Atormac
briv
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 3713  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  » Next article
  » Previous article 
  » Table of Contents
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (511 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  Introduction
 »  Materials and Me...
 »  Results
 »  Discussion
 »  Acknowledgments
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed3886    
    Printed142    
    Emailed2    
    PDF Downloaded125    
    Comments [Add]    
    Cited by others 11    

Recommend this journal

 


 
ORIGINAL ARTICLE
Year : 2009  |  Volume : 57  |  Issue : 5  |  Page : 584-588

Association study between C7673T polymorphism in apolipoprotein B gene and cerebral infarction with family history in a Chinese population


Institute of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan - 410 008, People's Republic of China

Date of Acceptance02-Jul-2009
Date of Web Publication20-Nov-2009

Correspondence Address:
Le Zhang
Institute of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan - 410 008, People's Republic of China

Login to access the Email id

Source of Support: Grants from National Natural Science Foundation of China (30600199),, Conflict of Interest: None


DOI: 10.4103/0028-3886.57805

Rights and Permissions

 » Abstract 

Background : Apolipoprotein B (ApoB) levels have been shown to be associate with risk of ischemic stroke. The apolipoprotein B gene (APOB) polymorphisms may influence levels of ApoB and risk of ischemic stroke, but whether they are associated with risk of ischemic cerebral infarction (CI) with family history (CIFH) or not is unknown. Aims : To investigate the possible association of the polymorphism of APOB C7673T with CIFH in Han Chinese from Changsha. Settings and Design : The study population included 47 patients with CIFH and 83 patients with cerebral infarction with no family histroy (CINFH). Control population included 100 healthy subjects with no history of ischemic stroke matched for age, sex, and ethnic background. Materials and Methods : The APOB C7673T polymorphism was analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma lipids levels were also examined by standard enzymatic methods and enzyme-linked immunosorbent assay (ELISA). Statistics : The statistical analysis was done using SPSS 14.0 software package. A P value < 0.05 was taken as significant. Results : This study showed an association between the APOB C7673T polymorphism and CI, especially CIFH in Han Chinese from Changsha. The T alleles frequency of the C7673T polymorphism was significantly higher in both the CIFH and CINFH groups when compared with the control group (P < 0.01; P < 0.05; respectively). And the T allele frequency in CIFH group (0.17) was higher than CINFH (0.09) group (P=0.056). In both the CIFH and CINFH groups the serum levels of TC and LDL cholesterol were significantly high in the TT and TC genotypes than that in the CC genotype (P < 0.01), while the serum level of HDL cholesterol in the TT and TC genotypes was significantly lower than that in the CC genotype (P < 0.05). Conclusions : The APOB C7673T polymorphism is related to CI, especially CIFH through changing serum lipid levels in a Chinese
population.


Keywords: Apolipoprotein B gene, C7673T polymorphism, cerebral infarction, family history


How to cite this article:
Zhang L, Zeng Y, Ma M, Yang Q, Hu Z, Du X. Association study between C7673T polymorphism in apolipoprotein B gene and cerebral infarction with family history in a Chinese population. Neurol India 2009;57:584-8

How to cite this URL:
Zhang L, Zeng Y, Ma M, Yang Q, Hu Z, Du X. Association study between C7673T polymorphism in apolipoprotein B gene and cerebral infarction with family history in a Chinese population. Neurol India [serial online] 2009 [cited 2021 Jul 31];57:584-8. Available from: https://www.neurologyindia.com/text.asp?2009/57/5/584/57805



 » Introduction Top


Ischemic stroke (IS) is the leading cause of mortality and disability in China, and in about 78% of ISs the mechanism is atherothrombotic. [1] There is significant familial aggregation in the occurrence of atherothrombotic IS. [2] The aetiology of IS is heterogeneous and the recent studies emphasises the contribution of genetic as well as environmental factors. [3] Although no gene has been convincingly shown to be of importance for cerebral ischemia (CI), the obvious candidate genes are those with an established or potential role in atherosclerosis. [4]

Apolipoprotein B (ApoB) plays a central role in lipid transport throughout the body. In addition to its lipid-transport function, ApoB is the major atherogenic apolipoprotein in humans and experimental animals. [5] The gene coding for ApoB is polymorphic, and it has been reported this genetically determined variation has a close relationship with the pathogenesis of atherosclerosis. [6] Although apolipoprotein B (APOB) C7673T polymorphism is not involved in amino acid change, it was reported to play an important role in the pathogenesis of atherosclerosis coronary heart disease and myocardial infarction. [7]

Our previous study has indicated that APOB C7673T polymorphism is associated with cerebral hemorrhage in Changsha Han Chinese. [8] In this study we, investigated the importance of APOB C7673T polymorphism as a risk factor for cerebral infarction with family history (CIFH) and also its relationship with serum lipid levels in the Chinese population.


 » Materials and Methods Top


This was a case-control study conducted in the Department of Neurology, Xiangya Hospital, Changsha, Hunan, People's Republic of China from January 2005 to October 2008. All subjects enrolled in the study were Han Chinese. The diagnosis of CI was established by clinical evaluation and brain magnetic resonance imaging (MRI). The diagnostic criteria were based on the World Health Organization International Classification of Diseases, 9 th Revision, codes 430-438. Patients with CIFH were defined as patients with at least one first degree relative with IS. The study population consisted of 47 patients with CIFH (25 males and 22 females; mean age, 53.48 ± 10.22 years) and 83 patients with cerebral infarction without family history (CINFH) (45 males and 38 females; mean age, 58.62 ± 10.37 years). The contols included 100 healthy subjects with no history of CI matched for age, sex and ethenic group (53 males and 47 females; mean age, 53.82 ± 13.26 years) and were randomly recurited from healthy individual of the hospital. The healthy controls were genotyped in our previous study. [8] Patients with cardioembolic CI and CI due to arteritis, trauma, hemotological diseases, and drugs were excluded. Other patients excluded from the study included patients with liver disease, renal disease, autoimmune diseases, pregnant women and also patients on lipid-lowering therapy within the previous five years.

Detailed information on vascular risk factors: Sex, age, body mass index (BMI), hypertension, diabetes mellitus, ischemic heart disease, smoking history (defines as current, past, or never), and medication use (particularly antihypertensive drug and lipid-lowering agents) was obtained from each subject at baseline. BMI was calculated by the formula, weight divided by square root of the height (kg/m 2 ) and hypertension was defined as blood pressure ≥ 140/90 mmHg measured on two separate occasions and/or the use of antihypertensive medication. All the subjects had their fasting serum total cholesterol (TC), triglyceride (TG), and high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), ApoAI, ApoB100 and lipoprotein(a) on the day of the event. Serum levels of TC, HDL, and TG were measured by standard enzymatic methods. LDL cholesterol levels were calculated with the Friedewald formula (LDL 5 TC- HDL-C-TG/5). If both, total cholesterol and triglyceride levels, are elevated then a modified formula was used: LDL-C 5 TC- HDL-C-(0.16 x TG), which provided an approximation with fair accuracy for most people. LP (a) levels were measured by ELISA. The levels of ApoB100 and ApoAI were detected by immunoturbidimetric assay.

Genomic DNA was extracted from peripheral blood leukocytes in all the patients and controls using proteinase K and the phenol/chloroform method. The determination of APOB C7673T polymorphism was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). [9] The amplification reaction was carried out using primers: 5´-GGAGACTATTCAGAAGCTAA-3´ and 5´-GAAGAGCCTGAAGACTGACT-3´ and the following cycling conditions. Each amplification reaction was performed with 100 ng of genomic DNA; 10 pmol of each primer; 2 μL of 10 x buffer solution; 200 μmol/L each of dATP, dCTP, dGTP, and dTTP; and 1 U of Taq polymerase in a total volume of 20 μL. The DNA fragments were generated from initial denaturation at 95°C for 2.5 minutes, followed by 30 cycles of denaturation at 94°C for 30 seconds, annealing at 58°C for 40 seconds, and extension at 72°C for 60 seconds, with final extension at 72°C for 5 minutes. The amplification products were digested with the restriction enzyme XbaI, and the fragments were separated on a 4% agarose gel. Five randomly chosen samples with positive genotyping results were confirmed further by direct sequencing of the PCR products with an automated DNA sequencer.

Statistical analyses were performed using SPSS 14.0. The mean levels of TC, TG, LDL, and HDL in different groups were compared using Student's t-test. Frequencies of the genotypes and alleles were analyzed using the x2 test. The odds ratio (OR) and 95% confidential intervel (CI) were calculated to measure the strength of the association. Statistical significance was defined as P < 0.05.


 » Results Top


Clinical characteristics

The characteristics of study subjects, patients and controls are summarized in [Table 1]. The two groups were well matched for age and sex. There were no significant differences in BMI, smoking history or history of ischemic heart diseases. The difference in history of hypertension, history of diabetes and family history of CI was significant.

Allele frequencies of apolipoprotein B gene C7673T polymorphism and genotypes

Results of the C7673T polymorphism are shown in [Figure 1] and the genotype distribution and the allele frequency for APOB C7673T polymorphism in [Table 2]. Genotype frequencies did not significantly deviate from Hardy-Weinberg equilibrium in patients with CI and in controls (P > 0.05). As shown in [Table 2], there were only two genotypes (TC and CC) in CIFH and CINFH groups, while there were three genotypes (TC, CC, and TT) in the control group. The T alleles frequency of the C7673T polymorphism was significantly higher in CIFH and CINFH groups when compared with the control group (P < 0.01; P < 0.05; respectively). And the T allele frequency in CIFH group (0.17) was higher than CINFH (0.09) group (P = 0.056), but with no statistical significant difference.

Effect on lipid profile

The relation between the C7673T polymorphism and the serum lipids in CIFH, CINFH and the control groups are shown in [Table 3]. In both the CIFH and CINFH groups the serum levels of TC and LDL cholesterol were significantly high in the TT and TC genotypes than that in the CC genotype (P < 0.01), while the serum level of HDL cholesterol in the TT and TC genotypes was significantly lower than that in the CC genotype ( P < 0.05). There were no significant differences in the serum levels of TG, ApoAI, ApoB100 and Lp(a) ( P > 0.05) among the subgroups in the CIFH, CINFH, and controls groups.


 » Discussion Top


Cerebral infarction is a disease with familial clustering [10,11] and is associated with ApoB. [12] The gene coding for ApoB is polymorphic and has a close relationship with the pathogenesis of atherosclerosis; [13] however, little is known about the role of the APOB polymorphism in patients with CIFH. In our study, the T allele frequency was significantly higher in patients with CIFH and CINFH than in control subjects ( P < 0.01, P < 0.05, respectively). Further, the T allele frequency in the CIFH group (0.17) was higher than in the CINFH (0.09) group. These results suggest the T allele of APOB C7637T polymorphism was not only associated with cerebral infarction, but also with CIFH in Han Chinese from Changsha. In our earlier study we have shown an association of T allele of APOB C7673T in cerebral hemorrhage. [8] The results from these two studies show further evidence for the association between atherosclerosis and APOB.

The APOB is located on chromosome 2q23, spanning approximately 43 kb and has 29 exons and 28 introns. [14] Polymorphisms in APOB may be associated with increased or decreased levels of APOB and LDL cholesterol. [15],[16] The C7673T polymorphism has been located just adjacent to the area of the LDL receptor. This polymorphism is a consequence of a C to T transversion at nucleotide 7673 in exon 26, which converts the 2488 codon ACC to ACT. The C7673T mutation creates an XbaI recognition site, that is called allele T (X +), digestion of the PCR product of the mutant allele by this enzyme generates 2 fragments (433 and 277 bp). Though polymorphism of APOB C7673T does not lead to direct amino acid change, it still may play an important role in the pathogenesis of atherosclerosis and is related to coronary heart disease and myocardial infarction. [7] All this suggests that the C7673T polymorphism of ApoB should have a potential effect on the pathogenesis of CI. Our study suggests that the T allele of APOB C7637T polymorphism is associated with CI and CIFH in Han Chinese from Changsha.

Our study found the serum TC and LDL cholesterol levels in patients with TC or TT genotypes were significantly higher while the HDL cholesterol was significantly lower than those in CC genotype. Some of the earlier studies have shown that the APOB C7673T polymorphism was associated with the serum levels of TC, LDL cholesterol and ApoB, and played an important role in the pathogenesis of atherosclerosis. [12],[17] Saha [17] demonstrated significantly low levels of serum HDL cholesterol in TC genotype than in the CC genotype, and the T allele of APOB C7673T polymorphism was negatively associated with the serum HDL cholesterol level. They also found that the median serum TC level in TT genotype was 11~14% higher than that in CC genotype of the C7673T polymorphism, and the median serum LDL cholesterol level in TT genotype was 21% higher than that in CC genotype. [17] Our findings were similar to the observations in the earlier studies, [17],[18] and have further established the association between the APOB C7673T polymorphism serum lipid metabolism in Han Chinese from Changsha.

The in vivo catabolism of serum lipoprotein is by its interaction with the lipoprotein receptor. Lipoprotein receptor is the protein located on the cell membrane and has a high affinity for the serum lipoprotein and the receptors are located on all the cell membranes, particularly on the hepatic cells and involved in the catabolism of LDL, intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) cholesterol. [19] Renges et al., [20] showed that APOB polymorphism was an important genetic marker, and exhibit transmission disequilibrium with other nearby DNA sequence mutations which could also affect serum lipid metabolism. Those DNA sequence mutations may occur in the ApoB receptor combination area, leading to ApoB protein structure changes and thus decreasing the ability of LDL cholesterol to bind to the receptor. This can affect the catabolism of LDL cholesterol and lead to increased serum lipid levels in vivo. [20] So we suppose APOB C7673T polymorphism correlates with CI, especially CIFH. It may be an internal susceptibility factor of serum lipid level increasing, and by changing the metabolism of serum lipid in vivo indirectly, APOB C7673T polymorphism takes part in the progression of atherosclerosis, and consequently takes part in the onset and progression of CI, especially of CIFH. Validation of our findings will require additional studies with more subjects.


 » Acknowledgments Top


This study is supported by grants from National Natural Science Foundation of China (30600199).

 
 » References Top

1.Wu L, Takahashi K, Kobayashi S, Tian G, Song L, Matui R, et al. Clinical characteristics of cerebral infarction in China and Japan. Rinsho Shinkeigaku 2004;44:335-41.  Back to cited text no. 1      
2.Shao YN, Shen J, Tan YF. A study on the etiology and epidemiology of familial aggregation in arteriosclerotic cerebral infarction. Zhonghua Liu Xing Bing Xue Za Zhi 1997;18:275-8.  Back to cited text no. 2      
3.Tonk M, Haan J. A review of genetic causes of ischemic and hemorrhagic stroke. J Neurol Sci 2007;257:273-9.  Back to cited text no. 3      
4.Kalaria RN. Advances in molecular genetics and pathology of cerebrovascular disorders. Trends Neurosci 2001;24:392-400.  Back to cited text no. 4      
5.Young SG. Recent progress in understanding apolipoprotein B. Circulation 1990;82:1574-94.  Back to cited text no. 5      
6.Chen Z, Fitzgerald RL, Saffitz JE, Semenkovich CF, Schonfeld G. Amino terminal 38.9% of apolipoprotein B-100 is sufficient to support cholesterol-rich lipoprotein production and atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23:668-74.  Back to cited text no. 6      
7.Baroni MG, Berni A, Romeo S, Arca M, Tesorio T, Sorropago G, et al. Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): Variation in LIPC gene associates with clinical outcomes in patients with established CAD. BMC Med Genet 2003;4:8.  Back to cited text no. 7      
8.Hu, ZY, Zhang L, Yang QD. Effect of APoB polymorphism on plasma lipid levels and cerebral hemorrhage in Changsha Han Chinese.Zhong Nan Da Xue Xue Bao Yi Xue Ban[J]. 2008;33:494-9.  Back to cited text no. 8      
9.Lin SK, Kao JT, Tsai SM, Tsai LY, Lin MN, Lai CJ, et al. Association of apolipoprotein E genotypes with serum lipid profiles in a healthy population of Taiwan. Ann Clin Lab Sci 2004;34:443-8.  Back to cited text no. 9      
10.Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E. Parental history of cardiovascular disease and risk of stroke. A prospective follow-up of 14371 middle-aged men and women in Finland. Stroke 1997;28:1361-6.  Back to cited text no. 10      
11.Meschia JF, Atkinson EJ, O'Brien PC, Brott TG, Brown RD, Jr., Hardy J. Familial clustering of stroke according to proband age at onset of presenting ischemic stroke. Stroke 2003;34:e89-91.  Back to cited text no. 11      
12.Benn M, Nordestgaard BG, Jensen JS, Tybjaerg-Hansen A. Polymorphisms in apolipoprotein B and risk of ischemic stroke. J Clin Endocrinol Metab 2007;92:3611-7.  Back to cited text no. 12      
13.Panayiotou A, Griffin M, Georgiou N, Bond D, Tyllis T, Tziakouri-Shiakalli C, et al. ApoB/ApoA1 ratio and subclinical atherosclerosis. Int Angiol 2008;27:74-80.  Back to cited text no. 13      
14.Whitfield AJ, Barrett PH, van Bockxmeer FM, Burnett JR. Lipid disorders and mutations in the APOB gene. Clin Chem 2004;50:1725-32.  Back to cited text no. 14      
15.Humphries SE. DNA polymorphisms of the apolipoprotein genes - their use in the investigation of the genetic component of hyperlipidaemia and atherosclerosis. Atherosclerosis 1988;72:89-108.  Back to cited text no. 15      
16.Bentzen J, Jorgensen T, Fenger M. The effect of six polymorphisms in the Apolipoprotein B gene on parameters of lipid metabolism in a Danish population. Clin Genet 2002;61:126-34.  Back to cited text no. 16      
17.Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in atherosclerosis. Circulation 2004;109:III2-7.  Back to cited text no. 17      
18.Saha N, Tay JS, Humphries SE. Apolipoprotein B-gene DNA polymorphisms (XbaI and EcoRI), serum lipids, and apolipoproteins in healthy Chinese. Genet Epidemiol 1992;9:1-10.  Back to cited text no. 18      
19.Bovenschen N, Mertens K, Hu L, Havekes LM, van Vlijmen BJ. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood 2005;106:906-12.  Back to cited text no. 19      
20.Renges HH, Wile DB, McKeigue PM, Marmot MG, Humphries SE. Apolipoprotein B gene polymorphisms are associated with lipid levels in men of South Asian descent. Atherosclerosis 1991;91:267-75.  Back to cited text no. 20      


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 807C/T polymorphism of platelet glycoprotein Ia gene is associated with cerebral hemorrhage in a Chinese population
Yi Zeng,Le Zhang,Zhiping Hu,Qidong Yang,Mingming Ma,Baoqiong Liu,Jian Xia,Hongwei Xu,Yunhai Liu,Xiaoping Du
International Journal of Neuroscience. 2015; : 1
[Pubmed] | [DOI]
2 Apolipoprotein B polymorphism distribution among a sample of obese Egyptian females with visceral obesity and its influence on lipid profile
Nayera E. Hassan,Sahar A. El-Masry,Waheba Ahmed Zarouk,Ahmed Ibrahim Abd Elneam,Enas Abdel Rasheed,Maged Mostafa Mahmoud
Journal of Genetic Engineering and Biotechnology. 2015; 13(2): 177
[Pubmed] | [DOI]
3 Association of C7673T polymorphism in apolipoprotein B gene with ischemic stroke in the Chinese population: a meta-analysis
Yuezhou Cao,Xinying Fan,Wusheng Zhu,Guihua Ni,Yun Qian,Yunfei Han,Minmin Ma
International Journal of Neuroscience. 2015; : 1
[Pubmed] | [DOI]
4 Association between the APOB XbaI and EcoRI polymorphisms and lipids in Chinese: a meta-analysis
Wei Gu,Mingduo Zhang,Shaojun Wen
Lipids in Health and Disease. 2015; 14(1)
[Pubmed] | [DOI]
5 Fibrinogen polymorphisms associated with sporadic cerebral hemorrhage in a Chinese population
Yi Zeng,Le Zhang,ZhiPing Hu,QiDong Yang,MingMing Ma,BaoQiong Liu,Jian Xia,HongWei Xu,Yunhai Liu,XiaoPing Du
Journal of Clinical Neuroscience. 2012; 19(5): 753
[Pubmed] | [DOI]
6 Polymorphism of the Apolipoprotein B Gene and Association with Plasma Lipid and Lipoprotein Levels in the Mongolian Buryat
Kenji Tsunoda,Shinji Harihara,Yuichi Tanabe,Bumbein Dashnyam
Biochemical Genetics. 2012; 50(3-4): 249
[Pubmed] | [DOI]
7 Fibrinogen polymorphisms associated with sporadic cerebral hemorrhage in a Chinese population
Zeng, Y. and Zhang, L. and Hu, Z. and Yang, Q. and Ma, M. and Liu, B. and Xia, J. and Xu, H. and Liu, Y. and Du, X.
Journal of Clinical Neuroscience. 2012; 19(5): 753-756
[Pubmed]
8 Polymorphism of the apolipoprotein b gene and association with plasma lipid and lipoprotein levels in the mongolian buryat
Tsunoda, K. and Harihara, S. and Tanabe, Y. and Dashnyam, B.
Biochemical Genetics. 2012; 50(3-4): 249-268
[Pubmed]
9 Objective assessment of stress levels and health status using routinely measured clinical laboratory parameters as biomarkers
Liu Hui,Li Shijun,Zhao Xinyu,Wang Yuai,Xu Xiaoting
Biomarkers. 2011; 16(6): 525
[Pubmed] | [DOI]
10 Objective assessment of stress levels and health status using routinely measured clinical laboratory parameters as biomarkers
Hui, L., Shijun, L., Xinyu, Z., Yuai, W., Xiaoting, X.
Biomarkers. 2011; 16(6): 525-529
[Pubmed]
11 Editorial: Geographical variations of prothrombotic polymorphisms: An important emerging risk factor for ischemic stroke
Thomas, M., Pandian, J.D.
Neurology India. 2009; 57(5): 523-524
[Pubmed]



 

Top
Print this article  Email this article
Previous article Next article
Online since 20th March '04
Published by Wolters Kluwer - Medknow