亚甲基四氢叶酸还原酶基因C677T多态性与中国2型糖尿病患者冠心病风险增加相关

doi:10.24920/003792

Abstract

Objective Chronic cardiovascular diseases induced by long-term poor blood glucose control are the main cause of death in patients with type 2 diabetes mellitus (T2DM). Previous researches report that methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms might influence the occurrence of coronary heart disease (CHD) in T2DM patients. The purpose of this study was to evaluate whether MTHFR C677T and A1298C mutations are associated with the risk of CHD in T2DM patients.
Methods A total of 197 subjects with T2DM were studied, of which 95 patients with CHD. The genotypes of MTHFR C677T and A1298C were analyzed by using dideoxy chain-termination method, and compared between patients with CHD and those without CHD.
Results We found that the frequency of the 677T allele was significantly higher in T2DM patients with CHD than those without CHD (P=0.011). However, there was no significant difference in any of the examined haplotypes between T2DM patients with and without CHD. Furthermore, the 677T allele was associated with a higher risk of CHD development in diabetic patients with lower homocysteine (Hcy) levels (≤15 μmol/L) (P=0.006), while no effect of MTHFR gene polymorphism on the incidence of CHD was found in patients with higher Hcy levels (>15 μmol/L) (P=0.491).
Conclusion The MTHFR C677T gene polymorphism is associated with the risk of CHD of diabetic patients and could be used as an effective marker for CHD in Chinese diabetic populations with normal Hcy levels.

Key words: methylenetetrahydrofolate reductase, gene polymorphism, type 2 diabetes mellitus, coronary heart diseases, homocysteine

Kunrong Wu, Shufang Zhang, Ziwan Guan, Xiaoli Li, Rui Li, Ying Yin, Yan Li. Methylenetetrahydrofolate Reductase Gene Polymorphism C677T is Associated with Increased Risk of Coronary Heart Disease in Chinese Type 2 Diabetic Patients[J].Chinese Medical Sciences Journal, 2021, 36(2): 103-109.

Figures/Tables 6

Table 1

Figure 1.

Table 2

Table 3

Table 4

Table 5

References 34.

[1.]	Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat Rev Endocrinol 2011; 8(4):228-36. doi: 10.1038/nrendo.2011.183. doi: 10.1038/nrendo.2011.183 pmid: 22064493
[2.]	International Diabetes Federation Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF Diabetes Atlas: estimates for the year 2013. Diabetes Res Clin Pract 2015; 109(3):461-5. doi: 10.1016/j.diabres.2015.05.037. doi: 10.1016/j.diabres.2015.05.037
[3.]	American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2004; 27 Suppl 1:S5-S10. doi: 10.2337/diacare.27.2007.s5. doi: 10.2337/diacare.27.2007.s5
[4.]	Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414(6865):813-20. doi: 10.1038/414813a. doi: 10.1038/414813a pmid: 11742414
[5.]	Rizvi S, Raza ST, Mahdi F. Association of genetic variants with diabetic nephropathy. World J Diabetes 2014; 5(6):809-16. doi: 10.4239/wjd.v5.i6.809. doi: 10.4239/wjd.v5.i6.809
[6.]	Sun J, Xu Y, Zhu Y, et al. Methylenetetrahydrofolate reductase gene polymorphism, homocysteine and risk of macroangiopathy in type 2 diabetes mellitus. J Endocrinol Invest 2006; 29(9):814-20. doi: 10.1007/BF03347376. doi: 10.1007/BF03347376
[7.]	Fekih-Mrissa N, Mrad M, Ibrahim H, et al. Methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C) polymorphisms and vascular complications in patients with type 2 diabetes . Can J Diabetes 2017; 41(4):366-71. doi: 10.1016/j.jcjd.2016.11.007. doi: S1499-2671(16)30784-5 pmid: 28341195
[8.]	Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1):111-3. doi: 10.1038/ng0595-111. doi: 10.1038/ng0595-111 pmid: 7647779
[9.]	Harmon DL, Woodside JV, Yarnell JW, et al. The common ‘thermolabile’ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM 1996; 89(8):571-7. doi: 10.1093/qjmed/89.8.571. doi: 10.1093/qjmed/89.8.571
[10.]	van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 1998; 62(5):1044-51. doi: 10.1086/301825. doi: 10.1086/301825 pmid: 9545395
[11.]	van der Put NM, Blom HJ. Neural tube defects and a disturbed folate dependent homocysteine metabolism. Eur J Obstet Gynecol Reprod Biol 2000; 92(1):57-61. doi: 10.1016/s0301-2115(00)00426-7. doi: 10.1016/s0301-2115(00)00426-7 pmid: 10986435
[12.]	Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354(9176):407-13. doi: 10.1016/S0140-6736(98)11058-9. doi: 10.1016/S0140-6736(98)11058-9 pmid: 10437885
[13.]	Stehouwer CD, Weijenberg MP, van den Berg M, et al Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol 1998; 18(12):1895-901. doi: 10.1161/01.atv.18.12.1895. doi: 10.1161/01.atv.18.12.1895
[14.]	Aso Y, Yoshida N, Okumura K, et al. Coagulation and inflammation in overt diabetic nephropathy: association with hyperhomocysteinemia. Clin Chim Acta 2004; 348(1-2):139-45. doi: 10.1016/j.cccn.2004.05.006. doi: 10.1016/j.cccn.2004.05.006
[15.]	Doupis J, Eleftheriadou I, Kokkinos A, et al. Acute hyperhomocysteinemia impairs endothelium function in subjects with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2010; 118(7):453-8. doi: 10.1055/s-0030-1248290. doi: 10.1055/s-0030-1248290
[16.]	Mtiraoui N, Ezzidi I, Chaieb M, et al. MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of diabetic nephropathy in type 2 diabetes patients . Diabetes Res Clin Pract 2007; 75(1):99-106. doi: 10.1016/j.diabres.2006.05.018. doi: 10.1016/j.diabres.2006.05.018
[17.]	Sun J, Xu Y, Zhu Y, et al. The relationship between MTHFR gene polymorphisms, plasma homocysteine levels and diabetic retinopathy in type 2 diabetes mellitus . Chin Med J (Engl) 2003; 116(1):145-7.
[18.]	Cao H, Huang DF, Mao L, et al. Association of homocysteine, methylenetetrahydrofolate reductase gene polymorphism with type 2 diabetes mellitus with cerebral infarction. Chin J Dis Control Prev 2010; 14(3):196-8. (In Chinese)
[19.]	Luo D, Yan SK, Cheng XQ, et al. Levels of homocysteine and polymorphisms of homocysteine metabolism related enzymes in patients with type 2 diabetes mellitus and coronary heart disease. J Hygiene Res 2009; 38(1):39-42. (In Chinese)
[20.]	Sun J, Xu Y, Xue J, et al. Methylenetetrahydrofolate reductase polymorphism associated with susceptibility to coronary heart disease in Chinese type 2 diabetic patients. Mol Cell Endocrinol 2005; 229(1-2):95-101. doi: 10.1016/j.mce.2004.09.003. doi: 10.1016/j.mce.2004.09.003
[21.]	Wu XF, Cheng LX, He MA. Association between polymorphism of methylenetetrahydrofolate reductase C677T and coronary heart disease. Acta Med Univ Sci Technol Huazhong 2009; 38(3):296-300. doi: 10.3870/ j.issn.1672-0741.2009.03.004. (In Chinese) doi: 10.3870/ j.issn.1672-0741.2009.03.004. (In Chinese
[22.]	Zhao XD, Wang L. The relationship of plasma homocysteine and the polymorphism of MTHFR gene with brain infaction in type 2 diabetes mellitus . Chin J Diabetes 2015; 23(2):107-9. doi: 10.3969/j.issn.1006-6187.2015.02.003. (In Chinese) doi: 10.3969/j.issn.1006-6187.2015.02.003. (In Chinese
[23.]	Wang GB, Shen QD, ping LD. Correlation between homocysteine levels and MTHFR C677T gene polymorphism of cerebral infarction . J Med Res 2017; 46(5):154-8. doi: 10.11969/j.issn.1673-548X.2017.05.038. (In Chinese) doi: 10.11969/j.issn.1673-548X.2017.05.038. (In Chinese
[24.]	Mata-Cases M, Artola S, Escalada J, et al. Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society. Rev Clin Esp 2015; 215(2):117-29. doi: 10.1016/j.rce.2014.10.012. doi: 10.1016/j.rce.2014.10.012 pmid: 25553948
[25.]	Cardiovascular Specialty Group in the First National Internal Medicine Conference. Recommendations on the naming and diagnostic criteria of coronary heart disease. Chin J Int Med 1981; 20(4):253-5. (In Chinese)
[26.]	Dzida G, Biłan A, Golon-Siekierska P, et al. Methylenetetrahydrofolate reductase gene polymorphism in patients with type 2 diabetes. Pol Arch Med Wewn 2001; 106(1):543-9.
[27.]	Beneš P, Kaňková K, Mužı́k J, et al. Methylenetetrahydrofolate reductase polymorphism, typeⅡ diabetes mellitus, coronary artery disease, and essential hypertension in the Czech population. Mol Genet Metab 2001; 73(2):188-95. doi: 10.1006/mgme.2001.3188. doi: 10.1006/mgme.2001.3188
[28.]	Settin A, El-Baz R, Ismaeel A, et al. Association of ACE and MTHFR genetic polymorphisms with type 2 diabetes mellitus: susceptibility and complications . J Renin Angiotensin Aldosterone Syst 2015; 16(4):838-43. doi: 10.1177/1470320313516172. doi: 10.1177/1470320313516172 pmid: 24452036
[29.]	Böger CA, Stubanus M, Haak T, et al. Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy . Nephrol Dial Transplant 2007; 22(1):154-62. doi: 10.1093/ndt/gfl512. doi: 10.1093/ndt/gfl512
[30.]	Brulhart MC, Dussoix P, Ruiz J, et al. The (Ala-Val) mutation of methylenetetrahydrofolate reductase as a genetic risk factor for vascular disease in non-insulin-dependent diabetic patients. Am J Hum Genet 1997; 60(1):228-9. pmid: 8981966
[31.]	Wirta V, Huang XH, Wirta O, et al. Mutation C677T of methylenetetrahydrofolate reductase gene is not associated with coronary artery disease, but possibly with albuminuria, in type 2 diabetic patients. Clin Chem Lab Med 1998; 36(8):625-8. doi: 10.1515/CCLM.1998.109. doi: 10.1515/CCLM.1998.109 pmid: 9806473
[32.]	Audelin MC, Genest JJ. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 2001; 159(2):497-511. doi: 10.1016/s0021-9150(01)00531-7. doi: 10.1016/s0021-9150(01)00531-7 pmid: 11730832
[33.]	Hoogeveen EK, Kostense PJ, Beks PJ, et al. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 1998; 18(1):133-8. doi: 10.1161/01.atv.18.1.133. doi: 10.1161/01.atv.18.1.133
[34.]	Yeromenko Y, Lavie L, Levy Y. Homocysteine and cardiovascular risk in patients with diabetes mellitus. Nutr Metab Cardiovasc Dis 2001; 11(2):108-16.

Items	T2DM patients without CHD	T2DM patients with CHD	Pvalue
n	102	95
Male [n (%)]	67 (65.69)	62 (65.26)	0.950
Age (yrs)	63.14±6.78	64.34±8.11	0.263
Current smoker [n (%)]	26 (25.49)	27 (28.42)	0.547
Age at T2DM diagnosis (yrs)	50.23±7.93	51.67±9.80	0.257
Diabetes duration (yrs)	12.91±5.97	12.66±6.66	0.642
BMI (kg/m²)	25.07±2.99	25.18±2.79	0.787
FPG (mmol/L)	7.95±2.08	8.10±2.33	0.733
HbA1c (%)	8.57±1.67	8.33±2.17	0.115
TC (mmol/L)	4.59±1.02	4.44±1.05	0.337
TG (mmol/L)	1.60±0.96	1.42±0.67	0.553
HDL-C (mmol/L)	1.21±0.28	1.20±0.39	0.523
LDL-C (mmol/L)	2.64±0.83	2.52±0.75	0.436
SBP (mm Hg)	133.26±12.42	131.01±13.62	0.228
DBP (mm Hg)	75.85±7.34	74.89±9.17	0.420
Scr (μmol/L)	66.21±18.40	70.25±22.48	0.128

Genotypes and alleles	T2DM patients [n (%)]		OR(95%CI)	P value
Genotypes and alleles	Without CHD (n=102)	With CHD (n=95)	OR(95%CI)	P value
CC	22 (21.57)	9 (9.47)
CT+TT	80 (78.43)	86 (90.53)	2.63 (1.14-6.05)	0.020
C allele	92 (45.10)	62 (32.63)
T allele	112 (54.90)	128 (67.37)	1.70 (1.13-2.56)	0.011

Genotypes and alleles	T2DM patients [n (%)]		OR (95%CI)	P value
Genotypes and alleles	Without CHD (n=100)	With CHD (n=67)	OR (95%CI)	P value
AA	64 (69.07)	48 (74.60)
AC+CC	36 (30.93)	19 (25.40)	0.70 (0.36-1.38)	0.303
A allele	162 (83.51)	115 (87.30)
C allele	38 (16.49)	19 (12.70)	0.70 (0.39-1.28)	0.251

Haplotypes*	Frequency		OR (95%CI)	P value
Haplotypes*	T2DM without CHD (n=67)	T2DM with CHD (n=67)	OR (95%CI)	P value
C-A	0.267	0.216	0.75 (0.45-1.26)	0.275
C-C	0.183	0.142	0.73 (0.40-1.34)	0.310
T-A	0.543	0.642	1.49 (0.95-2.33)	0.084

Hcy levels (μmol/L)	MTHFR genotypes	Patients without CHD (n)	Patients with CHD (n)	OR(95%CI)	P value
5-15.0	677CC	21	4
	677CT+TT	67	56	4.39 (1.42-13.54)	0.006
	1298AA	55	31
	1298AC+CC	31	10	0.57 (0.25-1.32)	0.189
>15.0	677CC	1	5
	677CT+TT	13	30	0.46 (0.05-4.35)	0.491
	1298AA	9	17
	1298AC+CC	5	9	0.95 (0.25-3.71)	0.945

Early edition

Current issue

Archive

Specialties & Topics

Author center

Reviewer center

Methylenetetrahydrofolate Reductase Gene Polymorphism C677T is Associated with Increased Risk of Coronary Heart Disease in Chinese Type 2 Diabetic Patients

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 6

References 34.

Related Articles 7

Metrics

Recommended 10

[1]	Zihan Chen,Zhou Zhao,Chuiwen Deng,Naishi Li. Association between Air Pollution and Type 2 Diabetes Mellitus in Developing Countries: A Systematic Review and Meta-Analysis [J]. Chinese Medical Sciences Journal, 2022, 37(3): 218-227.
[2]	Lin Ye, Wang Zhenlian, Yan Min, Zhu Feiyu, Duan Ye, Sun Zhiqin. Effect of Trimetazidine on Diabetic Patients with Coronary Heart Diseases: A Meta-Analysis of Randomized, Controlled Trials [J]. Chinese Medical Sciences Journal, 2020, 35(3): 226-238.
[3]	Yin Ying, Li Rui, Li Xiaoli, Wu Kunrong, Li Ling, Xu Yuedong, Liao Lin, Yang Rui, Li Yan. Association Between Homocysteine Level and Methylenetetrahydrofolate Reductase Gene Polymorphisms in Type 2 Diabetes Accompanied by Dyslipidemia [J]. Chinese Medical Sciences Journal, 2020, 35(1): 85-91.
[4]	Chen Zhiye, Zang Xiujuan, Liu Mengqi, Liu Mengyu, Li Jinfeng, Gu Zhaoyan, Ma Lin. Abnormal Alterations of Cortical Thickness in 16 Patients with Type 2 Diabetes Mellitus: A Pilot MRI Study^△ [J]. Chinese Medical Sciences Journal, 2017, 32(2): 75-82.
[5]	Ying Fan, Shan-xiao Zhang, Meng Ren, Li-feng Hong, Xiao-ni Yan. Impact of 1, 25-(OH)₂D₃ on Left Ventricular Hypertrophy in Type 2 Diabetic Rats [J]. Chinese Medical Sciences Journal, 2015, 30(2): 114-120.
[6]	Yi-jun Zhou*,Ai Li, Yu-ling Song, Hui Zhou, Yan Li, Yin-si Tang. Role of Sclerostin in the Bone Loss of Postmenopausal Chinese Women with Type 2 Diabetes [J]. Chinese Medical Sciences Journal, 2013, 28(3): 135-139.
[7]	Yu-jing Sun, Ming-wu Fang, Wen-quan Niu, Guang-ping Li, Jing-liang Liu, Shou-quan Ding, Ying Xu, Guo-shu Yu, Jian-qun Dong, Yun-jun Pan,Wei-ya Dong, Tian Wang, Jing-wen Cao, Xiao-bo Li, Zhong-xiang Wang, Guang-xue Yu, Hui-cheng Sun, Zhong-hou Jia, Jun Liu, Xiao-ming Wang, Qin Si, Qi-xia Wu, Wen-yu Zhou, Tong-chun Zhu and Chang-chun Qiu. Endothelial nitric oxide synthase gene polymorphisms associated with susceptibility to high altitude pulmonary edema in Chinese railway construction workers at Qinghai-Tibet over 4 500 meters above sea Level [J]. Chinese Medical Sciences Journal, 2010, 25(4): 215-222.