Age and Gender Affect the Relation between Methylenetetrahydrofolate Reductase C677T Genotype and Fasting Plasma Homocysteine Concentrations in the Framingham Offspring Study Cohort

Journal of Nutrition

Volumn 133, Issue 11, 2003, Pages 3416-3421

  Russo, Giuseppina T ^b   Friso, Simonetta ^c   Jacques, Paul F ^a   Rogers, Gail ^a   Cucinotta, Domenico ^b   Wilson, Peter W F ^d   Ordovas, Jose M ^a   Rosenberg, Irwin H ^a   Selhub, Jacob ^a  

^a TUFTS UNIVERSITY   (United States)

^b UNIVERSITY OF MESSINA   (Italy)

^c UNIVERSITY OF VERONA   (Italy)

^d BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Age; Folate; Genetics; Homocysteine; Methylenetetrahydrofolate reductase; Sex

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); FOLIC ACID; HOMOCYSTEINE; METHIONINE;

ADULT; AGE; ALLELE; ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DISEASE ASSOCIATION; FEMALE; GENE FREQUENCY; GENETIC POLYMORPHISM; GENOTYPE; HUMAN; HYPERHOMOCYSTEINEMIA; MAJOR CLINICAL STUDY; MALE; METHYLATION; RISK FACTOR; SEX DIFFERENCE;

EID: 0242577783     PISSN: 00223166     EISSN: None     Source Type: Journal    
DOI: 10.1093/jn/133.11.3416     Document Type: Article

References (65)

1. Boushey, C. J., Beresford, S. A., Omenn, G. S. & Motulsky A. G. (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J. Am. Med. Assoc. 274: 1049-1057.
2. D'Angelo, A. & Selhub, J. (1997) Homocysteine and thrombotic disease. Blood 90: 1-11.
3. Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J. Am. Med. Assoc. 288: 2015-2022.
4. Selhub, J. & Miller, J. W. (1992) The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am. J. Clin. Nutr. 55: 131-138.
5. Jacques, P. F., Rosenberg, I. H., Rogers, G., Selhub, J., Bowman, B. A., Gunter, E. W., Wright, J. D. & Johnson, C. L. (1999) Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am. J. Clin. Nutr. 69: 482-489.
6. Brattstrom, L., Lindgren, A., Israelsson, B., Andersson, A. & Hultberg, B. (1994) Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects. J. Intern. Med. 236: 633-641.
7. Brattstrom, L. E., Hultberg, B. L. & Hardebo, J. E. (1985) Folic acid responsive postmenopausal homocysteinemia. Metabolism 34: 1073-1077.
8. Boers, G. H., Smals, A. G., Trijbels, F. J., Leermakers, A. I. & Kloppenborg, P. W. (1983) Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J. Clin. Investig. 72: 1971-1976.
9. Blom, H. J., Boers, G. H., van den Elzen, J. P., van Roessel, J. J., Trijbels, J. M. & Tangerman, A. (1988) Differences between premenopausal women and young men in the transamination pathway of methionine catabolism, and the protection against vascular disease. Eur. J. Clin. Investig. 18: 633-638.
10. Morris, M. S., Jacques, P. F., Selhub, J. & Rosenberg, I. H. (2000) Total homocysteine and estrogen status indicators in the Third National Health and Nutrition Examination Survey. Am. J. Epidemiol. 152: 140-148.
11. Dierkes, J., Jeckel, A., Ambrosch, A., Westphal, S., Luley, C. & Boeing, H. (2001) Factors explaining the difference of total homocysteine between men and women in the European Investigation Into Cancer and Nutrition Potsdam study. Metabolism 50: 640-645.
12. Giltay, E. J., Hoogeveen, E. K., Elbers, J. M., Gooren, L. J., Asscheman, H. & Stehouwer, C. D. (1998) Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. J. Clin. Endocrinol. Metab. 83: 550-553.
13. Wouters, M. G., Moorrees, M. T., van der Mooren, M. J., Blom, H. J., Boers, G. H., Schellekens, L. A., Thomas, C. M. & Eskes, T. K. (1995) Plasma homocysteine and menopausal status. Eur. J. Clin. Investig. 25: 801-805.
14. Friedman, A. N., Bostom, A. G., Selhub, J., Levey, A. S. & Rosenberg, I. H. (2001) The kidney and homocysteine metabolism. J. Am. Soc. Nephrol. 12: 2181-2189.
15. Bostom, A. G. & Culleton, B. F. (1999) Hyperhomocysteinemia in chronic renal disease. J. Am. Soc. Nephrol. 10: 891-900.
16. Arnadottir, M., Hultberg, B., Nilsson-Ehle, P. & Thysell, H. (1996) The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand. J. Clin. Lab. Investig. 56: 41-46.
17. Norlund, L., Grubb, A., Fex, G., Leksell, H., Nilsson, J. E., Schenck, H. & Hultberg, B. (1998) The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin. Chem. Lab. Med. 36: 175-178.
18. Selhub, J., Jacques, P. F., Wilson, P. W., Rush, D. & Rosenberg, I. H. (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J. Am. Med. Assoc. 270: 2693-2698.
19. Stolzenberg-Solomon, R. Z., Miller, E. R., 3rd, Maguire, M. G., Selhub, J. & Appel, L. J. (1999) Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am. J. Clin. Nutr. 69: 467-475.
20. Nygard, O., Refsum, H., Ueland, P. M., Stensvold, I., Nordrehaug, J. E., Kvale, G. & Vollset, S. E. (1997) Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am. J. Clin. Nutr. 65: 136-143.
21. Jacques, P. F., Bostom, A. G., Wilson, P. W., Rich, S., Rosenberg, I. H. & Selhub, J. (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am. J. Clin. Nutr. 73: 613-621.
22. Kang, S. S., Zhou, J., Wong, P. W., Kowalisyn, J. & Strokosch, G. (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am. J. Hum. Genet. 43: 414-421.
23. Goyette, P., Sumner, J. S., Milos, R., Duncan, A. M., Rosenblatt, D. S., Matthews, R. G. & Rozen, R. (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat. Genet. 7: 195-200.
24. Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J., den Heijer, M., Kluijtmans, L. A., van den Heuvel, L. P. & Rozen, R. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10: 111-113.
25. Brattstrom, L., Wilcken, D. E., Ohrvik, J. & Brudin, L. (1998) Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 98: 2520-2526.
26. Klerk, M., Verhoef, P., Clarke, R., Blom, H. J., Kok, F. J. & Schouten, E. G. (2002) MTHFR 677C→ T polymorphism and risk of coronary heart disease: a meta-analysis. J. Am. Med. Assoc. 288: 2023-2031.
27. Jacques, P. F., Bostom, A. G., Williams, R. R., Ellison, R. C., Eckfeldt, J. H., Rosenberg, I. H., Selhub, J. & Rozen, R. (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93: 7-9.
28. Girelli, D., Friso, S., Trabetti, E., Olivieri, O., Russo, C., Pessotto, R., Faccini, G., Pignatti, P. F., Mazzucco, A. & Corrocher, R. (1998) Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction. Blood 91: 4158-4163.
29. Jacques, P. F., Kalmbach, R., Bagley, P. J., Russo, G. T., Rogers, G., Wilson, P. W., Rosenberg, I. H. & Selhub, J. (2002) The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J. Nutr. 132: 283-288.
30. Schaefer, E. J., Lamon-Fava, S., Johnson, S., Ordovas, J. M., Schaefer, M. M., Castelli, W. P. & Wilson, P. W. (1994) Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham Offspring Study. Arterioscler. Thromb. 14: 1105-1113.
31. Peacock, R. E., Temple, A., Gudnason, V., Rosseneu, M. & Humphries, S. E. (1997) Variation at the lipoprotein lipase and apolipoprotein AI-CIII gene loci are associated with fasting lipid and lipoprotein traits in a population sample from Iceland: interaction between genotype, gender, and smoking status. Genet. Epidemiol. 14: 265-282.
32. Russo, G. T., Meigs, J. B., Cupples, L. A., Demissie, S., Otvos, J. D., Wilson, P. W., Lahoz, C., Cucinotta, D., Couture, P., Mallory, T., Schaefer, E. J. & Ordovas, J.M. (2001) Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study. Atherosclerosis 158: 173-181.
33. Hegele, R. A., Evans, A. J., Tu, L., Ip, G., Brunt, J. H. & Connelly, P. W. (1994) A gene-gender interaction affecting plasma lipoproteins in a genetic isolate. Arterioscler. Thromb. 14: 671-678.
34. Feinleib, M., Kannel, W. B., Garrison, R. J., McNamara, P. M. & Castelli, W. P. (1975) The Framingham Offspring Study. Design and preliminary data. Prev. Med. 4: 518-525.
35. Dawber, T., Meadors, G. & Moore, F. J. (1951) Epidemiological approaches to heart disease: The Framingham Study. Am. J. Public Health 41: 279-286.
36. Kannel, W. B., Feinleib, M., McNamara, P. M., Garrison, R. J. & Castelli, W. P. (1979) An investigation of coronary heart disease in families. The Framingham offspring study. Am. J. Epidemiol. 110: 281-290.
37. (1979) The coronary primary prevention trial: design and implementation: the Lipid Research Clinics Program. J. Chronic Dis. 32: 609-631.
38. 2+ precipitation procedures for estimating cholesterol in high-density lipoprotein. Clin. Chem. 24: 853-856.
39. Friedewald, W. T., Levy, R. I. & Fredrickson, D. S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18: 499-502.
40. Larsen, K. (1972) Creatinine assay by a reaction-kinetic principle. Clin. Chim. Acta 41: 209-217.
41. Araki, A. & Sako, Y. (1987) Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J. Chromatogr. 422: 43-52.
42. Horne, D. W. & Patterson, D. (1988) Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. Clin. Chem. 34: 2357-2359.
43. Tamura, T., Freeberg, L. E. & Cornwell, P. E. (1990) Inhibition of EDTA of growth of Lactobacillus casei in the folate microbiological assay and its reversal by added manganese or iron. Clin. Chem. 36: 1993.
44. Shin, Y. S., Rasshofer, R., Friedrich, B. & Endres, W. (1983) Pyridoxal-5′-phosphate determination by a sensitive micromethod in human blood, urine and tissues; its relation to cystathioninuria in neuroblastoma and biliary atresia. Clin. Chim. Acta 127: 77-85.
45. Miller, S. A., Dykes, D. D. & Polesky, H. F. (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16: 1215.
46. Livak, K. J., Marmaro, J. & Todd, J. A. (1995) Towards fully automated genome-wide polymorphism screening. Nat. Genet. 9: 341-342.
47. Giesendorf, B. A., Vet, J. A., Tyagi, S., Mensink, E. J., Trijbels, F. J. & Blom, H. J. (1998) Molecular beacons: a new approach for semiautomated mutation analysis. Clin. Chem. 44: 482-486.
48. SAS Institute Inc. (1999) The SAS System for Windows, 8.0 ed. SAS Institute, Cary, NC.
49. Chango, A., Potier De Courcy, G., Boisson, F., Guilland, J. C., Barbe, F., Perrin, M. O., Christides, J. P., Rabhi, K., Pfister, M., Galan, P., Hercberg, S. & Nicolas, J. P. (2000) 5, 10-Methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU. VI. MAX). cohort. Br. J. Nutr. 84: 891-896.
50. Dekou, V., Whincup, P., Papacosta, O., Ebrahim, S., Lennon, L., Ueland, P. M., Refsum, H., Humphries, S. E. & Gudnason, V. (2001) The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British Regional Heart Study. Atherosclerosis 154: 659-666.
51. Rea, I. M., McMaster, D., Woodside, J. V., Young, I. S., Archbold, G. P., Linton, T., Lennox, S., McNulty, H., Harmon, D. L. & Whitehead, A. S. (2000) Community-living nonagenarians in Northern Ireland have lower plasma homocysteine but similar methylenetetrahydrofolate reductase thermolabile genotype prevalence compared to 70-89-year-old subjects. Atherosclerosis 149: 207-214.
52. Wang, X. L., Duarte, N., Cai, H., Adachi, T., Sim, A. S., Cranney, G. & Wilcken, D. E. (1999) Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Australian hospital-based population. Atherosclerosis 146: 133-140.
53. Ho, C. H. (2000) The influence of age, sex, vitamin B(12), folate levels and methylenetetrahydrofolate reductase C677T genetic mutations on plasma homocysteine in the Chinese population. Haematologica 85: 1051-1054.
54. Cappuccio, F. P., Bell, R., Perry, I. J., Gilg, J., Ueland, P. M., Refsum, H., Sagnella, G. A., Jeffery, S. & Cook, D. G. (2002) Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis 164: 95-102.
55. Spotila, L. D., Jacques, P. F., Berger, P. B., Ballman, K. V., Ellison, R. C. & Rozen, R. (2003) The influence of methylenetetrahydrofolate reductase (MTHFR) genotype on plasma homocysteine is dependent on age. Am. J. Epidemiol. 158 (in press).
56. Dunn, J., Title, L. M., Bata, I., Johnstone, D. E., Kirkland, S. A., O'Neill, B. J., Zayed, E., MacDonald, M. C., Dempsey, G. & Nassar, B. (1998) Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease. Clin. Biochem. 31: 95-100.
57. Ma, J., Stampfer, M. J., Hennekens, C. H., Frosst, P., Selhub, J., Horsford, J., Malinow, M. R., Willett, W. C. & Rozen, R. (1996) Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 94: 2410-2416.
58. Passaro, A., Vanini, A., Calzoni, F., Alberti, L., Zamboni, P. F., Fellin, R. & Solini, A. (2001) Plasma homocysteine, methylenetetrahydrofolate reductase mutation and carotid damage in elderly healthy women. Atherosclerosis 157: 175-180.
59. Brown, C. A., McKinney, K. Q., Young, K. B. & Norton, H. J. (1999) The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy. Mol. Genet. Metab. 67: 43-48.
60. Schwartz, S. M., Siscovick, D. S., Malinow, M. R., Rosendaal, F. R., Beverly, R. K., Hess, D. L., Psaty, B. M., Longstreth, W. T., Jr., Koepsell, T. D., Raghunathan, T. E. & Reitsma, P. H. (1997) Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation 96: 412-417.
61. Gudnason, V., Stansbie, D., Scott, J., Bowron, A., Nicaud, V., & Humphries, S. (1998) C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group. Atherosclerosis 136: 347-354.
62. Kauwell, G. P., Wilsky, C. E., Cerda, J. J., Herrlinger-Garcia, K., Hutson, A. D., Theriaque, D. W., Boddie, A., Rampersaud, G. C. & Bailey, L. B. (2000) Methylenetetrahydrofolate reductase mutation (677C→T) negatively influences plasma homocysteine response to marginal folate intake in elderly women. Metabolism 49: 1440-1443.
63. van der Mooren, M. J., Wouters, M. G., Blom, H. J., Schellekens, L. A., Eskes, T. K. & Rolland, R. (1994) Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women. Eur. J. Clin. Investig. 24: 733-736.
64. Mijatovic, V., Kenemans, P., Jakobs, C., van Baal, W. M., Peters-Muller, E. R. & van der Mooren, M. J. (1998) A randomized controlled study of the effects of 17β-estradiol-dydrogesterone on plasma homocysteine in postmenopausal women. Obstet. Gynecol. 91: 432-436.
65. van der Mooren, M. J., Mijatovic, V., van Baal, W. M. & Stehouwer, C. D. (1998) Hormone replacement therapy in postmenopausal women with specific risk factors for coronary artery disease. Maturitas 30: 27-36.