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| Year : 2008 | Volume
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| Issue : 6 | Page : 937-941 |
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| Polymorphism in methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and apolipoprotein E in hemodialysis patients |
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Fahad Al-Muhanna1, Samir Al-Mueilo1, Amein Al-Ali2, Emmanuel Larbi1, Abdullah Rubaish1, Mohammed Fakhry Abdulmohsen1, Alhussain Al-Zahrani3, Suad Al-Ateeq2
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
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 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 | |  |
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 | | |
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 | | |
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 | | |
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 | | |
We would like to extend our gratitude to King Faisal University for the financial support of this project.
| References | | |
| 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.  |
| 2. | Wilson PW. Established risk factors and coronary artery disease: the Framingham study. Am J Hypertens 1994;7(1):75-125. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 12. | CVD stript assay. Cat No. 4-240/4/241. HVD Vertnebs, Gasellschaft M.D.H., Wurzbachgasse. Vienna, Austria. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 18. | Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular diseases in chronic renal diseases. J Am Soc Nephrol 1998;9(S12):S16-23. |
| 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 |
| 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. |
| 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. |
| 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. |
| 23. | Van Buckxmeer FM, Mamotte CD. Apolipoprotein E4 homozygosity in young men with coronary heart disease. Lancet 1992;340 (8824):879-80. |
| 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. |
| 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. |
Correspondence Address:
Amein Al-Ali
College of Medicine, King Faisal University, P.O. Box 2114, Dammam 31451
Saudi Arabia
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PMID: 18974580 
[Table 1], [Table 2] |
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| This article has been cited by | | 1 |
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