Download PDF
Thromb Haemost 1999; 82(01): 19-23
DOI: 10.1055/s-0037-1614623
Rapid Communication
Schattauer GmbH

Genetic Polymorphism of 5,10-MTHFR Reductase Gene in Offspring of Patients with Myocardial Infarction

Maurizio Margaglione
1   From Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
,
Donatella Colaizzo
1   From Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
,
Giuseppe Cappucci
1   From Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
,
Annamaria del Popolo
1   From Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
,
Gennaro Vecchione
1   From Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
,
Elvira Grandone
1   From Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
,
Giovanni Di Minno
2   From Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy
› Author AffiliationsThe financial support of Telethon-Italy (Grant no. E.C 804) is gratefully acknowledged.
Further Information

Publication History

Received 05 February 1999

Accepted after resubmission 19 April 1999

Publication Date:
11 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

A family history of myocardial infarction is a major determinant of ischemic disease. A C->T677 polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified as a cause of mild hyperhomocysteinemia, a risk factor for arterial thrombosis. We have investigated the relationship between the MTHFR TT genotype and a family history of myocardial infarction in a cohort of 982 apparently healthy individuals. Subjects whose first-degree relatives suffered from a myocardial infarction, showed raised median age (p <0.001), total cholesterol (p <0.001) and plasma fibrinogen (p = 0.023) and a higher than normal frequency of C-reactive protein levels >0.33 mg/dl (p = 0.012). Moreover, when compared to subjects without such family history, a higher number of homozygotes for the T allele of the MTHFR gene (p = 0.027), and of the 4G allele of the plasminogen activator inhibitor-1 gene (p = 0.002) was found in the subsetting of the offspring of patients with myocardial infarction. In a multiple logistic regression analysis, age (OR 1.02 [95%-CI: 1.00-1.05]), total cholesterol (OR 1.40 [95%-CI: 1.14-1.71]), C-reactive protein levels >0.33 mg/l (OR: 1.87 [95%-CI: 1.10-3.20]), plasminogen activator inhibitor-1 4G/4G (OR: 1.84 [95%-CI: 1.27-2.66]), and MTHFR TT genotype (OR 1.62 [95%-CI: 1.08-2.42]), were all associated with a family history of myocardial infarction. Thus, the MTHFR TT genotype independently accounts for the risk of a family history for myocardial infarction in the present setting.

Keywords

Myocardial infarction - risk factors - genes - methylenetetrahydrofo-late reductase
 

  • References

  • 1 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and acute coronary syndromes. New Engl J Med 1992; 326: 242-50.
    CrossrefPubMedGoogle Scholar
  • 2 Kannell WB. Bishop lecture: Contribution of the Framingham study to preventive cardiology. J Am Coll Cardiol 1990; 15: 206-11.
    CrossrefPubMedGoogle Scholar
  • 3 Tuomiletho J, Kuulasmaa K. The WHO MONICA project. Assessing CHD mortality and morbidity. Int J Epidemiol 1989; 18 (03) (Suppl. 01) S38-S45.
    PubMedGoogle Scholar
  • 4 Malinow MR. Homocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990; 81: 2004-6.
    CrossrefPubMedGoogle Scholar
  • 5 Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a factor for vascular disease: probable benefits of folic acid intakes. JAMA 1995; 472: 1049-57.
    PubMedGoogle Scholar
  • 6 Genest Jr JJ, McNamara JR, Upson B, Salem DN, Ordovas JM, Schaefer EJ, Malinow MR. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 1991; 11: 1129-36.
    CrossrefPubMedGoogle Scholar
  • 7 Berg K, Malinow MR, Kierulf P, Upson B. Population variation and genetics of plasma homocyst(e)ine levels. Clin Genet 1992; 41: 315-21.
    PubMedGoogle Scholar
  • 8 Franken DG, Boers GH, Blom HJ, Cruysberg JR, Trijbels FJ, Hamel BC. Prevalence of familial hyperhomocysteinemia. Atherosclerosis 1996; 125: 71-80.
    CrossrefPubMedGoogle Scholar
  • 9 Kang SS, Zhou J, Wong PWK, Kowalysin J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988; 43: 414-21.
    PubMedGoogle Scholar
  • 10 Engbersen AMT, Franken DG, Boers GHJ, Stevens EMB, Trijbels FJM, Blom HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995; 56: 142-50.
    PubMedGoogle Scholar
  • 11 Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N. Thermo-labile methylenetetrahydrofolate reductase: an inherited risk factor for coronary heart disease. Am J Hum Genet 1991; 48: 536-45.
    PubMedGoogle Scholar
  • 12 Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1993; 88: 1463-9.
    CrossrefPubMedGoogle Scholar
  • 13 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GHJ, den Heijer M, Kluijtmans LAJ, van de Heuvel LP, Roen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
    CrossrefPubMedGoogle Scholar
  • 14 De Franchis R, Mancini FP, D’Angelo A, Sebastio G, Fermo I, De Stefano V, Margaglione M, Mazzola G, Di Minno G, Andria G. Elevated total plasma homocysteine and C>T mutation of 5,10 methylenetetrahydrofolate re-ductase gene in thrombotic vascular disease. Am J Hum Genet 1996; 59: 262-4.
    PubMedGoogle Scholar
  • 15 Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoky K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5,10-methylene tetrahydrofolate reductase (MTHFR) as risk factor for coronary artery disease. Circulation 1997; 95: 2032-6.
    CrossrefPubMedGoogle Scholar
  • 16 Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckmann RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol 1997; 17: 1157-62.
    CrossrefPubMedGoogle Scholar
  • 17 Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Mali-now MR, Willet WC, Rozen R. Methylenetetrahydrofolate reductase poly-morphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 1996; 94: 2410-6.
    CrossrefPubMedGoogle Scholar
  • 18 Deloughery TG, Evans A, Sadeghi A, McWilliams J, Henner WD, Taylor LM, Press RD. Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation 1996; 94: 3074-8.
    CrossrefPubMedGoogle Scholar
  • 19 Christensen B, Frosst P, Lussier-Cacan S, Selhub J, Goyette P, Rosenblatt DS, Genest J, Rozen R. Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease. Arterioscler Thromb Vasc Biol 1997; 17: 569-73.
    CrossrefPubMedGoogle Scholar
  • 20 Nora JJ, Lortscher RH, Spangler RD, Nora AH, Kimberling WJ. Genetic-epidemiologic study of early onset ischemic heart disease. Circulation 1980; 61: 503-8.
    CrossrefPubMedGoogle Scholar
  • 21 Deutscher S, Epstein F, Kjelsberg M. Familial aggregation of coronary heart disease. Circulation 1966; 33: 911-24.
    CrossrefPubMedGoogle Scholar
  • 22 Wang XL, Tam C, McCredie RM, Wilken DEL. Determinants of severity of coronary heart disease in Australian men and women. Circulation 1994; 89: 1974-81.
    CrossrefPubMedGoogle Scholar
  • 23 Tiret L, Kee F, Poirer O, Nicaud V, Lecerf L, Evans A, Cambou JP, Arvileir D, Luc G, Amouyel P, Cambien F. Deletion polymorphism in the angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet 1993; 341: 991-2.
    CrossrefPubMedGoogle Scholar
  • 24 Badenhop RF, Wang XL, Wilken DEL. Angiotensin-converting enzyme genotype in children and coronary events in their grandparents. Circulation 1995; 91: 1655-8.
    CrossrefPubMedGoogle Scholar
  • 25 Tonstad S, Refsum H, Siversten M, Christophersen B, Ose L, Ueland PM. Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives. Pediatr Res 1996; 40: 47-52.
    CrossrefPubMedGoogle Scholar
  • 26 Tonstad S, Refsum H, Ueland PM. Association between plasma total homo-cysteine and parental history of cardiovascular disease in children with hypercholesterolemia. Circulation 1997; 96: 1803-8.
    CrossrefPubMedGoogle Scholar
  • 27 Margaglione M, Cappucci G, Colaizzo D, Giuliani N, Vecchione G, Gran-done E, Pennelli O, Di Minno G. Plasminogen activator inhibitor-1 (PAI-1) gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 1998; 18: 152-6.
    CrossrefPubMedGoogle Scholar
  • 28 Margaglione M, Di Minno G, Grandone E, Vecchione G, Celentano E, Cap-pucci G, Giordano M, Grilli M, Simone P, Fusilli S, Panico S, Mancini M. Raised plasma fibrinogen concentrations in subjects attending a metabolic ward. Relation to family history and vascular risk factors. Thromb Haemost 1995; 73: 579-83.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Margaglione M, Di Minno G, Grandone E, Vecchione G, Celentano E, Cap-pucci G, Grilli M, Simone P, Panico S, Mancini M. Abnormally high circulating levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke. Arterioscler Thromb 1994; 14: 1741-5.
    CrossrefPubMedGoogle Scholar
  • 30 Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the b fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Margaglione M, Grandone E, Cappucci G, Colaizzo D, Giuliani N, Vecchi-one G, D’Addedda M, Di Minno G. An alternative method for PAI-1 promoter polymorphism (4G/5G) typing. Thromb Haemost 1997; 77: 605-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/ deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (Dipeptyl carboxypeptidase 1). Nucleic Acid Res 1992; 20: 1433
    PubMedGoogle Scholar
  • 33 Margaglione M, Grandone E, Vecchione G, Cappucci G, Giuliani N, Co-laizzo D, Celentano E, Panico S, Di Minno G. Plasminogen activator inhib- itor-1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward. Relation to polymorphisms of the PAI-1 and the angiontensin converting enzyme (ACE) genes. Arterioscl Thrombos Vasc Biol 1997; 17: 2082-7.
    PubMedGoogle Scholar
  • 34 Tybjærg-Hansen Angerholm-Larsen B, Humphries SE, Abildgaard S, Schnohr P, Nordestgaard BG. A common mutation (G-455 ->A) in the β-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease. A study of 9,127 individuals based on the Copen-hagen City Heart Study. J Clin Invest 1997; 99: 3034-9.
    CrossrefPubMedGoogle Scholar
  • 35 Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Weinberg R, Webber LS, Berenson GS. Hereditary and environmental influence on cardiovascular risk factors for children. The Bogalusa Heart Study. Am J Epidemiol 1982; 116: 385-93.
    CrossrefPubMedGoogle Scholar
  • 37 Mitchell BD, Kammerer CM, Blangero J, Rainwater DL, Dyke B, Hixson JE, Henkel RD, Sharp M, Comuzzie AG, VandeBerg JL, Stern MP, Mac-Cluer JW. Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. Circulation 1996; 94: 2159-70.
    CrossrefPubMedGoogle Scholar
  • 38 Goldbourt U, Neufeld HN. Genetic aspect of arteriosclerosis. Arteriosclerosis 1986; 6: 357-77.
    CrossrefPubMedGoogle Scholar
  • 39 de Faire U. Ischemic heart disease in death discordant twins. A study in 205 male and female pairs. Acta Med Scand Suppl 1974; 568: 101-9.
    PubMedGoogle Scholar
  • 40 Berg K. Twin research in coronary heart disease. In:. Parisi GL, Nance WL. (eds). Twin research 3: Epidemiological and Clinical Studies New York: Alan R Liss; 1981: 117-30.
    Google Scholar
  • 41 Parra HJ, Arveiler D, Evans AE, Cambou JP, Amouyel P, Bingham A, McMaster D, Schaffer P, Douste-Blazy P, Luc G, Richard JL, Ducimetière P, Fruchart JC, Cambien F. A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease. Arterioscler Thromb 1992; 12: 701-7.
    CrossrefPubMedGoogle Scholar
  • 42 Humphries SE. The genetic contribution to the risk of thrombosis and cardiovascular disease. Trends Cardiovasc Med 1994; 4: 8-17.
    CrossrefPubMedGoogle Scholar
  • 43 Humphries SE, Ye S, Talmud P, Bara L, Wilhelmsen L, Tiret L. on behalf of the European Atherosclerosis Research Study (EARS) group. European atheroclerosis research study: genotype at the fibrinogen locus (G-455-A β-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment interaction. Arterioscler Thromb Vasc Biol 1995; 15: 96-104.
    CrossrefPubMedGoogle Scholar
  • 44 Brattström L, Wilcken DEL, Öhrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease. The results of a meta-analysis. Circulation 1998; 98: 2520-6.
    CrossrefPubMedGoogle Scholar
  • 45 Guttormsen AB, Ueland PM, Nesthus I, Nygård O, Schneede J, Vollset SE, Refsum H. Determinants and vitamin responsiveness of intermediate hyper-homocysteinemia (>40 μmol/liter). The Hordaland Homocysteine Study. J Clin Invest 1996; 98: 2174-83.
    CrossrefPubMedGoogle Scholar
  • 46 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-9.
    CrossrefPubMedGoogle Scholar
  • 47 Refsum H, Ueland PM. Recent data are not in conflict with homocysteine as a cardiovascular risk factor. Curr Opinion Lipidol 1998; 9: 533-9.
    CrossrefPubMedGoogle Scholar
  • 48 Førde OH, Thelle DS. The Tromsø Heart Study: risk factors for coronary heart disease related to the occurrence of myocardial infarction in first-degree relatives. Ann J Epidemiol 1977; 105: 192-9.
    PubMedGoogle Scholar
  • 49 Silberberg J, Alexander H, Wlodarczyk J, Basta M, Hensley M, Hughes J, Ray C. Accuracy of reported family history of heart disease: impact of “don’t know” responses. Aust N Z J Med 1994; 24: 386-9.
    CrossrefPubMedGoogle Scholar
  • 50 Napier JA, Metzner H, Johnson BC. Limitation of morbidity and mortality data obtained from family histories: a report from the Tecumseh community health study. Am J Public Health 1972; 62: 30-5.
    CrossrefPubMedGoogle Scholar
  • 51 Rose GA. The diagnosis of ischemic heart pain and intermittent claudication in field surveys. Bull World Health Organ 1962; 27: 645-58.
    PubMedGoogle Scholar