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(Clinical Chemistry. 2000;46:1910-1915.)
© 2000 American Association for Clinical Chemistry, Inc.

Articles

Synergistic Effect between Apolipoprotein E and Angiotensinogen Gene Polymorphisms in the Risk for Early Myocardial Infarction

Alberto Batalla1, Ruth Alvarez2, Julián R. Reguero3, Sergio Hevia3, Gustavo Iglesias-Cubero3, Victoria Alvarez2, Arturo Cortina3, Pelayo González2, Mateo M. Celada4, Alfonso Medina4 and Eliecer Coto2,a

1 Servicio Cardiología, Hospital de Cabueñes, 33280 Gijón, Spain.

2 Laboratorio Genética Molecular-Instituto Investigación Nefrológica and
3 Servicio Cardiología, Hospital Central de Asturias, 33006 Oviedo, Spain.

4 Servicio Medicina Interna, Hospital Monte Naranco, E-33006 Oviedo, Spain.
a Author for correspondence. Fax 34-985-273657; e-mail ecoto{at}hcas.Insalud.es


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Several studies based on different populations worldwide have described an association between cardiovascular diseases and genetic variations in the apolipoprotein E (APOE), angiotensinogen (AGT), angiotensin receptor type 1 (AT1R), and angiotensin-converting enzyme (ACE) genes. In addition, there is growing evidence of an interaction between hypercholesterolemia and the renin-angiotensin system in the risk for hypertension and atherosclerosis.

Methods: To determine whether the DNA polymorphisms in APOE ({epsilon}2, {epsilon}3, and {epsilon}4 alleles), AGT (M235T), AT1R (1166 A/C), and ACE (I/D) are associated with early onset of myocardial infarction (MI), we genotyped 220 patients and 200 controls <55 years of age. Patients and controls were males from the same homogeneous Caucasian population. Data concerning hypertension, diabetes, and tobacco consumption were recorded. The lipid profiles of patients and controls were also determined.

Results: APOE, ACE, AGT, and AT1R allele and genotype frequencies did not differ between patients and controls. None of these polymorphisms was related to the biochemical values in patients or controls. The frequency of individuals who were both APOE {epsilon}4 allele carriers and AGT-TT homozygotes was significantly higher in patients than in controls (11% vs 3.5%; P = 0.0037). In patients, the frequency of {epsilon}4 carriers was significantly higher (P <0.00001) in those who were AGT-TT (46%) than those who were AGT-MT/MM (14%). Mean cholesterol was significantly higher in AGT-TT + APOE {epsilon}34/44 patients than in the TM/MM + {epsilon}34/44 or TT + {epsilon}23/33 genotypes (P = 0.029).

Conclusions: Our data suggest a synergistic effect between the APOE and AGT polymorphisms and early MI. The increased risk could be mediated in part through higher cholesterol concentrations among individuals who are AGT-TT + APOE {epsilon}4 allele carriers.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Apolipoprotein E (ApoE)1 is a plasma protein involved in cholesterol transport. ApoE is encoded by a polymorphic gene on chromosome 19 (the APOE gene), and three alleles ({epsilon}2, {epsilon}3, and {epsilon}4) have been described. These alleles differ in the amino acids at residues 112 (Cys in {epsilon}3 and {epsilon}2, and Arg in {epsilon}4) and 158 (Arg in {epsilon}3, Cys in {epsilon}2, and Arg in {epsilon}4) (1)(2). The APOE {epsilon}4 allele is a well-recognized risk factor for Alzheimer disease, and several case-control studies have described an increased risk for coronary artery disease (CAD) among {epsilon}4 carriers, with {epsilon}44 homozygotes showing an earlier onset of the disease (3)(4)(5)(6)(7)(8)(9)(10). However, other authors have found a nonsignificantly increased or even a decreased frequency of the {epsilon}4 allele among CAD patients (11)(12). Compared with {epsilon}33 homozygotes, carriers of the {epsilon}2 and {epsilon}4 alleles showed decreased and increased LDL-cholesterol, respectively (13). The {epsilon}2 allele has also been associated with higher triglyceride concentrations (14).

DNA polymorphisms in the angiotensinogen (AGT), angiotensin receptor type 1 (AT1R), and angiotensin-converting enzyme (ACE) genes have been linked to the risk of developing cardiovascular diseases. Among these polymorphisms, the ACE insertion/deletion (I/D) and the AGT-235M/T polymorphisms have been linked with differences in ACE and angiotensin II (Ang II) concentrations in plasma. Compared with individuals with an ACE-ID/II or AGT-MM/TM genotype, ACE-DD and AGT-TT genotypes have significantly higher concentrations of ACE and angiotensin, respectively (15)(16). The ACE-DD and AGT-TT genotypes have been associated with an increased risk for CAD in some studies, but not others (17)(18)(19). Several metaanalyses have investigated the association of the ACE polymorphism with myocardial infarction (MI). Whereas some authors found evidence for an association between the DD genotype and MI, others failed to confirm this result and suggested a bias toward publishing positive associations (20)(21)(22).

There is growing evidence of an interaction between the renin-angiotensin system and hypercholesterolemia in the risk for hypertension and atherosclerosis. Hypercholesterolemia induces vascular expression of AT1R in rabbits (23)(24), and ACE inhibitors and AT1R antagonists attenuate atherogenesis in hyperlipidemic rabbits and APOE-deficient mice, an animal model of atherosclerosis (25)(26). In addition, Ang II stimulates cholesterol biosynthesis in macrophages, an effect mediated by increased expression of hydroxymethylglutaryl (HMG)-CoA reductase (27).

To determine whether variations in the APOE, AGT, AT1R, and ACE genes contribute to the risk for early MI, we genotyped 220 Spanish male MI patients and 200 healthy controls younger than 55 years. The relationships between the genotypes and several clinical and biochemical markers were also analyzed.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients and controls
A total of 220 male consecutive patients (mean age, 43 ± 5 years; range, 26–55 years) were evaluated during the period 1994–1999. These patients had suffered a first episode of MI, defined according to the guidelines of the WHO MONICA protocol (28). Blood was obtained from the patients during hospitalization, after a 12-h fast, and the lipid profile was determined immediately. Patients were defined as hypertensive if they had a documented history of hypertension, with a systolic blood pressure >140 mmHg. In addition, smoking histories were collected from all patients by means of a structured questionnaire. None of the patients had a familial history of hypercholesterolemia or coronary disease.

We also recruited 200 male healthy controls (hospital staff, eligible residents, and blood donors; mean age, 42 ± 6 years; range, 21–55 years), who were matched with patients for age and ethnicity. Although blood pressure was not measured in these controls, they did not have cardiovascular disease or diabetes. None of the controls was using lipid-lowering or antihypertensive drugs. All patients and controls were residents in the region of Asturias (Northern Spain; total population, 1 million) and gave their consent to participate in the study. This study was approved by the Ethical Committee of Hospital Central Asturias.

apoe genotyping
Genomic DNA (100 ng) was PCR-amplified in a final volume of 30 µL containing 30 pmol of each primer (5'-TCCAAGGAGCTGCAGGCGGCGCA-3' and 5'-ACAGAATTCGCCCCGGCCTGGTACACTGCCA-3'), 2 mmol/L each dNTP, 2 mmol/L MgCl2, 1x Taq polymerase buffer, 100 mL/L deionized formamide, and 1 U of Taq DNA-polymerase. PCR consisted of 30 cycles of 95 °C for 30 s, 62 °C for 1 min, and 75 °C for 30 s, followed by a final extension of 5 min at 72 °C. A 20-µL aliquot of each reaction was digested with 20 U of HhaI and electrophoresed on a 4% agarose gel. Restriction digestion fragments were stained with ethidium bromide and photographed. The APOE alleles were identified as described previously (2).

agt, at1r, and ace genotyping
A C-to-T change in the AGT gene produces a polymorphism at amino acid 235 (M235T). To analyze this polymorphism, we PCR-amplified genomic DNA with primers 5'-GATGCGCACAAGGTCCTG-3' and 5'-CAGGGTGCTGTCCACACTGGCTCGC-3' (annealing at 62 °C). Reactions were digested with the restriction enzyme BstUI and electrophoresed on a 3% agarose gel. Alleles were visualized as fragments of 303 bp (allele M) and 279 bp (allele T).

The 1166 A/C polymorphism in the 3' region of the AT1R gene and the 287-bp insertion/deletion (I/D) polymorphism in the ACE gene were analyzed as described previously (29). Each DD genotype was confirmed through a second PCR with primers specific for the insertion sequence (30).

statistical analysis
Differences of allele and genotype frequencies were compared using the {chi}2 test. Odds ratios and their 95% confidence intervals were also calculated. The Student t-test was used to compare two means, and ANOVA was used when more than two groups were compared. A P value <0.05 indicated a statistically significant effect. For the statistical analysis, we used the computer program BMDP-New Systems (BMDP Statistical Software).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The clinical characteristics and lipid values of the controls and patients with early MI are summarized in Table 1 . MI was strongly associated with cigarette smoking in our population. In addition, 35% and 11% of the patients were hypertensive and diabetic, respectively.


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  		Table 1. Clinical characteristics and TC, HDL-cholesterol, and triglycerides in the 220 patients with MI and the 200 controls.

The APOE, AGT, AT1R, and ACE genotype frequencies are summarized in Table 2 . In our population, the APOE {epsilon}4 allele and genotype frequencies were similar between patients and controls. AGT, ACE, and AT1R allele and genotype frequencies did not differ between patients and controls. Mean biochemical values did not differ between the genotypes of each of the four polymorphisms in patients or controls (Table 2 ).


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  		Table 2. APOE, ACE, AGT, and AT1R genotype frequencies in patients and controls, and lipid values in controls and patients (controls/patients) according to the genotype.

APOE, AGT, AT1R, and ACE allele and genotype frequencies did not differ between patients with or without diabetes, or with or without hypertension (data not shown). We analyzed a possible synergistic effect between the APOE and the AGT, AT1R, and ACE polymorphisms. The APOE genotype did not modify the risk associated with the ACE or AT1R genotypes (Table 3 ). However, the frequency of carriers of the APOE {epsilon}4 allele was significantly higher among the AGT-TT patients compared with the TM/MM patients (P <0.00001). The frequency of AGT-TT + APOE {epsilon}4 carriers was significantly higher in the overall patient group compared with controls [24 of 220 (11%) vs 7 of 200 (3.5%); P = 0.0037; Table 3 ]. Thus, {epsilon}34/44 + AGT-TT individuals would have an almost fourfold higher risk of suffering an early episode of MI (odds ratio, 3.38; 95% confidence interval, 1.5–8.17).


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  		Table 3. Distribution of the APOE genotype according to the AGT, ACE, and AT1R genotypes in the patients, and to the AGT genotype in controls.

Mean cholesterol concentrations were significantly higher in TT + {epsilon}44/34 patients (n = 24; 2480 mg/L) compared with the TM/MM + {epsilon}44/34/24 or TT + {epsilon}33/23 genotypes (n = 196; 2160 mg/L; P = 0.029; Table 4 ). A total of 94 patients had a total cholesterol (TC) value higher than the mean value (2200 mg/L), and 14 (15%) were TT + {epsilon}34/44, compared with only 10 of the 126 (8%) with a TC value below the mean (P = 0.012). Among the controls, the mean TC value was not significantly higher in those with the TT + {epsilon}34/44/24 genotype (n = 7) compared with the other genotypes (n = 193; 2250 ± 500 vs 2040 ± 400 mg/L; P = 0.07).


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  		Table 4. Mean cholesterol, HDL, and triglycerides in patients according to APOE + AGT genotype.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Compared with other Caucasian populations, we found a lower frequency of the APOE {epsilon}4 allele. This result is in agreement with previous reports that showed the lowest frequency for the {epsilon}4 allele in Southern European populations (31)(32)(33)(34)(35). The role of APOE genotype in the risk of CAD has been analyzed previously (4)(5)(6)(7)(8)(9)(10)(11)(12)(36)(37)(38). For the {epsilon}4 allele, a significantly increased frequency in patients compared with healthy controls has been described in some studies, but not others. These discrepancies could be partly attributable to the fact that these studies analyzed different populations worldwide and that the {epsilon}4 allele could be a risk factor when associated with other genetic or environmental factors. This allele has been associated with increased LDL-cholesterol in response to dietary fat (13)(38)(39)(40). It is thus possible that the influence of the APOE {epsilon}4 allele as a risk factor for MI is limited to populations that consume a high-fat diet.

According to previous results, AGT-235TT and ACE-DD individuals have increased plasma concentrations of angiotensin and ACE, respectively (15)(16). These genotypes have been associated with a higher CAD risk (17)(18)(19). However, only the DD genotype was associated with a slight, nonsignificant increased risk of developing early MI in our population. We had previously described a synergistic effect between the ACE-DD and AT1R-CC genotypes in the risk for early CAD (29).

We also investigated a synergistic effect between the APOE and the AGT, AT1R, and ACE polymorphisms. According to our results, the APOE {epsilon}4 allele increased the risk of suffering an episode of MI among those with an AGT-TT genotype. The frequency of AGT-TT + {epsilon}4 carriers was higher in the overall patient group compared with controls, and the frequency of APOE {epsilon}4 carriers was higher among patients who were AGT-TT compared with patients who were TM/MM. Mean cholesterol was significantly higher in patients who were AGT-TT + {epsilon}4 carriers than in patients who were {epsilon}4 carriers + TM/MM or {epsilon}33/23 + TT. Taken together, these data suggest that individuals who are {epsilon}4 carriers + AGT-TT are at an increased risk of suffering an early episode of CAD, and this effect could be related to higher cholesterol concentrations.

The published results are variable with respect to the association between polymorphisms of ACE, AGT, AT1R, and APOE with CAD, hypertension, and MI. This variability could be partly attributable to the differences in the risk factors associated with these diseases. In this way, the proportion of smokers may be one important cause for this variability. The patients in our study had MI before the age of 55, and most of them were smokers. Among older patients, lipid disorders may play a more important role. It is very likely that smoking and the associated low HDL-cholesterol concentrations are the primary causes of MI among the patients in this study. Therefore, the synergistic effects of the polymorphisms at the AGT and APOE genes are likely modulating the effects of smoking on hypertension (AGT) and cholesterol (APOE) concentrations.

The existence of a synergistic effect between the AGT and APOE genotypes is in agreement with recent findings that described an interaction between lipid metabolism and the renin-angiotensin system in cardiovascular pathophysiology. Recently, Keidar et al. (27) showed that Ang II injected intraperitoneally into APOE-deficient mice increased the atherosclerotic lesion area, and peritoneal macrophages showed an increased rate of cholesterol biosynthesis mediated by an increased expression of HMG-CoA reductase. This would lead to macrophage cholesterol accumulation and foam cell formation, a major early event in the development of atherosclerosis. The stimulatory effect of Ang II on HMG-CoA reductase concentrations and cholesterol synthesis in APOE-deficient mice was blocked by treatment with losartan, an AT1R blocker (27). Losartan also had an antiatherogenic effect in non-human primates with diet-induced hypercholesterolemia (41). Endothelial dysfunction was greatly improved in hypercholesterolemic men treated with ACE inhibitors, and a reduction in aortic cholesterol content in cholesterol-fed rabbits treated with the ACE inhibitor enalapril has been reported (42)(43). Statins down-regulate AT1R expression in hypercholesterolemic men, a fact that could in part explain the beneficial effect of these drugs (44). Patients with familial hypercholesterolemia and a DD genotype would have an increased risk of CAD (45).

Our work has several limitations, some of which are inherent to case-control studies. The study was based on MI patients from a small region, and all of the patients were male and younger than 55 years. The sample was therefore small. However, the frequencies for the four polymorphisms were in the Hardy-Weinberg equilibrium, suggesting the absence of population biases. Finally, if studies based on other populations confirm our results, genotyping of APOE and AGT polymorphisms could identify individuals at a higher risk of developing MI.


   Acknowledgments
 
This work was supported by Grant FIS 99/0924 (to E.C.). R.A. and P.G. were the recipients of fellowships from the Spanish Fondo de Investigaciones Sanitarias and Fundación Mapfre, respectively.


   Footnotes
 
1 Nonstandard abbreviations: ApoE, apolipoprotein E; CAD, coronary artery disease; AGT, angiotensinogen; AT1R, angiotensin receptor type 1; ACE, angiotensin-converting enzyme; Ang II, angiotensin II; MI, myocardial infarction; HMG, hydroxymethylglutaryl; and TC, total cholesterol.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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 Clin. Chem.Home page
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