Mutation A1298C of methylenetetrahydrofolate reductase: Risk for early coronary disease not associated with hyperhomocysteinemia

Abstract

Diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to coronary artery disease (CAD). In a case-control study we determined the prevalence of two common MTHFR polymorphisms, C677T and A1298C, in 161 male patients under the age of 50 years with angiographically documented CAD and compared it to that in 211 healthy controls. Genotyping was also performed in a random population sample, consisting of 149 men and 121 women at an average age of 40 years. The studied group had classic risk factors of atherosclerosis but did not differ in fasting plasma homocysteine, folic acid, and vitamin B12 levels in either the control group or population sample. The frequency of the 1298C allele was significantly higher in CAD (0.304) than in controls (0.199) or the population sample (0.235). Allele 1298C showed a significant association with early-onset CAD both in homozygotes and in heterozygous carriers. These findings were further supported by comparisons with the population sample. Homozygosity for allele 677T showed a tendency to associate with CAD. Allele 1298C of MTHFR is associated with early-onset CAD (carriers- RR = 1.71, 95% CI: 1.13-2.59; homozygotes- RR = 3.09, 95% CI: 1.36-7.02), even when blood homocysteine levels are not elevated.

Genotype and haplotype distributions of MTHFR 677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis

“…As a result, the MTHFR 677 and 1298 genotype distribution was available in a total of 22 manuscripts (Akar et al 2001;Barber et al 2000;Chango et al 2000;Fodinger et al 2000;Friedman et al 1999;Hanson et al 2001;Kaiser et al 2000;Lachmeijer et al 2001;Meisel et al 2001;Rady et al 1999;Richter et al 2001;Shen et al 2001;Skibola et al 1999;Song et al 2001;Szczeklik et al 2001;van der Put et al 1998;Weisberg et al 1998;Wiemels et al 2001;Zusterzeel et al 2000) (Table 1). To obtain the MTHFR genotype distribution in the general population, we used 19 different control populations, which included healthy adults, infants, and neonates, from 16 manuscripts (population "W1") (Akar et al 2001;Barber et al 2000;Chango et al 2000;Fodinger et al 2000;Friedman et al 1999;Kaiser et al 2000;Lachmeijer et al 2001;Meisel et al 2001;Rady et al 1999;Richter et al 2001;Shen et al 2001;Skibola et al 1999;Szczeklik et al 2001;van der Put et al 1998;Wiemels et al 2001;Zusterzeel et al 2000). We excluded data derived from Chinese populations (Song et al 2001) because only 17% (123/724) of MTHFR alleles in the control northern Chinese population ...…”

“…There was a significant increase in the TT/AA (P Ͻ 0.0001) genotype frequency, and a decrease in the CC/AA (P Ͻ 0.025) and CC/AC (P Ͻ 0.05) genotype frequencies, indicating an increase in the T/A haplotype frequency and a decrease in the C/A haplotype frequency, in an Ashkenazi Jewish population (Rady et al 1999). There was a significant increase in the CC/AA (P Ͻ 0.0001) genotype frequency, and a decrease in the CC/CC (P Ͻ 0.005), CT/ AC (P Ͻ 0.001), and TT/AA (P Ͻ 0.001) genotype frequencies, indicating an increase in the C/A haplotype frequency and a decrease in the T/A and C/C haplotype frequencies, in Poland (R2 and R3 in Table 1 combined) (Szczeklik et al 2001). There was also a significant increase in the CC/AC genotype frequency in Turkey (Akar et al 2001) (P Ͻ 0.005).…”

Acute Myocardial Infarction in a Young Man Complicated With Left Ventricular Thrombi

“…The importance of hemostasis in the pathogenesis of AMI has been firmly established, and the gene polymorphisms involved in the premature CAD have been elucidated (Table II). [12][13][14][15][16][17][18][19][20][21][22] However, the interpretation of polymorphism for premature onset AMI requires further evaluation.…”

Variabilidade genética MTHFR no desenvolvimento da doença arterial coronária

“…Ambos os polimorfismos do gene MTHFR foram considerados fatores de risco para DAC 7,8,9,10 . A associação do polimorfismo MTHFR C677T com DAC foi confirmada por alguns estudos, nos quais a prevalência de portadores do alelo alterado foi maior no grupo DAC em relação aos controles [10][11][12][13][14] por outro lado, outros trabalhos não confirmam tal associação 15,16,17 .…”

“…A associação do polimorfismo MTHFR C677T com DAC foi confirmada por alguns estudos, nos quais a prevalência de portadores do alelo alterado foi maior no grupo DAC em relação aos controles [10][11][12][13][14] por outro lado, outros trabalhos não confirmam tal associação 15,16,17 . Em relação ao polimorfismo MTHFR A1298C, o alelo alterado foi associado com início precoce da DAC, independente dos níveis de Hcy 9 .…”