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1 From the Serviço de Gastrenterologia, Instituto Português de Oncologia Francisco Gentil, Centro Regional Oncológico Sul–Sociedade Anónima, Lisbon, Portugal
2 Address reprint requests to M Cravo, Serviço de Gastrenterologia, Instituto Português de Oncologia Francisco Gentil, CROL-SA, Rua Professor Lima Bastos, 1093 Lisboa codex, Portugal. E-mail: marilia.cravo{at}sapo.pt.
See corresponding article on page 155.
Homocysteine is a sulfur-containing amino acid that in recent years has become the subject of interest because of epidemiologic studies linking hyperhomocysteinemia with increased risk of occlusive vascular disease (1). Disposal of plasma or serum total homocysteine (tHcy) involves 2 metabolic pathways, remethylation and transsulfuration, which seem to be nutritionally regulated. The remethylation of tHcy into methionine requires folate and vitamin B-12, whereas vitamin B-6 is involved in tHcy removal through the transsulfuration pathway.
The possible link between tHcy and alcoholism stems from the fact that the abovementioned vitamins can be affected by chronic alcohol consumption (2). Hyperhomocysteinemia in chronic alcoholics was first reported by Hultberg et al (3), who found significantly higher concentrations of tHcy in a group of alcoholics hospitalized for detoxification than in a group of control subjects. Later, our group also confirmed that chronic alcoholics had tHcy concentrations twice those observed in nondrinkers, and we investigated further the correlation between folate, vitamin B-12, and vitamin B-6 status (4). Besides lower concentrations of these vitamins in chronic drinkers, we found a negative and significant correlation between plasma concentrations of tHcy and pyridoxal-5'-phosphate and a weaker negative correlation with red blood cell folates. These results strongly suggest that, by interfering with folate or vitamin B-6 metabolism, chronic alcohol abuse could impair the disposal of tHcy through the transsulfuration and transmethylation pathways, with the final result being a rise in tHcy concentrations. More recently, an animal study showed that alcohol ingestion, with or without folate deficiency, impairs the expression or activity (or both) of transmethylation enzymes that regulate homocysteine concentrations (5).
Since then, several studies have examined the relation between alcohol intake and plasma tHcy concentrations, but the results were rather contradictory (6-8). Whereas heavy alcohol abuse undoubtedly resulted in markedly elevated tHcy, the effect of moderate ethanol consumption on tHcy did not show a consistent pattern. These discrepancies may be related either to different methods of quantifying alcohol intake—ie, in grams per day rather than in drinks per month—or to the different types of alcoholic beverage consumed. Most studies are consistent with the observation that tHcy concentrations are significantly lower in beer drinkers (4, 6, 8) than in wine or spirits consumers. This difference may have to do with the fact that the amount of alcohol in beer is considerably lower (3.5%) than that in wine and spirits (12% and >35%, respectively) and also with the fact that beer is a rich source of folate and vitamin B-6, whereas wine and spirits contain negligible amounts of these vitamins (9). Consumption of beer in small amounts, despite its being an alcoholic beverage, could have a null or even a lowering effect on tHcy, as later confirmed by van der Gaag et al (10) in a prospective controlled study. This lowering effect on tHcy suggests a J-shaped effect, which is also consistent with the relations between alcohol consumption and the prevalence of cardiovascular disease, long known as the French paradox.
The article by Chiuve et al (11) in this issue of the Journal confirms the association between folate, ethanol, and tHcy and also extends our understanding of how the 677CT polymorphism of methylenetetrahydrofolate reductase (MTHFR) may further modify the interaction between these variables. MTHFR is involved in the vitamin B-12–dependent methylation of homocysteine to methionine, and, in 1988, Kang et al (12) first reported a variant of MTHFR that was distinguished from the normal enzyme by its lower activity and its thermolability. This variant is caused by a point mutation (677CT transition) at a polymorphic site that results in a valine substitution for an alanine. Heterozygotes (CT) and homozygotes (TT) have 71% and 33%, respectively, of the activity of the wild-type MTHFR (CC). The effect of the thermolabile variant of MTHFR on plasma homocysteine is now clear. Russo et al (13) showed that, when plasma folate concentrations were high, tHcy was low and unrelated to MTHFR genotype. However, when plasma folate concentrations were low, tHcy concentrations were significantly higher in carriers of the variant allele. The study by Chiuve et al was based on a sample of 988 premenopausal women with no history of cardiovascular disease who were part of the Nurses' Health Study II cohort. The study aimed to examine whether the associations between folate intake and fasting plasma folate and tHcy concentrations were modified by MTHFR genotype or by alcohol intake. On the basis of self-reported alcohol use, women were divided into nondrinkers, those consuming <15 g alcohol/d, and those consuming >15 g alcohol/d. In secondary analyses, women who drank >50 g ethanol/d were excluded because heavy alcohol consumers may have dose responses between folate status and tHcy concentrations that are significantly different from those of moderate drinkers. In their cohort, Chiuve et al observed, consistent with previous studies, that tHcy concentrations decreased significantly with both folate intake and plasma folate concentrations and that the MTHFR polymorphism modified the dose-response association between folate intake and tHcy (P for interaction = 0.05). Thus, women with the thermolabile variant of MTHFR677 (CT or TT) had significantly higher tHcy concentrations at low intakes of folate, whereas wild-type carriers had the smallest reduction in tHcy across extreme quintiles of folate intake. This finding reinforces the concept already discussed by others (12) that variant carriers are more sensitive to low folate intake, which raises the hypothesis that the protective effect of folate in regard to colorectal cancer or vascular disease is significantly more determinant in subjects carrying the polymorphic allele than in those carrying the nonpolymorphic allele. With respect to alcohol intake, the authors observed that the variant or polymorphic allele modified the association between folate intake and tHcy (P for interaction = 0.04), because higher folate intake was only modestly associated with lower tHcy among light drinkers (<15 g/d) and nondrinkers, whereas an inverse relation was significantly stronger among moderate drinkers (>15 g/d). As does the polymorphic allele, alcohol intake seems to exacerbate this modulating effect of folate status on tHcy concentrations. Furthermore, the inverse association between folate intake and tHcy among moderate alcohol drinkers was primarily limited to women with the variant allele for MTHFR, in whom there was a significant interaction between alcohol intake and genotype (P = 0.01). To my knowledge, this is the first study in which the interactions between genotype, alcohol intake, and folate intake are examined together in a large group of apparently healthy persons. Although moderate alcohol consumers with the variant allele had high concentrations of tHcy at low folate intake, tHcy was no longer high in those with high folate intake. This was true only after the exclusion of heavy drinkers (>50 g/d) from the analysis, which highlights the fact that, whereas the adverse effects of moderate ethanol intake might be overcome through adequate folate supplementation, the same might not be true for the effects of heavy alcohol abuse.
We conclude that the elevation of tHcy among women who consume low amounts of folate and drink moderate amounts of alcohol seems to be further magnified in the presence of the variant MTHFR677 allele. This study adds further evidence that tHcy values must be interpreted in light of multiple variables such as age, sex, and smoking and drinking habits, among other lifestyle factors that may interact with each other as well as with several genetic traits of the methionine-homocysteine cycle, thereby influencing the final tHcy concentration.
ACKNOWLEDGMENTS
The author had no personal or financial conflict of interest with the article on which this editorial comments or with the study reported in the article.
REFERENCES
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