Laraqui Abdelilah, Allami Abdellatif, Carrié Alain, Raisonnier Alain, Coiffard Anne-Sofie, Benkouka Fatima, Bendriss Abdenabi, Benjouad Abdelaziz, Bennouar N, El Kadiri Nizar, Benomar Anwar, Fellat Seddik, Benomar Mohamed
Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Rabat, Morocco; UFR Biochimie Immunologie, Faculté des Sciences, Université Mohamed V. Rabat, Morocco; Laboratoire de Biochimie Médicale A, Unité Fonctionnelle Endocrinologie-Moléculaire-Oncologie, CHU Pitié-Salpêtrière, Paris, France.
Eur J Intern Med. 2007 Oct;18(6):474-83. doi: 10.1016/j.ejim.2007.02.020. Epub 2007 Jul 12.
Hyperhomocyteinemia (HHcy) is a risk factor for coronary artery disease (CAD), and methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms may contribute to plasma total homocysteine (tHcy) variation. We investigated the association of polymorphisms 1298A-->C in the MTHFR gene, 2756A-->G in the MTR gene, and 66A-->G in the MTRR gene with tHcy levels and with CAD in patients undergoing coronary angiography.
CAD patients (n=151) and control subjects (n=79) were compared regarding the prevalence of the polymorphisms, risk factors, and biochemical parameters.
The mean tHcy concentration was significantly higher in CAD patients than in control subjects (P<0.001). HHcy (tHcy>/=15 mumol/l) conferred an OR of CAD of 4.1 (95% CI 2.2-7.5, P<0.001). In both cases and controls, smokers had a higher tHcy level than non-smokers and demonstrated a markedly increased risk for CAD (OR=2.5, 95% CI 1.7-3.3, P<0.001). The allele frequencies of the MTHFR 1298A-->C, MTR 2756A-->G, and MTRR 66A-->G mutations were 36.7%, 15.7%, and 36.6%, respectively. The 1298C allele frequency was significantly higher in the CAD group than in controls (P<0.05) and showed a significant association with CAD in heterozygote carriers. There was no statistically significant difference between cases and controls in the frequencies of the A2756G alleles/genotypes in the MTR gene and of the A66G alleles/genotypes in the MTRR gene. The contributions to tHcy levels of the three common mutations were statistically significant. The heterozygosity of the MTHFR 1298AC genotype, MTR 2756G allele, and MTRR 66G allele yielded an OR of 3.4, 2.0, and 2.1, respectively, for having HHcy.
We suggest that HHcy confers a risk for CAD, and smokers with tHcy are at a greatly increased risk. Our finding supports an important role of the MTHFR gene in CAD and provides evidence of polygenic regulation of tHcy.
高同型半胱氨酸血症（HHcy）是冠状动脉疾病（CAD）的一个危险因素，亚甲基四氢叶酸还原酶（MTHFR）、甲硫氨酸合成酶（MTR）和甲硫氨酸合成酶还原酶（MTRR）基因多态性可能导致血浆总同型半胱氨酸（tHcy）水平变化。我们研究了MTHFR基因1298A→C、MTR基因2756A→G和MTRR基因66A→G多态性与接受冠状动脉造影患者的tHcy水平及CAD的相关性。
比较CAD患者（n = 151）和对照者（n = 79）的多态性患病率、危险因素及生化参数。
CAD患者的平均tHcy浓度显著高于对照者（P < 0.001）。HHcy（tHcy≥15μmol/L）使CAD的OR为4.1（95%CI 2.2 - 7.5，P < 0.001）。在病例组和对照组中，吸烟者的tHcy水平均高于非吸烟者，且CAD风险显著增加（OR = 2.5，95%CI 1.7 - 3.3，P < 0.001）。MTHFR 1298A→C、MTR 2756A→G和MTRR 66A→G突变的等位基因频率分别为36.7%、15.7%和36.6%。CAD组的1298C等位基因频率显著高于对照组（P < 0.05），且在杂合子携带者中与CAD显著相关。MTR基因的A2756G等位基因/基因型及MTRR基因的A66G等位基因/基因型在病例组和对照组中的频率无统计学显著差异。三种常见突变对tHcy水平的影响具有统计学意义。MTHFR 1298AC基因型、MTR 2756G等位基因和MTRR 66G等位基因的杂合性导致HHcy的OR分别为3.4、2.0和2.1。
我们认为HHcy会增加CAD风险，tHcy水平升高的吸烟者风险大幅增加。我们的发现支持MTHFR基因在CAD中的重要作用，并为tHcy的多基因调控提供了证据。
