Polymorphisms in Genes Involved in Homocysteine Metabolism in the INCHIANTI Study

Abstract number: P2271

Giusti¹ B, Corsi² AM, Gori¹ AM, Lenti¹ M, Lari¹ B, Ferrini¹ S, Pepe¹ G, Ferrucci³ L, Gensini¹ GF, Abbate¹ R

¹¹Department of Medical and Surgical Critical Area, Thrombosis Centre, University of Florence, Italy ¹¹Department of Medical and Surgical Critical Area, Thrombosis Centre, University of Florence, Italy ²²Laboratory of Clinical Epidemiology, Geriatric Department, National Institute of Research and Care on Aging (INRCA), Florence, Italy ³³Longitudinal Studies Section, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, USA

Total blood levels of homocysteine (tHcy) have been shown to depend on both environmental and genetic factors, and to be associated with the risk of developing atherosclerosis with its complications of coronary heart disease and stroke. Hyperhomocysteinemia may be associated with the presence of polymorphisms in genes codifying for enzymes involved in the Hcy metabolism. Aim of this study was to evaluate in the InCHIANTI Study, a prospective population-based Italian study of risk factors for disability in late life: (1) total homocysteine, folic acid, vitamin B12 and B6 levels and (2) the association between homocysteine levels and the genetic polymorphisms of methionine metabolism enzyme: C677T and A1298C of 5, 10-methylenetetrahydrofolate reductase (MTHFR), and A2756G of methionine synthase (MTR) gene polymorphisms. We studied 586 men (78% aged, >=65 years) and 734 women (81% aged, >=65 years) randomly selected from the people living near Florence. Homocysteine plasma levels were significantly (P < 0.0001) higher in men than in women and significantly correlated with increasing age (r= 0.46; P < 0.0001). Serum folic acid, vitamin B6 and B12 were 6.3 (0.7–45.3) nmol/L, 25.3 (0.4–689.2) nmol/L and 285 (25.2–1488.1) pmol/L respectively. A significant genotype-phenotype association (P < 0.01) between homocysteine levels and C677T MTHFR polymorphisms was observed; no significant association with A1298C MTHFR or A2756G MTR polymorphisms was found. Furthermore, in subjects with folic acid <5 nmol/L we observed a significant genotype-phenotype association (P < 0.001) between homocysteine plasma levels and C677T MTHFR polymorphism, but not in those with folic acid >=5 nmol/L. Among all the possible combinations of the 3 analyzed polymorphisms, the more frequent combined genotypes resulted 677CT/1298AC/2756AA (28.6%), 677TT/1298AA/2756AA (19.6%) and 677CT/1298AA/2756AA (16.7%). Homocysteine levels were significantly (P < 0.01) higher in combination 677TT/1298AA/2756AA, 16.6 (15.8–17.5) than in all the other possible combinations. These data demonstrate that homocysteine levels were influenced by C677T MTHFR polymorphism, but not A1298C MTHFR or A2756G MTR polymorphisms, in subjects with reduced folic acid levels.

coronary artery disease.