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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
24
Badenhop RF,
Wang XL,
Wilken DEL.
Angiotensin-converting enzyme genotype in children and coronary events in their grandparents. Circulation 1995; 91: 1655-8.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
