The Methylenetetrahydrofolate Reductase C677T Gene Mutation is Associated with Hyperhomocysteinemia, Cardiovascular Diseases and Plasma BNP Levels in Korea

Abstract

목적 : 고호모시스테인혈증은 심혈관 질환의 위험 인자로서, 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T 유전자 변이와 관련이 있다고 알려져 왔다. 한편, B-type natriuretic peptide (BNP)는 새로운 심혈관 질환의 표지자로 최근에 사용되기 시작하였다. 본 연구의 목적은, 심혈관 질환에서 1) MTHFR C677T 유전자 변이와 혈장 Homocysteine (Hcy) 농도와의 연관성, 2) 위험인자로서의 MTHFR C677T, 3) MTHFR C677T 돌연변이와 혈장 BNP 농도와의 연관성, 4) Hcy 농도와 BNP 농도와의 상관 관계 등을 확인하는 것이다. 실험 방법 : BNP를 측정한 227명이 실험 대상이었다. 측정항목은 BNP, creatine kinase (CK), the myocardial isoenzyme of CK (CK-MB), troponin I (TnI), homocysteine (Hcy), C-reactive protein (CRP), lactate dehydrogenase (LDH), folate 였다. MTHFR C677T 유전적 다형성은 중합효소 연쇄 반응과 제한효소 분절 길이 다형성 기법을 이용, 전기 영동법으로 확인했다. 통계 기법은 Fisher’s exact test, χ2 analysis, Student t test, one-way analysis of variances (ANOVA), Multiple regression analysis 및 Pearson correlation을 이용했다. 결과 : MTHFR 동형접합성 변이(TT)의 빈도는 심혈관 질환 군에서 심혈관 질환이 없는 군에 비해 유의하게 높았다(P = 0.000). 동형접합성 변이에서의 혈장 Hcy 농도는 정상 대조군(CC) 및 이형접합성 변이(CT)에 비해서 통계적으로 유의하게 높았다(P = 0.000). 혈장 BNP 농도는 MTHFR C677T 유전자 변이가 있는 군에서 변이가 없는 군에 비해 유의하게 높았다(P < 0.05). 혈장 BNP 농도와 Hcy 농도는 통계적으로 유의한 양의 상관 관계가 있었다(r = 0.196, P < 0.001). 다중 로지스틱 회귀 분석상 증가된 혈중 BNP, CRP, Hcy 농도 및 MTHFR C677T 변이의 존재는 독립적으로 심혈관 질환의 예측에 기여하였다. 결론 : 심혈관 질환에서 MTHFR C677T 유전자 변이는 1) 혈장 Hcy 농도와 연관이 있고, 2) 심혈관 질환의 독립적인 위험인자이며, 3) 혈장 BNP 농도와 연관이 있다. 4) 혈장 Hcy와 BNP 농도는 심혈관 질환에서 양의 상관 관계가 있다.;PURPOSES : Hyperhomocysteinemia has been known to be a risk factor for cardiovascular diseases and associated with a common mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (677 C to T). On the other hand, B-type natriuretic peptide (BNP) is a new marker for cardiovascular diseases. The purposes of this study are to confirm 1) the association between the MTHFR C677T mutation and the plasma homocysteine (Hcy) levels, 2) the MTHFR C677T mutation as a risk factor, 3) the association of the MTHFR C677T mutation and the plasma BNP levels, 4) the correlation between Hcy and BNP levels, in cardiovascular diseases. METHODS : Two hundred twenty seven patients in whom BNP was measured were enrolled in this study. Laboratory parameters included BNP, creatine kinase (CK), the myocardial isoenzyme of CK (CK-MB), troponin I (TnI), Hcy, C-reactive protein (CRP), lactate dehydrogenase (LDH) and folate. Cardiovascular diseases included ischemic heart disease, congestive heart failure (CHF), valvular heart disease, arrhythmia, or a combination of these diseases. The MTHFR genotype was evaluated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) shown by electrophoresis technique. Statistical analyses were performed with Fisher’s exact test, χ2 analysis, Student t test, one-way analysis of variances (ANOVA), multiple regression analysis and Pearson correlation. RESULTS : The prevalence of TT homozygotes was significantly higher in patients with cardiovascular diseases than in patients without cardiovascular diseases (P = 0.000). The patients with TT homozygous mutation had the highest plasma Hcy levels, compared with those of the patients with CC homozygous wild type or CT heterozygous mutant type (P = 0.000). Plasma BNP concentrations were significantly higher in patients with MTHFR C677T mutation relative to in patients without mutation (P < 0.05). Plasma BNP concentrations were positively correlated with Hcy concentrations (r = 0.196, P < 0.001). In the multivariate logistic regression analysis, elevated concentrations of BNP, CRP, Hcy and the presence of the MTHFR C677T mutation independently contributed to the prediction of the cardiovascular diseases. CONCLUSIONS : In cardiovascular diseases, the MTHFR C677T mutation 1) is associated with the plasma Hcy levels, 2) is an independent risk factor for the cardiovascular diseases, 3) is associated with the plasma BNP levels. 4) The plasma Hcy levels are positively correlated with the plasma BNP levels in cardiovascular diseases.