甲硫氨酸合成酶（MS）基因A2756G多态性与2型糖尿病大血管并发症的相关性研究
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摘要
目的 研究甲硫氨酸合成酶(MS)基因A2756G多态性与2型糖尿病大血管并发症(本文主要指2型糖尿病合并冠心病和2型糖尿病合并脑梗死)的关系。方法 采用聚合酶链反应—限制性片段长度多态性(PCR-RFLP)方法鉴定安徽地区733例汉族人MS基因A2756G多态性基因型，比较基因型频率及等位基因频率并进行群体关联分析；并且对各组间临床一般资料，糖、脂代谢相关指标进行比较。733例受试者分为四组：对照组(CON)178例，无大血管及微血管并发症的2型糖尿病组(T2DM)273例，2型糖尿病大血管并发症组(T2DM+AS)189例(其中包括合并冠心病64例，合并脑梗死111例，合并糖尿病足14例)以及不伴糖尿病的单纯大血管病变组(AS)93例(其中包括冠心病16例，脑梗死77例)。结果 安徽地区汉族人群存在MS基因A2756G多态性，其G等位基因频率与西方人群比较明显降低，具有统计学显著性差异(P＜0.05)；2型糖尿病大血管并发症组及其亚组的不同基因型及等位基因频率与对照组比较，无统计学显著性差异(P＞0.05)。临床一般资料中，2型糖尿病大血管并发症组及其亚组的年龄、收缩压与2型糖尿病组比较，具有统计学显著性差异(P＜0.05)。Logistic回归分析表明，MS基因A2756G多态性不参与2型糖尿病大血管并发症的致病过程(G等位基因OR=0.855，95％CI=0.529～1.383，P=0.523)，而年龄、收缩压与2型糖尿病大血管并发症独立显著相关(年龄OR=1.076，95％CI=1.028～1.127，P=0.002；收缩压OR=1.028，95％CI=1.002～1.054，P=0.033)。结论 年龄、收缩压可能是2型糖尿病大血管并发症的独立危险因素，MS基因A2756G多态性与安徽地区汉族人群2型糖尿病大血管并发症的遗传易感性无关。
Objective To explore the association between A2756G polymorphism of methionine synthase (MS) gene and type 2 diabetes mellitus with macrovascular complications. Methods The genotypes of MS gene A2756G polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique in 733 Chinese Han population of Anhui region including 178 normal subjects (CON), 273 diabetics without angiopathy (T2DM), 189 patients with diabetic macrovascular complications of atherosclerosis (T2DM+AS) [64 with coronary heart disease (T2DM+CHD), 111 with cerebral infarction (T2DM+CI) and 14 with diabetic food] and 93 non-diabetic patients with macroangiopathy of atherosclerosis (AS) [16 with coronary heart disease (CHD) and 77 with cerebral infarction (CI)]. We compared the genotype and allele frequencies in these groups and studied the relationship between the polymorphism and diabetic macrovascular complications by population-based association analysis. Results The G allele prevalences
of MS gene A2756G polymorphism in Chinese Han population of Anhui region were significantly lower than that in western populations (P<0.05). There were no significant differences in the genotype and allele frequencies among these groups of CON,T2DM,T2DM+AS and AS (P>0.05). By general clinical characteristics age as well as systonic blood pressure (SBP) was significantly increased in T2DM+AS group or subgroups compared with T2DM (P<0.05). Logistic regression analysis showed that not the polymorphism but age increment or SBP was related independently and significantly to type 2 diabetes mellitus with macrovascular complications (OR=0.855, 95%CI=0.529~1.383, P=0.523 for G allele; OR=1.076,95%CI=1.028~1.127,P=0.002 for age; OR=1.028, 95%CI=1.002-1.054,P=0.033 for SBP). Conclusions The results suggested that age increment as well as SBP is an independent risk factor for type 2 diabetes mellitus with
macrovascular complications and the MS gene A2756G polymorphism has no relationship to the hereditary susceptibility for that.
Objective To explore the association between A2756G polymorphism of methionine synthase (MS) gene and type 2 diabetes mellitus with macrovascular complications. Methods The genotypes of MS gene A2756G polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique in 733 Chinese Han population of Anhui region including 178 normal subjects (CON), 273 diabetics without angiopathy (T2DM), 189 patients with diabetic macrovascular complications of atherosclerosis (T2DM+AS) [64 with coronary heart disease (T2DM+CHD), 111 with cerebral infarction (T2DM+CI) and 14 with diabetic food] and 93 non-diabetic patients with macroangiopathy of atherosclerosis (AS) [16 with coronary heart disease (CHD) and 77 with cerebral infarction (CI)]. We compared the genotype and allele frequencies in these groups and studied the relationship between the polymorphism and diabetic macrovascular complications by population-based association analysis. Results The G allele prevalences
of MS gene A2756G polymorphism in Chinese Han population of Anhui region were significantly lower than that in western populations (P<0.05). There were no significant differences in the genotype and allele frequencies among these groups of CON,T2DM,T2DM+AS and AS (P>0.05). By general clinical characteristics age as well as systonic blood pressure (SBP) was significantly increased in T2DM+AS group or subgroups compared with T2DM (P<0.05). Logistic regression analysis showed that not the polymorphism but age increment or SBP was related independently and significantly to type 2 diabetes mellitus with macrovascular complications (OR=0.855, 95%CI=0.529~1.383, P=0.523 for G allele; OR=1.076,95%CI=1.028~1.127,P=0.002 for age; OR=1.028, 95%CI=1.002-1.054,P=0.033 for SBP). Conclusions The results suggested that age increment as well as SBP is an independent risk factor for type 2 diabetes mellitus with
macrovascular complications and the MS gene A2756G polymorphism has no relationship to the hereditary susceptibility for that.
引文
[1] Horait PK,Garber AJ.Diabetes and atherosclerosis[J]. Endocr Pract, 1998;4: 112～119.
[2] 沈稚舟 等主编．糖尿病慢性并发症．上海：上海医科大学出版社，1999；4～7．
[3] John Alcolado. Genetics of diabetic complications[J]. Lancet, 1998; 351 (3): 230～231.
[4] Fanapour PC,Yug B,Kochar KS.Hyperhomocysteinemia: an additional cardiovascular risk factor[J]. WMJ, 1999;98(8): 51～54.
[5] 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[J]. Arterioscler Thromb Vasc Biol, 1998; 18: 133～138.
[6] Harmon DL, Young IS, Peng K, et al. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations[J]. Genet Epidemiol, 1999; 17(4): 298～309.
[7] Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology[J]. Eur J Pediatr, 1998; 157(Suppl 2): S54～S59.
[8] Chen LH, Liu ML, Hwang HY, et al. Human methionine synthase: cDNA cloning, gene localization and expression[J]. J Biol Chem, 1996; 272(6): 3628～3634.
[9] 李仕明．糖尿病足检查方法及诊断标准．中国糖尿病杂志，1996；4(2)：126．
[10] Leclerc D, Campeau E, Goyette P, et al. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cb1G complementation group of folate cobalamin disorders[J]. Human Molecular Genetics, 1996; 12(5): 1867～1874.
[11] 戴崇文，张广森．缺血性心、脑血管疾病患者同型半胱氨酸代谢相关酶基因突变频度的研究．中华血液学杂志，2001；22(9)：484～487．
[12] Chen J, Stampfer MJ, Ma J, et al. Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of
myocardial infarction[J]. Atherosclerosis, 2001; 154: 667～672.
[13] Wang XL, Duarte N, Cai H, et al. Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Australian hospital-based population[J]. A therosclerosis, 1999; 146: 133～140.
[14] Passaro A, Delia K, Pareschi PL, et al. Factors influencing plasma homocysteine levels in type 2 diabetes[J]. Diabetes Care, 2000;23(3): 420～421.
[15] Fonseca VA, Mudaliar S, Schmidt B, et al. Plasma homocysteine concentrations are regulated by acute hyperinsulinemia in nondiabetic but not type 2 diabetic subjects[J]. Metabolism, 1998;47: 686～689.
[16] Bar-on H, Kidron M, Friedlander Y, et al. Plasma total homocysteine levels in subject with hyperinsulinemia[J]. J Intern Med, 2000; 247: 287～294.
[17] Cai H, Wang XL, Colagiuri S, et al. Methionine synthase D919G mutation in type 2 diabetes and its relation to vascular events[J]. Diabetes Care, 1998;21 (10): 1774～1775.
[18] Chen C, Halkos ME, Surowiec SM, et al. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models[J]. J Surg Res, 2000;88: 26～33.
[19] Hofmann MA, Kohl B, Zumbach MS, et al.Hyperhomocysteinemia and endothelial dysfunction in IDDM[J].Diabetes Care,1998;21: 841～848.
[20] Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease: enhanced collagen production and accumulation by smooth muscle cells[J]. Arterioscler Thromb Vasc Biol, 1997; 17: 2074～2081.
[21] Freyburger G, Labrouche S, Sassoist G, et al. Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular disease[J]. Thromb Haemost, 1997;73: 466～471.
[22] Ling Q, Hajjar KA. Inhibition of endothelial cell thromboresistance by
homocysteine[J]. J Natr, 2000; 130(2s suppl): 373s～376s.
[23] Welch GN, Loscalzo J. Homocysteine and atherosclerosis[J]. N Engl J Med, 1998; 338: 1042～1050.
[24] Tsai MY, Welge BG, Hanson NQ et al. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases[J]. Atherosclerosis, 1999; 143: 163～170.
[25] Wang XL, Cai H, Cranney G, et al. The frequency of a common mutation of the methionine synthase gene in the Australian population and its relation to smoking and coronary artery disease[J]. J Cardiovasc Risk, 1998;5: 289～295.
[26] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)[J]. Lancet, 1998; 352: 837～853.
[2] 沈稚舟 等主编．糖尿病慢性并发症．上海：上海医科大学出版社，1999；4～7．
[3] John Alcolado. Genetics of diabetic complications[J]. Lancet, 1998; 351 (3): 230～231.
[4] Fanapour PC,Yug B,Kochar KS.Hyperhomocysteinemia: an additional cardiovascular risk factor[J]. WMJ, 1999;98(8): 51～54.
[5] 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[J]. Arterioscler Thromb Vasc Biol, 1998; 18: 133～138.
[6] Harmon DL, Young IS, Peng K, et al. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations[J]. Genet Epidemiol, 1999; 17(4): 298～309.
[7] Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology[J]. Eur J Pediatr, 1998; 157(Suppl 2): S54～S59.
[8] Chen LH, Liu ML, Hwang HY, et al. Human methionine synthase: cDNA cloning, gene localization and expression[J]. J Biol Chem, 1996; 272(6): 3628～3634.
[9] 李仕明．糖尿病足检查方法及诊断标准．中国糖尿病杂志，1996；4(2)：126．
[10] Leclerc D, Campeau E, Goyette P, et al. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cb1G complementation group of folate cobalamin disorders[J]. Human Molecular Genetics, 1996; 12(5): 1867～1874.
[11] 戴崇文，张广森．缺血性心、脑血管疾病患者同型半胱氨酸代谢相关酶基因突变频度的研究．中华血液学杂志，2001；22(9)：484～487．
[12] Chen J, Stampfer MJ, Ma J, et al. Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of
myocardial infarction[J]. Atherosclerosis, 2001; 154: 667～672.
[13] Wang XL, Duarte N, Cai H, et al. Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Australian hospital-based population[J]. A therosclerosis, 1999; 146: 133～140.
[14] Passaro A, Delia K, Pareschi PL, et al. Factors influencing plasma homocysteine levels in type 2 diabetes[J]. Diabetes Care, 2000;23(3): 420～421.
[15] Fonseca VA, Mudaliar S, Schmidt B, et al. Plasma homocysteine concentrations are regulated by acute hyperinsulinemia in nondiabetic but not type 2 diabetic subjects[J]. Metabolism, 1998;47: 686～689.
[16] Bar-on H, Kidron M, Friedlander Y, et al. Plasma total homocysteine levels in subject with hyperinsulinemia[J]. J Intern Med, 2000; 247: 287～294.
[17] Cai H, Wang XL, Colagiuri S, et al. Methionine synthase D919G mutation in type 2 diabetes and its relation to vascular events[J]. Diabetes Care, 1998;21 (10): 1774～1775.
[18] Chen C, Halkos ME, Surowiec SM, et al. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models[J]. J Surg Res, 2000;88: 26～33.
[19] Hofmann MA, Kohl B, Zumbach MS, et al.Hyperhomocysteinemia and endothelial dysfunction in IDDM[J].Diabetes Care,1998;21: 841～848.
[20] Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease: enhanced collagen production and accumulation by smooth muscle cells[J]. Arterioscler Thromb Vasc Biol, 1997; 17: 2074～2081.
[21] Freyburger G, Labrouche S, Sassoist G, et al. Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular disease[J]. Thromb Haemost, 1997;73: 466～471.
[22] Ling Q, Hajjar KA. Inhibition of endothelial cell thromboresistance by
homocysteine[J]. J Natr, 2000; 130(2s suppl): 373s～376s.
[23] Welch GN, Loscalzo J. Homocysteine and atherosclerosis[J]. N Engl J Med, 1998; 338: 1042～1050.
[24] Tsai MY, Welge BG, Hanson NQ et al. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases[J]. Atherosclerosis, 1999; 143: 163～170.
[25] Wang XL, Cai H, Cranney G, et al. The frequency of a common mutation of the methionine synthase gene in the Australian population and its relation to smoking and coronary artery disease[J]. J Cardiovasc Risk, 1998;5: 289～295.
[26] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)[J]. Lancet, 1998; 352: 837～853.