBP-1c and Elovl6 as targets for obesity-related disorders. Yakugaku Zasshi, 2015, 135(9): 1003-1009.
24.	Matsuzaka T, Kuba M, Koyasu S, et al. Hepatocyte Elovl6 determines ceramide acyl-chain length and hepatic insulin sensitivity in mice. Hepatology, 2019.
25.	Zhao H, Matsuzaka T, Nakano Y, et al. Elovl6 deficiency improves glycemic control in diabetic db/db mice by expanding beta-cell mass and increasing insulin secretory capacity. Diabetes, 2017, 66(7): 1833-1846.

1. Zhou M, Wang H, Zhu J, et al. Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. Lancet, 2016, 387(115): 251-272.
2. 陈伟伟, 高润霖, 刘力生, 等. 《中国心血管病报告 2016》概要. 中国循环杂志, 2017, 32(6): 521-530.
3. Wu S, Wu B, Liu M, et al. Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol, 2019, 18(4): 394-405.
4. Dichgans M, Pulit SL, Rosand J. Stroke genetics: discovery, biology, and clinical applications. Lancet Neurol, 2019, 18(6): 587-599.
5. Humphries SE, Morgan L. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol, 2004, 3(4): 227-236.
6. Moon YA, Shah NA, Mohapatra S, et al. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem, 2001, 276(48): 45358-45366.
7. Matsuzaka T, Shimano H, Yahagi N, et al. Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs. J Lipid Res, 2002, 43: 911-920.
8. Saito R, Matsuzaka T, Karasawa T, et al. Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol, 2011, 31(9): 1973-1979.
9. WHO MONICA Project Principal Investigators. The World Health Organization MONICA project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. J Clin Epidemiol, 1988, 41(2): 105-114.
10. Zhou BF. Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases─report for meta-analysis of prospective studies on optimal cut-off points of body mass index in Chinese adults. Biomed Environ Sci, 2002, 15(3): 245-252.
11. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998, 15(7): 539-553.
12. Chalmers J, MacMahon S, Mancia G, et al. 1999 World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. Guidelines sub-committee of the World Health Organization. Clin Exp Hypertens, 1999, 21(5/6): 1009-1060.
13. Kelly TN, Gu DF, Chen J, et al. Cigarette smoking and risk of stroke in the Chinese adult population. Stroke, 2008, 39(6): 1688-1693.
14. 中国成人血脂异常防治指南制定联合委员会. 中国成人血脂异常防治指南. 中华心血管病杂志, 2007, 35(5): 390-419.
15. Morcillo S, Martín-Núñez GM, Rojo-Martínez G, et al. ELOVL6 genetic variation is related to insulin sensitivity: a new candidate gene in energy metabolism. PLoS One, 2011, 6(6): e21198.
16. Liu Y, Wang F, Yu XL, et al. Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus. Braz J Med Biol Res, 2013, 46(7): 623-628.
17. Jakobsson A, Westerberg R, Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res, 2006, 45(3): 237-249.
18. 邢华苑, 王颜刚. ELOVL6 基因 rs9997926 位点多态性与 2 型糖尿病病人胰岛素抵抗的相关性. 青岛大学医学院学报, 2017, 53(1): 84-86, 90.
19. Sunaga H, Matsui H, Anjo S, et al. Elongation of long-chain fatty acid family member 6 (Elovl6)-driven fatty acid metabolism regulates vascular smooth muscle cell phenotype through AMP-activated protein kinase/Krüppel-like factor 4 (AMPK/KLF4) signaling. J Am Heart Assoc, 2016, 5(12): e004014.
20. Takamura TA, Tsuchiya T, Oda M, et al. Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) as a novel predictor of clinical outcome after endovascular therapy in patients with peripheral artery disease (PAD). Atherosclerosis, 2017, 263: 192-197.
21. Kuba M, Matsuzaka T, Matsumori R, et al. Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model. Sci Rep, 2015, 5: 17604.
22. Matsuzaka T, Atsumi A, Matsumori R, et al. Elovl6 promotes nonalcoholic steatohepatitis. Hepatology, 2012, 56(6): 2199-2208.
23. Shimano H. SREBP-1c and Elovl6 as targets for obesity-related disorders. Yakugaku Zasshi, 2015, 135(9): 1003-1009.
24. Matsuzaka T, Kuba M, Koyasu S, et al. Hepatocyte Elovl6 determines ceramide acyl-chain length and hepatic insulin sensitivity in mice. Hepatology, 2019.
25. Zhao H, Matsuzaka T, Nakano Y, et al. Elovl6 deficiency improves glycemic control in diabetic db/db mice by expanding beta-cell mass and increasing insulin secretory capacity. Diabetes, 2017, 66(7): 1833-1846.

West China Medical Journal

Effect of ELOVL6 gene on large artery atherosclerosis stroke risk in Han Chinese population in Chengdu

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