Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 1612 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 6  |  Page : 937-941
Polymorphism in methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and apolipoprotein E in hemodialysis patients


1 Department of Internal Medicine, College of Medicine, King Faisal University, Dammam, Saudi Arabia
2 Departments of Biochemistry, College of Medicine, King Faisal University, Dammam, Saudi Arabia
3 Department of Microbiology, College of Medicine, King Faisal University, Dammam, Saudi Arabia

Click here for correspondence address and email
 

   Abstract 

The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, apolipoprotein E (apo s4) gene polymorphism and polymorphism of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with end-stage renal disease (ESRD). To determine the prevalence of these mutations in Saudi patients with ESRD on hemodialysis, we studied the allelic frequency and genotype distribution in patients receiving hemodialysis and in a control group, all residing in the Eastern Province of Saudi Arabia. The genotypes were determined using allele specific hybridization procedures and were confirmed by restriction fragment length polymorphism. The T allele frequency and homozygous genotype of MTHFR in ESRD patients were 14% and 2.4%, respectively compared to 13.4% and 0%, respectively in the control group. The allele frequency and homozygous genotype of 4G/4G PAI-1 gene polymorphism were 46.4% and 4.8% respectively in ESRD patients compared to 57.1% and 32% respectively in the control group. The apo s4 allele frequency and homozygous genotype distribution in hemodialysis patients were 7% and 2.4%, respectively compared to 13% and 2% in the control group. Although allele frequency of C677T of MTHFR was statistically similar in the hemodialysis patients and in the control group, the homozygotes T allele genotype was over repre­sented in the hemodialysis group compared to normal. The prevalence of PAI-1 4G/4G polymorphism in ESRD patients was lower when com-pared to the control group. The prevalence of apo s4 allele did not differ significantly between the two groups. The present results demonstrate that all three studied polymorphic mutations are present in our population and that they may contribute to the etiology of the disease in our area.

Keywords: MTHFR, PAI-1, Apo c4, ESRD, Hemodialysis, Polymorphism

How to cite this article:
Al-Muhanna F, Al-Mueilo S, Al-Ali A, Larbi E, Rubaish A, Abdulmohsen MF, Al-Zahrani A, Al-Ateeq S. Polymorphism in methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and apolipoprotein E in hemodialysis patients. Saudi J Kidney Dis Transpl 2008;19:937-41

How to cite this URL:
Al-Muhanna F, Al-Mueilo S, Al-Ali A, Larbi E, Rubaish A, Abdulmohsen MF, Al-Zahrani A, Al-Ateeq S. Polymorphism in methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and apolipoprotein E in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2020 Nov 27];19:937-41. Available from: https://www.sjkdt.org/text.asp?2008/19/6/937/43468

   Introduction Top


Cardiovascular risk factors play a major role in increased morbidity and mortality of end stage renal disease (ESRD) patients on hemo­dialysis. The Framingham study found that such risk factors are very common in these hemo­dialysis patients. [1],[2] A high prevalence of cardiovascular death may be explained by multiple factors present in patients with progressive renal disease including hypertension, hyper­lipidemia, hyperhomocysteinemia, and diabetes mellitus. [3],[4],[5],[6] In addition to acquired clinical cha­racterization, genotypic constitution could also influence the different risk factors affecting morbidity and mortality in hemodialysis pa­tients. Among these identified genetic risk fac­tors is the C677T melhylenetetrahydrofolate reductase (MTHFR) polymorphism, which is associated with hyperhomocysteinemia. [7] Others include the allele epselion 4 of apolipoprotein E (apo c4), which is associated with higher mean plasma cholesterol and triglyceride con­centrations, and consequently leads to a higher risk of coronary disease. [8],[9] The 4G/4G poly­morphism of plasminogen activator inhibitor (PAI-1) gene, which is associated with higher plasma PAI-1 activity, is considered as another genetic factor associated with an increased risk of coronary heart disease. [10],[11]

In the present study, we examined the allelic frequency and genotype distribution of C677T MTHFR, 4G/4G PAI-1 and allele apo ε4 in hemodialysis patients in the Eastern Province of Saudi Arabia and in a normal control group.


   Methods Top


We studied chronic HD patients attending the hemodialysis unit of King Fahad University Hospital, Al-Khobar during 2005. Control sub­jects (n=40) were recruited from the same age group and geographical area. The sole exclu­sion criterion for control subjects was past, present or family history of renal disease. Written consents were obtained from all the study patients and controls.

Blood samples were collected in EDTA tubes and were frozen until analysis. DNA samples were extracted from 300 µL whole blood by standard procedures. Genotypes were deter­mined by a reverse-hybridization assay deve­loped by Vienna Laboratory. [12] In this method, the relevant gene sequences are simultaneously amplified in vitro and biotin labeled in a single amplification reaction. The amplified products are selectively hybridized to a test strip that contains allele specific oligonucleotide probes immobilized as an array of parallel lines. The results are routinely confirmed by restriction fragment length polymorphism (RLP) proce­dures. [13] The procedures encompass the ampli­fication of a specific DNA fragment by poly­merase chain reaction (PCR) using specific primers as previously described. Allele fre­quencies are calculated by allele counting. The expected genotype frequencies are calculated according to the Hardy Weinberg law and compared to the observed genotype.


   Results Top


The data revealed that the prevalence of the T allele and the homozygous TT genotype of MTHFR in the control group to be 13.4% and 0.0%, respectively [Table 1]. However, the prevalence of the T allele did not differ signi­ficantly in the ESRD patients and the control group. However, the distribution of genotype between the two groups was different with frequencies of heterozygote and homozygote for the T allele at 27.9% and 0%, respectively in the control group compared to 22% and 2.4% in the ESRD patients.

The prevalence of 4G alleles and homo­zygous 4G/4G genotype of PA1-1 in the control group were 42.9.1% and 18.4%, res­pectively, while it was 53.6% and 11.9% for the ESRD patients [Table 1].

Apo ε4 allele frequency and homozygous genotype distribution in hemodialysis patients were 7% and 7.1%, respectively, compared to 13% and 2% in the control group [Table 2].


   Discussion Top


The data revealed that the prevalence of the T allele and the homozygous TT genotype of MTHFR in the control group was lower than those reported for this variant in other popu­lations, [14],[15] the prevalence of 4G allele was similar to that reported in European coun­tries, [16] and the prevalence of ε4/4 genotype in our population is significantly lower than that reported in similar populations in Europe. [17]

There are striking differences in the increased rate of morbidity and mortality in different populations. [18],[19] This is due to both acquired and genetic risk factors. Among the genetic factors, which modify the increased risk of morbidity and mortality in ESRD patients on hemodialysis is the prevalence of the C677T MTHFR mutation, [20] and consequent elevation in serum homocysteine. Progressive renal failure is also associated with increasing serum total homocysteine level. [11] Although our results indicate that the allele frequency in our two groups was similar, the genotypic study indi­cated that the prevalence of homozygosity for the C677T mutation was over represented in the ESRD patients when compared to normal controls. This agrees with previously published data in other populations. [7]

Our results indicate that the allele frequency of the deleterious 4G/4G allele of the PA1-1 gene, which is related to elevated serum PAI-1 levels, in the patients on hemodialysis was statistically lower when compared to normal controls. It has been suggested that the asso­ciation of 4G allele coupled with an increase in tissue PAI-1 may stabilize plaques, which in turn reduces the risk of cerebrovascular disease. [21]

It has been shown that the frequency of Apo c4 allele is higher in the ESRD patients compared to the general population. [22],[23] In a recent meta-analysis of 14 studies, carriers of the ε4 allele had a higher coronary risk than ε2 or ε3 carriers. [24] However, inconsistency con­cerning the risk effects of Apo E polymor­phism has been reported. [17],[20] Factors including ethnicity, gender, and lifestyle can influence a specific ApoE phenotype. In the present study, there was no significant difference in Apo ε4 allelic frequency or genotype distribution bet­ween ESRD patients and controls. In addition, the present results indicate that the allele frequency of apo ε2 in patients on hemo­dialysis was slightly higher than that in the control group. Apo ε2 has been reported to be more frequent in diabetic patients with renal failure than in diabetic patients without renal failure. [25]

We conclude that the present results show that all three polymorphic mutations, which have been studied are present in our population and that they may contribute towards the etiology of the disease in our area.


   Acknowledgment Top


We would like to extend our gratitude to King Faisal University for the financial support of this project.

 
   References Top

1.Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk factor from the Framingham study. Stroke 1991;2(6):312-8.  Back to cited text no. 1    
2.Wilson PW. Established risk factors and coro­nary artery disease: the Framingham study. Am J Hypertens 1994;7(1):75-125.  Back to cited text no. 2    
3.Bostom AG, Lathrop L. Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology and potential relationship to arteriosclerotic outcomes.Kidney Int 1997;52(1):10-20.  Back to cited text no. 3    
4.Halimi S, Zmirou D, Benjamou PY, et al. Huge progression of diabetes prevalence and inci­dence among dialysed patients in mainland France and overseas French territories: a second national survey six years apart. Diabetes Meta 1999;25:507-12.  Back to cited text no. 4    
5.Kawamura M, Fijimoto S, Hisanaga S, Yamamoto Y, Eto T. Incidence, outcome and risk factors of cerebrovascular events in patients undergoing maintenance hemodialysis. Am J Kidney Dis 1998;31(6):991-6.  Back to cited text no. 5    
6.Tylicki L, Fodinger M, Puttinger H, et al. Methylenetetrahydrofolate reductase gene polymorphisms in essential hypertension relation: with the development of hypertensive end-stage renal disease. Am J Hypertens 2005; 18(11):1442-8.  Back to cited text no. 6    
7.Kimura H, Gejyo F, Suzuki S, Takeda T, Miyazaki R, Yoshida H. A c677t Mutation in the MTHFR gene modifies serum cysteine in dialysis patients. Am J kidney Dis 2000;36(5): 925-33.  Back to cited text no. 7    
8.Lim PS, Liu CS, Hong CJ, Wei YH. Preva­lence of apolipoprotein E genotypes in ischae­mic cerebrovascular disease in end-stage renal disease patients. Nephrol Dial Transplant 1997;12(9):1916-20.  Back to cited text no. 8    
9.Feussner G, Wey S, Bommer J, Deppermann D, Grutzmacher P, Ziegler R. Apolipoprotein E phenotypes and hyperlipdemia in patients under maintenance hemodialysis. Hum Genet 1992;88(3):307-12.  Back to cited text no. 9    
10.Wong TY, Poon P, Szeto CC, Chang JC, Li PK. Association of pasminogen activator inhi­bitor-1 4G/4G genotype and type 2 diabetic nephropathy in Chinese patients. Kidney Int 2000;57(2):632-8.  Back to cited text no. 10    
11.Eriksson P, Kallin B, Van't Hooft, Bavenholm P, Hamsten A. Allele specific increase in basal transcription of the plasminogen activator inhi­bitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92(6):1851-5.  Back to cited text no. 11    
12.CVD stript assay. Cat No. 4-240/4/241. HVD Vertnebs, Gasellschaft M.D.H., Wurzbachgasse. Vienna, Austria.  Back to cited text no. 12    
13.Frosst P. Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reducatase. Nat Genet 1995;10:111-3.  Back to cited text no. 13    
14.Scholtz CL, Odendaal HJ, Thiart R, et al. Analysis of two mutations in MTHFR gene associated with mild hyperhomocysteinemia­heterogeneous distribution in the South African population. S Afr Med J 2002;92(6): 464-7.  Back to cited text no. 14    
15.Hanson NQ, Aras O, Yong F, Tsai MY. C677T and A1298C polymorphism of the methylene­tetrahydrofolate reductase gene: Incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 2001;47(4): 661-6.  Back to cited text no. 15    
16.Endlet G, Lalouschek W, Exner M, Mitterbauer G, Haring D, Manhalter C. The 4G/4G geno­type at nucleotide position-675 in the pro­motor region of the plasminogen activator inhibitor 1 (PAI-1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol 2000;110:467-71.  Back to cited text no. 16    
17.Olmer M, Renucci JE, Planeus R, Bouchoureb D, Purgus R. Preliminary evidence for a role of apolipoprotein E alleles in identifying hemo­dialysis patients at high vascular risk. Nephrol Dial Transplant 1997;12(4):691-3.  Back to cited text no. 17    
18.Foley RN, Parfrey PS, Sarnak MJ. Epidemio­logy of cardiovascular diseases in chronic renal diseases. J Am Soc Nephrol 1998;9(S12):S16-23.  Back to cited text no. 18    
19.Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: a cross sectional study. J Am Soc Nephrol 2001;12:516-23  Back to cited text no. 19    
20.Foldinger M, Mannhalter C, Wolfl G, et al. Mutation (677C to T) in the methylenetetra­hydrofolate reductase gene aggravates hyper­homocysteinemia in hemodialysis patients. Kidney Int 1997;2:517-23.  Back to cited text no. 20    
21.Hoekstra T, Geleijnse JM, Kluft C, Giltay EJ, Kok FJ, Schouten EG. 4G/4G genotype of PAI-1 gene is associated with reduced risk of stroke in elderly. Stroke 2003;34(12):2822-8.  Back to cited text no. 21    
22.Pernod G, Bosson JL, Golshayan D, et al. The Diamant Alpin Dialysis Cohort study, clinico - biological characteristics and cardiovascular genetic risk profile of incident patients. J Nephrol 2004;17(1):66-75.  Back to cited text no. 22    
23.Van Buckxmeer FM, Mamotte CD. Apolipo­protein E4 homozygosity in young men with coronary heart disease. Lancet 1992;340 (8824):879-80.  Back to cited text no. 23    
24.Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E allele and risk of coro­nary disease: a metaanalysis. Arterioscler Thromb Vasc Biol 1996;16(10):1250-5.  Back to cited text no. 24    
25.Horita K, Eto M, Makino I. Apolipoprotein E2, renal failure and lipid abnormalities in non­insulin dependent diabetes mellitus. Athero­sclerosis 1994;107(2):203-11.  Back to cited text no. 25    

Top
Correspondence Address:
Amein Al-Ali
College of Medicine, King Faisal University, P.O. Box 2114, Dammam 31451
Saudi Arabia
Login to access the Email id


PMID: 18974580

Rights and Permissions



 
 
    Tables

  [Table 1], [Table 2]

This article has been cited by
1 Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations
Zhang, L. and Yin, R.-X. and Liu, W.-Y. and Miao, L. and Wu, D.-F. and Aung, L.H.H. and Hu, X.-J. and Cao, X.-L. and Wu, J.-Z. and Pan, S.-L.
Lipids in Health and Disease. 2010; 9(123)
[Pubmed]



 

Top
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
  Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
    Introduction
    Methods
    Results
    Discussion
    Acknowledgment
    References
    Article Tables
 

 Article Access Statistics
    Viewed2429    
    Printed87    
    Emailed0    
    PDF Downloaded466    
    Comments [Add]    
    Cited by others 1    

Recommend this journal