The A677V MTHFR Allele Is Not Associated With Carotid Atherosclerosis in Octogenarians
To the Editor:
We read with interest the article by Bova et al,1 published in the October 1999 issue of Stroke, on the association of the MTHFR A677V gene allele with carotid atherosclerosis. We have just finished a study aimed to characterize very old people with “vascular successful aging” (VSA), which we define according to the following criteria: (1) age ≥75 years; (2) negative history for cardiovascular disease; (3) absence of clinical symptoms and ultrasonographic/Doppler signs (duplex sonography) of extracoronary (epiaortic, abdominal aortic, iliac, and femoral) atherosclerosis, ie, lack of any focal protrusion ≥1.5 mm; and (4) absence of clinical symptoms and ECG signs of coronary artery disease. These subjects were compared with a control group selected by the following criteria: (1) age ≥75 years and (2) presence of carotid atherosclerosis, ie, a plaque inducing a 30% to 50% stenosis. They may have a positive history for cardiovascular disease, provided that no acute episode occurred in the 3 months before inclusion in the study. A total of 57 subjects, 29 with VSA and 28 with carotid atherosclerosis (AG), were enrolled. The mean age in both groups was >80 years (80.9 and 81.8, respectively). We found several differences between the VSA subjects and controls in plasma and LDL antioxidant levels as well as in LDL oxidation level. Among the possible genetic markers of vascular successful aging, we also determined the A677V MTHFR gene polymorphism by the method of Frosst et al,2 but we did not find any association with the vascular status. The frequency of the A677V allele was 52% in the VSA group and 39% in the AG group (χ2=NS), while the frequency of homozygosity was 36% in VSA and 10% in the AG group (χ2=NS). Genotype frequencies conformed to the Hardy-Weinberg equilibrium. In the study of Bova et al, the subjects were significantly younger than in our study and the control group suffered from mild carotid atherosclerosis. Because atherosclerosis is a progressive disease, subjects with a mild stenosis in adult age, as the control group presented in the study, might develop greater stenosis in late life and therefore might not represent an ideal control for comparison. Moreover, only 19% of the subjects with severe carotid atherosclerosis were homozygous, a condition that has been clearly associated with increased homocysteine levels.2
Our results suggest that this polymorphism is not associated with the presence, or with the absence, of moderate to severe carotid atherosclerosis in very advanced age. However, it is possible that the A677V gene polymorphism is associated with atherosclerosis in a younger population as well as in different ethnic groups.
- Copyright © 2000 by American Heart Association
Bova I, Chapman J, Sylantiev C, Korczyn AD, Bornstein NM. The A677V methylenetetrahydrofolate reductase gene polymorphysm and carotid atherosclerosis. Stroke.. 1999;30:2180–2182.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers CJH, den Heiljer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylentetrahydrofolate reductase. Nat Genet.. 1995;10:111–113. Letter.
Spence JD, Malinow MR, Barnett PA, Marian AJ, Freeman D, Hegele RA. Plasma homocysteine concentration, but not MTHFR genotype, is associated with variation in carotid plaque area. Stroke.. 1999;30:969–973.
We thank Zuliani and colleagues for describing their observations on carotid stenosis and the MTHFR 677c-t allele. As these authors note, their patient population was significantly older than the patients in our study and were chosen by somewhat different criteria. In this population the MTHFR 677c-t allele was less common in patients with moderate carotid stenosis than in age-matched patients with no significant cardiovascular disease. Although it is difficult to compare our study with the results of Zuliani et al, the differences between elderly and younger patients seem to be analogous with the well-established association of the APOE ε4 allele and Alzheimer’s disease. In the case of APOE, the ε4 allele is associated with earlier age of onset of disease; due to earlier mortality in Alzheimer’s disease, in the population aged >80 years it is no longer more common in Alzheimer patients than in controls.R1 R2
Scacchi R, De Bernardini L, Mantuano E, Donini LM, Vilardo T, Corbo RM. Apolipoprotein E (APOE) allele frequencies in late-onset sporadic Alzheimer’s disease (AD), mixed dementia and vascular dementia: lack of association of epsilon 4 allele with AD in Italian octogenarian patients. Neurosci Lett.. 1995;201:231–234.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PCJ, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Tanzi RE, al e. Apolipoprotein E, survival in Alzheimer’s disease patients, and the competing risks of death and Alzheimer’s disease. Neurology.. 1995;45:1323–1328.