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The methylenetetrahydrofolate reductase gene polymorphism (C677T) is associated with increased cardiovascular mortality in Hungary
International Journal of Cardiology 97 (2004) 333 – 334 www.elsevier.com/locate/ijcard
Letter to the Editor
The methylenetetrahydrofolate reductase gene polymorphism (C677T ) is associated with increased cardiovascular mortality in Hungary ´ kos Kalina a,*, Andrew E. Czeizel b A b
a Department of Cardiology, MA´V Hospital, Budapest, Hungary Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
Received 6 August 2003; accepted 7 August 2003
Abstract The gene for methylenetetrahydrofolate reductase (MTHFR) has two different alleles (C and T), where the T is associated with decreased enzyme activity, hyperhomocysteinaemia, and increased risk for thromboembolism in coronary heart disease (CHD). The study was conducted using a sample of 378 Hungarian newborn infants: 96 control subjects (age: 59.9 F 8.6 years) with chest pain and 315 CHD patients (61.4 F 7.5 years). All adult subjects had undergone coronary angiography. It can be concluded that the carriers of T allele with CHD died earlier due to myocardial infarction and the C allele with lower homocysteine level may provide protection against fatal coronary artery occlusion. D 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Coronary heart disease; Hyperhomocysteinaemia; Methylenetetrahydrofolate reductase; Myocardial infarction
Hyperhomocysteinaemia is a major independent and graded risk factor of atherothrombotic diseases and can be caused by dysfunction of the folate-dependent enzyme methylenetetrahydrofolate reductase (MTHFR). Previously, a common C ! T transition at nucleotide 677 of the MTHFR gene was identified. The observation is that TT homozygotes are predisposed to hyperhomocysteinaemia especially in those with relatively low folate intake [1,2]. Some studies have found an association between TT genotype and coronary heart disease (CHD) [2 –5], while others have not [4,6 – 9]. Our study was conducted on a randomly selected sample of 378 newborn infants (boys: 198); 96 control subjects with chest pain (males: 64, mean age F S.D.: 59.9 F 8.6 years) and 315 CHD patients (214, 61.4 F 7.5) in Hungary. The studied individuals were Hungarian Caucasians, have not kept any special diet so far in their lives, have not regularly taken any vitamin tablets, have not had any kidney or liver disease, and were not in relationship with each other. All adult subjects have undergone coronary angiography consecutively, and thus we can identify three groups: (i) patients
* Corresponding author. Ta´ncsics M. 20, Budapest 1014, Hungary. Tel.: +36-302-636823; fax: +36-1-3023104. ´ . Kalina). E-mail address: [email protected] (A 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.08.021
with negative coronary artery status, (ii) patients with nonsignificant coronary artery stenosis (less than 50% diameter loss), and (iii) patients with significant coronary artery stenosis of at least one single vessel (more than 50% diameter loss). Following this, within three groups, we separately investigated those who had suffered myocardial infarction (MI) at any time before. The genotyping for the MTHFR was performed by a polymerase chain reaction amplification and was digested with the HinfI restriction enzyme as described by Frosst et al. [1]. There was no significant difference concerning the polymorphism of the MTHFR gene in the newborns (CC: 43.7%, CT: 45.2%, and TT: 11.1%), non-CHD (45.8%, 41.7%, and 12.5%), and overall CHD (43.9%, 46.3%, and 9.8%) groups mentioned above. After a further division of all CHD groups into subgroups, whether their case history contained MI or not, we conducted subgroup analyses. The age of the subgroups did not significantly differ from each other. We state that those carrying the T allele occur significantly less frequently ( P = 0.05) in the severe CHD cases without MI (47.6%, 47.6%, and 4.8%) than the severe CHD cases who have gotten over MI (38.9%, 46.9%, and 14.2%). According to a meta-analysis including 12 studies, the proportion of the CT genotype was 45.2% and the TT was
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A´. Kalina, A.E. Czeizel / International Journal of Cardiology 97 (2004) 333–334
11.2% in the control group, which just corresponds to the Hungarian figures in newborn infants, while in the CHD group, the proportion of the CT occurrence was 43.9% and the TT genotype was 13.2%, which constitutes a significant difference in Japan population [4]. Another meta-analysis based on 10 studies shows that in the control group, the CT genotype occurred in 46.5%, and the TT in 11.1%, while in the CHD group, the CT was found in 45.6% and the TT genotype in 19.8% [3], which is also a significant difference. Recently, a huge meta-analysis shows that the TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status [2]. In a huge study with angiographically confirmed CHD patients, the CT genotype was found to be 45.1%, while the TT genotype was measured as 8.3% [6]. In another similar investigation in Germany, the CT genotype was 40.4%, and the TT genotype was measured as 9.9% [8]. The allele frequency of the control group did not significantly differ from that of the diseased ones in either of the investigations. Comparing these with our results, this means a lower T allele frequency in both patients and controls. In another smaller investigation in Hungary, patients with CHD showed TT genotype to be substantially more frequent (20%), like in a similar examination in Korea (18.8%) [9,10]. In our results, it can be observed that the TT form is less frequent, particularly in the CHD patients with significant stenosis, not having MI previously (4.8%). Our hypothesis is for the explanation of these findings that the 677 TT genotype tends to be more causally involved in cases with premature death due to severe CHD [11]. Therefore, any single polymorphic variant may have a small impact when all populations are considered, but may confer significant risk in particular subgroups [7]. At the same time, Morita et al. [5] reported that the frequency of MTHFR mutation was correlated with the severity of stenotic lesions and the number of stenotic coronary arteries, suggesting that this mutation is closely associated with the severity of CHD. This could be an explanation that in our survey, the cases carrying the 677 TT already died earlier in the more severe form of CHD. In conclusion, the current analysis shows that in the Hungarian population, the C677T mutation of the MTHFR
gene has importance for early fatal coronary artery occlusion. The T allele causes lower MTHFR enzyme activity and elevated homocysteine level, which lead to the earlier death of severe CHD patients.
References [1] Frosst P, Blom HJ, Milos R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111 – 3. [2] Klerk M, et al. The MTHFR Studies Collaboration Group. MTHFR 677 C ! T polymorphism and risk of coronary heart disease. JAMA 2002;288:2023 – 31. [3] Kluijtmans LAJ, Whitehead AS. Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease. Eur Heart J 2001;22:294 – 9. [4] Jee SH, Beaty TH, Suh I, Yoon YS, Appel LJ. The methylenetetrahydrofolate reductase gene is associated with increased cardiovascular risk in Japan, but not in other populations. Atherosclerosis 2000; 153:161 – 8. [5] Morita H, Taguchi J, Kurihara H. Genetic polymorphism of 5,10methylenetetrahydrofolate reductase as a risk factor for coronary artery disease. Circulation 1997;95:2032 – 6. [6] Meisel C, Cascorbi I, Gerloff T, Stangl V, Laule M, Mu¨ller MM, et al. Identification of six MTHFR genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease. Atherosclerosis 2001;154:651 – 8. [7] Brattstro¨m L, Wilcken DEL, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinaemia but not to vascular disease: the results of a meta-analysis. Circulation 1998;98:2520 – 6. [8] Rotenbacher D, Fischer GH, Hoffmeister A, Hoffmann MM, Ma¨rz W, Bode G, et al. Homocysteine and methylenetetrahydrofolate reductase genotype: association with risk of coronary heart disease and relation to inflammatory, haemostatic, and lipid parameters. Atherosclerosis 2002;162:193 – 200. [9] Kim HC, Hwang YK, Choi MT, Shin YW, Hong YS. The methylenetetrahydrofolate reductase gene polymorphism in Koreans with coronary heart disease. Int J Cardiol 2001;78:13 – 7. [10] Ma´rk L, Erdei F, Markizay J, Kondacs A, Katona A. Effect of treatment with folic acid and vitamin B6 on lipid and homocysteine concentrations in patients with coronary artery disease. Nutrition 2002; 18:428 – 9. [11] Kluijtmans LAJ, Whitehead AS. Reduced frequency of the thermo labile methylenetetrahydrofolate reductase genotype in the elderly (letter). Atherosclerosis 1999;146:395 – 7.
Letter to the Editor
The methylenetetrahydrofolate reductase gene polymorphism (C677T ) is associated with increased cardiovascular mortality in Hungary ´ kos Kalina a,*, Andrew E. Czeizel b A b
a Department of Cardiology, MA´V Hospital, Budapest, Hungary Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
Received 6 August 2003; accepted 7 August 2003
Abstract The gene for methylenetetrahydrofolate reductase (MTHFR) has two different alleles (C and T), where the T is associated with decreased enzyme activity, hyperhomocysteinaemia, and increased risk for thromboembolism in coronary heart disease (CHD). The study was conducted using a sample of 378 Hungarian newborn infants: 96 control subjects (age: 59.9 F 8.6 years) with chest pain and 315 CHD patients (61.4 F 7.5 years). All adult subjects had undergone coronary angiography. It can be concluded that the carriers of T allele with CHD died earlier due to myocardial infarction and the C allele with lower homocysteine level may provide protection against fatal coronary artery occlusion. D 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Coronary heart disease; Hyperhomocysteinaemia; Methylenetetrahydrofolate reductase; Myocardial infarction
Hyperhomocysteinaemia is a major independent and graded risk factor of atherothrombotic diseases and can be caused by dysfunction of the folate-dependent enzyme methylenetetrahydrofolate reductase (MTHFR). Previously, a common C ! T transition at nucleotide 677 of the MTHFR gene was identified. The observation is that TT homozygotes are predisposed to hyperhomocysteinaemia especially in those with relatively low folate intake [1,2]. Some studies have found an association between TT genotype and coronary heart disease (CHD) [2 –5], while others have not [4,6 – 9]. Our study was conducted on a randomly selected sample of 378 newborn infants (boys: 198); 96 control subjects with chest pain (males: 64, mean age F S.D.: 59.9 F 8.6 years) and 315 CHD patients (214, 61.4 F 7.5) in Hungary. The studied individuals were Hungarian Caucasians, have not kept any special diet so far in their lives, have not regularly taken any vitamin tablets, have not had any kidney or liver disease, and were not in relationship with each other. All adult subjects have undergone coronary angiography consecutively, and thus we can identify three groups: (i) patients
* Corresponding author. Ta´ncsics M. 20, Budapest 1014, Hungary. Tel.: +36-302-636823; fax: +36-1-3023104. ´ . Kalina). E-mail address: [email protected] (A 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.08.021
with negative coronary artery status, (ii) patients with nonsignificant coronary artery stenosis (less than 50% diameter loss), and (iii) patients with significant coronary artery stenosis of at least one single vessel (more than 50% diameter loss). Following this, within three groups, we separately investigated those who had suffered myocardial infarction (MI) at any time before. The genotyping for the MTHFR was performed by a polymerase chain reaction amplification and was digested with the HinfI restriction enzyme as described by Frosst et al. [1]. There was no significant difference concerning the polymorphism of the MTHFR gene in the newborns (CC: 43.7%, CT: 45.2%, and TT: 11.1%), non-CHD (45.8%, 41.7%, and 12.5%), and overall CHD (43.9%, 46.3%, and 9.8%) groups mentioned above. After a further division of all CHD groups into subgroups, whether their case history contained MI or not, we conducted subgroup analyses. The age of the subgroups did not significantly differ from each other. We state that those carrying the T allele occur significantly less frequently ( P = 0.05) in the severe CHD cases without MI (47.6%, 47.6%, and 4.8%) than the severe CHD cases who have gotten over MI (38.9%, 46.9%, and 14.2%). According to a meta-analysis including 12 studies, the proportion of the CT genotype was 45.2% and the TT was
334
A´. Kalina, A.E. Czeizel / International Journal of Cardiology 97 (2004) 333–334
11.2% in the control group, which just corresponds to the Hungarian figures in newborn infants, while in the CHD group, the proportion of the CT occurrence was 43.9% and the TT genotype was 13.2%, which constitutes a significant difference in Japan population [4]. Another meta-analysis based on 10 studies shows that in the control group, the CT genotype occurred in 46.5%, and the TT in 11.1%, while in the CHD group, the CT was found in 45.6% and the TT genotype in 19.8% [3], which is also a significant difference. Recently, a huge meta-analysis shows that the TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status [2]. In a huge study with angiographically confirmed CHD patients, the CT genotype was found to be 45.1%, while the TT genotype was measured as 8.3% [6]. In another similar investigation in Germany, the CT genotype was 40.4%, and the TT genotype was measured as 9.9% [8]. The allele frequency of the control group did not significantly differ from that of the diseased ones in either of the investigations. Comparing these with our results, this means a lower T allele frequency in both patients and controls. In another smaller investigation in Hungary, patients with CHD showed TT genotype to be substantially more frequent (20%), like in a similar examination in Korea (18.8%) [9,10]. In our results, it can be observed that the TT form is less frequent, particularly in the CHD patients with significant stenosis, not having MI previously (4.8%). Our hypothesis is for the explanation of these findings that the 677 TT genotype tends to be more causally involved in cases with premature death due to severe CHD [11]. Therefore, any single polymorphic variant may have a small impact when all populations are considered, but may confer significant risk in particular subgroups [7]. At the same time, Morita et al. [5] reported that the frequency of MTHFR mutation was correlated with the severity of stenotic lesions and the number of stenotic coronary arteries, suggesting that this mutation is closely associated with the severity of CHD. This could be an explanation that in our survey, the cases carrying the 677 TT already died earlier in the more severe form of CHD. In conclusion, the current analysis shows that in the Hungarian population, the C677T mutation of the MTHFR
gene has importance for early fatal coronary artery occlusion. The T allele causes lower MTHFR enzyme activity and elevated homocysteine level, which lead to the earlier death of severe CHD patients.
References [1] Frosst P, Blom HJ, Milos R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111 – 3. [2] Klerk M, et al. The MTHFR Studies Collaboration Group. MTHFR 677 C ! T polymorphism and risk of coronary heart disease. JAMA 2002;288:2023 – 31. [3] Kluijtmans LAJ, Whitehead AS. Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease. Eur Heart J 2001;22:294 – 9. [4] Jee SH, Beaty TH, Suh I, Yoon YS, Appel LJ. The methylenetetrahydrofolate reductase gene is associated with increased cardiovascular risk in Japan, but not in other populations. Atherosclerosis 2000; 153:161 – 8. [5] Morita H, Taguchi J, Kurihara H. Genetic polymorphism of 5,10methylenetetrahydrofolate reductase as a risk factor for coronary artery disease. Circulation 1997;95:2032 – 6. [6] Meisel C, Cascorbi I, Gerloff T, Stangl V, Laule M, Mu¨ller MM, et al. Identification of six MTHFR genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease. Atherosclerosis 2001;154:651 – 8. [7] Brattstro¨m L, Wilcken DEL, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinaemia but not to vascular disease: the results of a meta-analysis. Circulation 1998;98:2520 – 6. [8] Rotenbacher D, Fischer GH, Hoffmeister A, Hoffmann MM, Ma¨rz W, Bode G, et al. Homocysteine and methylenetetrahydrofolate reductase genotype: association with risk of coronary heart disease and relation to inflammatory, haemostatic, and lipid parameters. Atherosclerosis 2002;162:193 – 200. [9] Kim HC, Hwang YK, Choi MT, Shin YW, Hong YS. The methylenetetrahydrofolate reductase gene polymorphism in Koreans with coronary heart disease. Int J Cardiol 2001;78:13 – 7. [10] Ma´rk L, Erdei F, Markizay J, Kondacs A, Katona A. Effect of treatment with folic acid and vitamin B6 on lipid and homocysteine concentrations in patients with coronary artery disease. Nutrition 2002; 18:428 – 9. [11] Kluijtmans LAJ, Whitehead AS. Reduced frequency of the thermo labile methylenetetrahydrofolate reductase genotype in the elderly (letter). Atherosclerosis 1999;146:395 – 7.