No Evidence of Association Between Prothrombotic Gene Polymorphisms and the Development of Acute Myocardial Infarction at a Young Age

Abstract

Background— We investigated the association between 9 polymorphisms of genes encoding hemostasis factors and myocardial infarction in a large sample of young patients chosen because they have less coronary atherosclerosis than older patients, and thus their disease is more likely to be related to a genetic predisposition to a prothrombotic state. Methods and Results— This nationwide case-control study involved 1210 patients who had survived a first myocardial infarction at an age of <45 years who underwent coronary arteriography in 125 coronary care units and 1210 healthy subjects matched for age, sex, and geographical origin. None of the 9 polymorphisms of genes encoding proteins involved in coagulation (G-455A β-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9; and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: OR, 0.9; CI, 0.8 to 1.2), fibrinolysis (G185T factor XIII: OR, 1.2; CI, 0.9 to 1.6; and 4G/5G plasminogen activator inhibitor type 1: OR, 0.9; CI, 0.7 to 1.2), or homocysteine metabolism (C677T methylenetetrahydrofolate reductase: OR, 0.9; CI, 0.8 to 1.1) were associated with an increased or decreased risk of myocardial infarction. Conclusions— This study provides no evidence supporting an association between 9 polymorphisms of genes encoding proteins involved in hemostasis and the occurrence of premature myocardial infarction or protection against it.

Methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism and late infarct-related coronary artery patency after thrombolysis

“…However, this is the first study to evaluate the hypothesis whether MTHFR C677T polymorphism is associated with late infarct-related artery patency after thrombolysis in patients with acute myocardial infarction. The relationship between MTHFR polymorphism and occluded infarct-related artery was independent of possible confounding variables and may have epidemiological significance, since the frequency of MTHFR 677TT genotype was relatively high (22%) and similar to that previously reported for Italian patients with history of myocardial infarction [15,21]. In our study, the distribution of MTHFR C677T genotypes followed the Hardy-Weinberg equilibrium, both in patients with persistently occluded and in those with patent infarct-related vessel, suggesting that there was no strong genetic selection; however, our findings might be influenced by another genetic region/gene that is in linkage disequilibrium with the MTHFR polymorphism.…”

“…T transition determines a valine substitution for an alanine residue in the protein [13,14]; MTHFR 677TT-derived enzymatic variant is characterized by heat inactivation at 46°C and an activity of 30-50% of normal. Frequency of MTHFR 677TT homozygosis is well known in healthy individuals, ranging from 1.4% in African Americans [35], to 10% in Japanese [36], 12-13% in United States and United Kingdom [37,38] and 15-20% in Italian people [15,21,39]. In a meta-analysis, MTHFR 677TT genotype was associated with a slight, but significant overall rise in coronary artery disease risk (odds ratio 1.16) [17].…”

“…We expected a frequency of MTHFR 677TT homozygosis of about 20% in the Italian population with acute myocardial infarction [15,21] and an occurrence of a 30-day patent infarct-related artery after thrombolysis of about 50% [4,5,22]. Thus, a sample size of at least 80 patients (with at least 40 patients in each group) would provide an 80% power to detect a two-fold difference in the frequency of MTHFR 677TT homozygosis with an alpha (P-value) of 0.05.…”

“…T) [14]; individuals with the MTHFR 677TT genotype have a moderate increase in homocysteine levels [13]. Previous studies have investigated the role of MTHFR C677T genotype in the occurrence of coronary artery disease [15,16], and a meta-analysis has suggested that 677C ? T mutation may be associated with an overall increase in coronary artery disease risk [17]; indeed, it is widely accepted that MTHFR 677TT genotype may represent a cardiovascular risk factor if a folate deficiency occurs concomitantly [17].…”

Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

“…The case–control studies included the Exome Sequencing Project Early-Onset Myocardial Infarction (ESP-EOMI) study conducted by the National Heart, Lung, and Blood Institute, 11 the Italian Atherosclerosis Thrombosis and Vascular Biology (ATVB) study, 12 the Ottawa Heart Study (OHS), 13 the Precocious Coronary Artery Disease (PROCARDIS) study, 14 the Pakistan Risk of Myocardial Infarction Study (PROMIS), 15 the Registre Gironi del COR (Gerona Heart Registry or REGICOR) study, 16 and the Munich Myocardial Infarction (Munich-MI) study. 17 The prospective cohort studies included the Atherosclerosis Risk in Communities (ARIC) study 18 and the Jackson Heart Study (JHS).…”