Relation between plasma homocysteine, gene polymorphisms of homocysteine metabolism-related enzymes, and angiographically proven coronary artery disease

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

doi:10.1016/j.ejim.2007.02.020

« Previous Next »European Journal of Internal Medicine
Volume 18, Issue 6 , Pages 474-483, October 2007

Relation between plasma homocysteine, gene polymorphisms of homocysteine metabolism-related enzymes, and angiographically proven coronary artery disease

Abdelilah Laraqui
- 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
- Corresponding author. Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, BP 1326-Rabat R.P. 10000, Morocco. Tel.: +212 63 14 43 96; fax: +212 37 67 32 32.
Abdellatif Allami
- Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Rabat, Morocco
- UFR Biologie Cellulaire et Moléculaire, Faculté des Sciences, Université Abdelmalek Es-Saadi, Tétouan, Morocco
Alain Carrié
- Laboratoire de Biochimie Médicale A, Unité Fonctionnelle Endocrinologie-Moléculaire-Oncologie, CHU Pitié-Salpêtrière, Paris, France
Alain Raisonnier
- Laboratoire de Biochimie Médicale A, Unité Fonctionnelle Endocrinologie-Moléculaire-Oncologie, CHU Pitié-Salpêtrière, Paris, France
Anne-Sofie Coiffard
- Laboratoire de Biochimie Médicale A, Unité Fonctionnelle Endocrinologie-Moléculaire-Oncologie, CHU Pitié-Salpêtrière, Paris, France
Fatima Benkouka
- UFR Biochimie Immunologie, Faculté des Sciences, Université Mohamed V. Rabat, Morocco
Abdenabi Bendriss
- UFR Biologie Cellulaire et Moléculaire, Faculté des Sciences, Université Abdelmalek Es-Saadi, Tétouan, Morocco
Abdelaziz Benjouad
- UFR Biochimie Immunologie, Faculté des Sciences, Université Mohamed V. Rabat, Morocco
N. Bennouar
- Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Rabat, Morocco
Nizar El Kadiri
- Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Rabat, Morocco
Anwar Benomar
- Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Rabat, Morocco
Seddik Fellat
- Ligue Nationale de Lutte Contre les Maladies Cardiovasculaires, Unité d'Etudes des Facteurs Métaboliques et Polymorphismes Génétiques, Rabat, Morocco
Mohamed Benomar
- Ligue Nationale de lutte contre les maladies cardiovasculaires, Service de Cardiologie A, CHU Ibn-Sina, Rabat, Morocco

Received 31 May 2006; received in revised form 12 November 2006; accepted 15 February 2007. published online 15 July 2007.

Abstract

Background

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.

Methods

CAD patients (n=151) and control subjects (n=79) were compared regarding the prevalence of the polymorphisms, risk factors, and biochemical parameters.

Results

The mean tHcy concentration was significantly higher in CAD patients than in control subjects (P<0.001). HHcy (tHcy≥15 μmol/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.

Conclusion

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.

Keywords: Coronary artery disease, Risk factors, Genes, Homocysteine, Metabolism