© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
C-Reactive Protein in Offspring Is Associated With the Occurrence of Myocardial Infarction in First-Degree Relatives
From Unita’ di Aterosclerosi e Trombosi, IRCCS "Casa Sollievo della Sofferenza (CSS)," S Giovanni Rotondo (M.M., G.C., D.C., G.V., E.G.), and Istituto di Medicina Interna e Geriatria, Università di Palermo (G.D.M.), Palermo, Italy.
Correspondence and reprint requests to Maurizio Margaglione, MD, Unità di Aterosclerosi e Trombosi, IRCCS "Casa Sollievo della Sofferenza," viale Cappuccini, San Giovanni Rotondo (FG) 71013, Italy. E-mail ate.tro{at}operapadrepio.it
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Abstract |
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Abstract—The relevance of elevated levels of C-reactive protein (CRP) in cardiovascular disease is gaining increasing recognition. A family history of coronary artery disease is a major determinant of coronary artery disease in the offspring. In a cohort of 1048 individuals without clinical evidence of atherosclerosis, we investigated the relationships between CRP levels and a family history of myocardial infarction. We measured CRP, fibrinogen, plasminogen activator inhibitor-1, total cholesterol, triglycerides, and some genetic polymorphisms: plasminogen activator inhibitor-1 (4G/5G), fibrinogen (Bß-chain G
A-455), and
angiotensin-converting enzyme insertion/deletion (I/D).
Clinical data were collected by a World Health Organization–modified
questionnaire for cardiovascular disease. When compared
with subjects without first-degree relatives who had suffered a
myocardial infarction (n=867), subjects with such first-degree
relatives (n=181) were older (P=0.001), more often
hypertensive (P<0.001), and homozygous for the 4G
allele (4G/4G) of the plasminogen activator
inhibitor-1 gene (P=0.003). In addition,
they had a higher body mass index (P=0.036), raised
plasma fibrinogen (P<0.007) and total
cholesterol (P<0.001) concentrations, and
CRP levels >0.33 mg/L (P=0.005). In a multiple logistic
regression analysis, age (odds ratio [OR] 1.03, 95%
confidence interval [95% CI] 1.01 to 1.05), total
cholesterol (OR 1.35, 95% CI 1.11 to 1.65),
plasminogen activator inhibitor-1
4G/4G (OR 1.72, 95% CI 1.20 to 2.45), and CRP levels >0.33 mg/L (OR
1.75, 95% CI 1.05 to 2.91) were all independently associated with a
positive family history of myocardial infarction. We therefore conclude
that raised levels of CRP independently identify the offspring of
patients with a myocardial infarction.
Key Words: myocardial infarction • risk factors • thrombosis
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Introduction |
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In population studies, in addition to a series of environmental factors, a family history of coronary artery disease is a major predictor of coronary artery disease. A parental history of coronary artery disease is associated with an increased risk of myocardial ischemia.1 The presence of coronary artery disease in relatives by itself is considered to be an independent risk factor for developing a myocardial infarction in other family members.1 2 Previous reports have investigated whether dietary fat composition, apo(a) phenotypes, and Lp(a) plasma levels are independently associated with a parental history of myocardial infarction.3 4 5 Angiotensin-converting enzyme (ACE) gene and lipoprotein lipase gene polymorphisms have been found associated with a history of coronary artery disease in fathers and in second-degree relatives.6 7 8 We have previously found that the 4G/4G gene variant of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with a history of coronary artery disease in a first-degree relative.9
Raised concentrations of C-reactive protein (CRP) have been found to predict recurrent ischemia, myocardial infarction, and sudden death among patients with multiple risk factors for coronary artery disease and angina pectoris.10 11 12 In the ECAT study, raised levels of CRP at baseline consistently predicted myocardial infarction or sudden death over the 3 years of follow-up.11 Increased CRP concentrations reflect the inflammatory condition of the vascular wall. Concentrations of CRP have been found to increase with age, body mass index (BMI), and cigarette smoking.13 Overweight and cigarette smoking are associated with a high risk of myocardial infarction.14 The aggregation of myocardial infarction in families1 2 and the observation that dietary or other lifestyle factors are more commonly shared by individuals living in the same household suggest that raised CRP concentrations, as a nonspecific index of inflammation, may explain part of the risk of myocardial infarction associated with a positive family history. No information is available on CRP as related to a familial history of myocardial infarction. An association with a family history of myocardial infarction may indicate the presence of familially transmitted factors. In a cohort of individuals without clinical evidence of atherosclerosis, we have evaluated the relationships between CRP, risk factors for myocardial infarction, and the occurrence of myocardial infarction in their first-degree relatives.
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Methods |
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Subjects
From January 1995 to October 1996 and after approval of the local Ethics Committee, the study was carried out according to the Principles of the Declaration of Helsinki. Informed consent was obtained from 1192 of the 1319 (90.4%) employees of the "Casa Sollievo della Sofferenza" Hospital, S Giovanni Rotondo, southern Italy. Biochemical and/or clinical data could not be completed in 138 individuals (10.5%). Moreover, all subjects with a history of clinical atherosclerosis (n=6) were excluded from the study. Thus, 1048 employees (22 to 66 years old, 79.5%) were enrolled. All were white, none was the offspring of a consanguineous marriage, and all of their parents and grandparents had been born in the same region. The male/female ratio of the sample was 0.77 (men=457, 43.6%; women=591, 56.4%). Blood was collected by venipuncture between 9 and 11 AM after 12 to 15 hours of fasting and abstinence from alcohol ingestion. Platelet-free plasma obtained by centrifugation (2000g x10 minutes at room temperature) was immediately divided into aliquots of 500 µL each in plastic tubes (Nunc) and frozen at -70°C until assayed (within 12 months). A detailed clinical summary with emphasis on personal and family history of myocardial infarction was obtained from all subjects by a specially trained staff employing a previously validated questionnaire15 prepared according to the World Health Organization questionnaire for angina pectoris and cardiovascular disease. In addition to questions about symptoms of ischemic heart disease, peripheral vascular disease, and previous vascular surgery, information concerning stroke history and vascular risk factors, diabetes mellitus, hypertension, drug use, and alcohol and smoking habits was also obtained. Hypertension was defined as a systolic blood pressure >140 mm Hg and/or a diastolic blood pressure >90 mm Hg in the sitting position after 10 minutes of supine rest on at least 3 different occasions.16 Subjects with a positive personal history of diabetes mellitus or with fasting blood glucose levels >126 mg/dL were considered diabetics.17 Alcohol drinkers and smokers were defined as never/past consumers or current consumers.
Biochemical and Genetic Variables
Serum concentrations of total cholesterol and
triglycerides were detected enzymatically by employing
commercially available reagents (Roche).15 18 Plasma
fibrinogen was assayed by the Clauss clotting method by using reagents
and the CoA Data 2000 apparatus from
Boehringer-Mannheim. PAI-1 antigen plasma levels were assayed
by ELISA methods with kits (Imulyse) from Biopool-Menarini. Reference
pooled, normal plasma from 216 apparently healthy male and female
volunteers (29 to 70 years old) who had been instructed to avoid any
medication for at least 1 week was prepared and stored under the same
conditions applied to the study’s subjects’ samples. The intra-assay
and interassay coefficients of variation of fibrinogen did not exceed
8% and those of PAI-1 antigen, 4.5%. CRP was assayed by rate
nephelometry (N latex CRP mono, Behring Institute) according to the
manufacturer’s recommendations. Because of the reduced precision in
the low range of the assay (0.175 to 0.33 mg/L), a cutoff value of 0.33
mg/L was employed as the lower detection limit.
Blood samples were collected and DNA was extracted according to
standard protocols.15 The fibrinogen Bß-chain -455
GA polymorphism was evaluated as previously
reported,19 with some modifications.15 As to
the PAI-1 4G/5G polymorphism, a mutated
oligonucleotide was synthesized that inserts within the
amplification product a site for the BslI
enzyme.20 Polymerase chain reaction (PCR) techniques,
primers, and experimental conditions employed for ACE genotyping were
the ones suggested by Rigat et al,21 with some
modifications.22 PCR assays were carried out on
50-µL-volume samples in a Perkin Elmer–Cetus thermal cycler. Each
sample contained 0.5 µg of genomic DNA, 15 pmol of each primer, and 1
U of thermostable Taq polymerase. The amplification
products were resolved electrophoretically in a 2% (fibrinogen
Bß-chain GA -455 and ACE I/D) or a 4% (PAI-1 4G/5G) agarose gel
with a 40 mmol/L Tris-acetate buffer, pH 7.7, containing 1
mmol/L EDTA; the gels were then stained with 0.5 µg/mL ethidium
bromide and visualized by UV light.
Statistical Analysis
All analyses were performed according to the Statistical
Package for the Social Science (SPSS 6.0.1 for the
Macintosh). Because their distributions were skewed, plasma fibrinogen,
BMI, PAI-1 antigen, cholesterol, and
triglyceride levels were logarithmically transformed to
allow the use of parametric tests. CRP data were entered as a
categorical variable with 0.33 mg/L as the cutoff value.
Differences in baseline characteristics between sexes were evaluated by
the Student’s t test, Mann-Whitney U test, and
2 test, as appropriate. Additional
analyses were performed after stratification of the entire
sample on the basis of quartiles of age (quartile cutting points at 31,
36, and 44 years) and according to the median value of total
cholesterol (4.87 mmol/L). The allelic frequencies
were estimated by gene counting, and genotypes were scored. The
figures obtained for each genotype were compared with those
predicted in a population by Hardy-Weinberg equilibrium
(2 test). The significance of the difference
in the alleles and genotypes observed between the groups
was tested by using 2 analysis. Odds
ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Appropriate models were set up to evaluate in a multiple logistic
regression analysis the independent relationship between CRP
levels >0.33 mg/L and a family history of myocardial infarction and
potential interactions. The likelihood-ratio test was applied to
determine which variables to remove from the model. Adjusted ORs
and 95% CIs were calculated with logistic regression models.
Statistical significance was taken at a P value <0.05.
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Results |
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Characteristics of the Study Population
Table 1
shows the demographic
characteristics of the study sample analyzed as a whole and
stratified according to the presence or absence of a first-degree
relative’s history of myocardial infarction. The 2 groups differed
with respect to median age (P<0.001), total
cholesterol (P<0.001), plasma fibrinogen levels
(P=0.007), and BMI (P=0.036). In addition, the
group whose first-degree relatives had suffered a myocardial infarction
(n=181) had a significantly higher number of subjects who were
hypertensive(P<0.001), with CRP levels >0.33 mg/L
(P=0.017), and with a 4G/4G PAI-1 genotype
(P=0.003). There was no difference between the groups with
respect to sex, alcohol consumption, cigarette smoking,
triglycerides, PAI-1 antigen, and ACE I/D polymorphism.
The genotype frequencies of the fibrinogen Bß-chain GA
-455 polymorphism (P=0.080) approximated a
statistically significant value. Pearson’s coefficients showed a close
correlation between each of the following: plasma fibrinogen, age, BMI,
total cholesterol, PAI-1 antigen, and
triglycerides (P always <0.001), as well as
among subjects with (P always <0.05) and those without
(P always <0.02) a family history of myocardial
infarction.
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Genotype frequencies of the PAI-1 4G/5G, ACE I/D, and
fibrinogen Bß-chain GA -455 gene polymorphisms and the
allele frequencies calculated were similar to those observed in
samples from the same region15 22 23 24 and in other white
samples19 25 26 27 and did not differ from those predicted
by Hardy-Weinberg equilibrium (PAI-1 4G 49.8, 95% CI 47.7 to 51.9;
PAI-1 5G 50.2, 95% CI 48.1 to 52.3; ACE D 65.2, 95% CI 63.2 to 67.2;
ACE I 35.1, 95% CI 33.1 to 37.1; fibrinogen Bß-chain G 79.5, 95% CI
77.8 to 81.2; and fibrinogen Bß-chain A 20.5, 95% CI 18.8 to 22.2).
When stratified according to a family history of myocardial infarction,
no difference was found as to ACE I/D and fibrinogen Bß-chain GA
-455 gene polymorphisms (genotype and allele
distributions). In contrast, subjects whose first-degree relatives had
suffered a myocardial infarction showed a significantly higher
frequency of the PAI-1 4G allele (n=201, 55.5% in subjects with;
n=843, 48.6% in those without such family history; OR 1.32, 95% CI
1.05 to 1.66, P=0.020). The PAI-1 4G/4G genotype
behaved similarly (n=62, 34.3% in subjects with; n=206, 23.8% in
those without a positive family history; OR 1.67, 95% CI 1.18 to 2.36,
P=0.003).
CRP Levels and Environmental and Genetic Risk Factors
When the sample was analyzed according to CRP levels
(Table 2), subjects whose levels were
>0.33 mg/L turned out to be more often older, hypertensive,
overweight, hyperlipidemic, and carriers of high plasma
levels of fibrinogen and PAI-1 antigen than subjects with CRP levels
below this cutoff value. A lower frequency of ACE DD carriers was
observed among subjects whose first-degree relatives had suffered a
myocardial infarction (Table 2). In addition, the percentage of
subjects with first-degree relatives who had suffered a myocardial
infarction was 1.5- to 2-fold higher in subjects with CRP levels >0.33
mg/L than in those with lower circulating concentrations of this
variable (16.4% and 26.0%, respectively, P=0.017). The
latter observation was further analyzed in a multiple
regression analysis (Table 3).
After adjustment for age (in years), total cholesterol (in
millimoles per liter), and PAI-1 4G/4G carrier status (yes/no), the
adjusted OR for subjects with CRP levels >0.33 mg/L was 1.75 (95% CI
1.05 to 2.91). The prevalence risk estimates for a 1-mmol/L increase in
total cholesterol and for carriers of the PAI-1 4G/4G
genotype were 1.35 (95% CI 1.11 to 1.65) and 1.72 (95% CI
1.20 to 2.45), respectively. A significant relationship between
first-degree family history of myocardial infarction and age was also
observed (OR 1.03, 95% CI 1.01 to 1.05).
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Logistic regression models performed with interaction terms excluded
any interaction between CRP and age (P=0.862), total
cholesterol (P=0.192), and PAI-1 4G/4G carrier
status (P=0.913). The effects of CRP and age (or PAI-1 4G/4G
carrier status) on the association with a first-degree relative
with a history of myocardial infarction was additive. The association
was significantly stronger with increasing age, especially in subjects
whose CRP levels were >0.33 mg/L (Figure 1). Likewise, the 4G/4G subset exhibited
a significantly higher prevalence OR, with a further increase in risk
estimate among subjects with CRP levels >0.33 mg/L (Figure 2). When the subjects were stratified
according to the median value of total cholesterol
(4.87 mmol/L), a significantly increased OR was observed
especially in the subset with CRP levels >0.33 mg/L (Figure 3).
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P<0.005.
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Discussion |
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Twin studies have documented an important genetic component in the pathogenesis of coronary artery disease.28 29 The familial aggregation of risk factors for coronary artery disease suggests that in addition to environmental factors such as lifestyle habits, genetic factors play a significant role in determining their phenotypic expression.30 This implies that the susceptibility to atherothrombosis is largely accounted for by the clustering of several, possibly inherited, risk factors.31 In the present setting, the PAI-1 4G/5G polymorphism—but not the fibrinogen Bß-chain G
A -455 and ACE
I/D polymorphisms—identified the offspring of subjects with a
history of myocardial infarction (crude OR 1.66). This finding is in
agreement with a previous report32 but disputes other
studies.6 7 These inconsistencies may reflect differences
in the genetic background of different ethnic groups. However, the
possibility of a play of chance cannot be ruled out by the present
data. One should also consider that the calculated ORs only reflect the
association between a set of variables and a family history of
myocardial infarction. Part of this risk may be mediated by other risk
factors that have an important genetic component, eg, high blood
pressure and diabetes mellitus.
In addition to genetic factors, the increased risk associated with a
family history of myocardial infarction is currently attributed to the
environmental factors that are more closely shared by individuals
belonging to the same household. CRP levels become raised with age,
BMI, and smoking habit.13 In our population, subjects
whose CRP levels were >0.33 mg/L but differed for total
cholesterol, triglycerides, PAI-1 antigen, and
fibrinogen were more frequently hypertensive and had a higher BMI
compared with subjects carrying CRP levels <0.33 mg/L (Table 2
). The subsets with CRP above or below 0.33 mg/L also differed
for median age (Table 2). In the present study, BMI, total
cholesterol, triglycerides, plasma fibrinogen,
and PAI-1 antigen values increased with increasing age. The age of the
relatives may account for the difference between the 2 groups, as older
subjects obviously have older relatives. However, age was not the most
significant variable associated with a family history of myocardial
infarction in our setting (Table 3). Thus, factors other than
age are likely to play a role in this relationship. In a multiple
regression model, the association between CRP and a positive family
history was independent of established risk factors, a significant
excess (adjusted OR 1.75) of a family history being present in
carriers of CRP levels >0.33 mg/L in the present setting.
Moreover, although logistic regression analysis eliminated the
association between plasma fibrinogen, hypertension, and positive
family history, it had only minor effects on the association between a
family history of myocardial infarction and CRP (Table 3).
Higher levels of CRP may be a cumulative indicator of the effect of
cardiovascular risk factors, ie, hypertension, obesity,
and hyperlipidemia.
In the present report, raised CRP concentrations enhanced the prevalence ORs of genetic as much as of environmental variables. Three-dimensional analysis of prevalence rates of family history, CRP, and age revealed a significant prevalence risk estimate for subjects with CRP levels >0.33 mg/L from the second to the fourth quartile of age. Likewise, a nearly 4-fold increase in OR was observed among individuals carrying the PAI-1 4G/4G genotype with CRP >0.33 mg/L compared with non-4G/4G subjects with CRP <0.33 mg/L. When the effect of total cholesterol was considered, a significant association with family history was mainly observed in subjects whose CRP levels were >0.33 mg/L.
A possible limitation of the present investigation was the collection of clinical data by a questionnaire. However, in the Tromsø Heart Study, there was a 78% agreement between a self-reported history of myocardial infarction in first-degree relatives and physician’s records, hospital records, and death certificates.33 Such agreement was >86% in an Australian Study.34 In the Tecumseh Community Health Study35 as well as in the study by Badenhop et al,7 underreporting of coronary events was more likely to occur than overreporting. In our study, information was collected by a well-trained staff and was limited to definite coronary ischemic events according to the World Health Organization questionnaire. This questionnaire has a specificity and a sensitivity of 91% and 81%, respectively, for angina pectoris; 91% and 87%, respectively, for myocardial infarction; and 100% and 92%, respectively, for intermittent claudication.36 Any inaccuracy would tend to lower rather than enhance risk estimates of a positive family history.
The mechanisms by which CRP levels are related to coronary
artery disease37 are unclear. Vascular injury is an
inflammatory and proliferative event, possibly enhanced by smoking
and/or activation of the immune system (infection, immune disorders,
etc).38 39 Elevated antibody titers against a variety of
microorganisms (eg, cytomegalovirus, Chlamydia) have been
observed in patients with coronary artery
disease.40 41 It is conceivable that an elevated CRP
level is a nonspecific but very sensitive marker of the inflammatory
response to the injury. Similar to fibrinogen and PAI-1, CRP is an
acute-phase reactant. Genetic determinants have been shown to be
particularly relevant in the regulation of plasma fibrinogen and PAI-1
levels. Such regulation is unlikely to involve the molecular variations
so far explored in the genes coding for fibrinogen and
PAI-1.42 This implies that molecular variations of the
genes playing a role in the acute-phase reaction (eg, interleukins like
interleukin-6 and monokines like tumor necrosis factor-
) should be
taken into account, and their clinical impact should be explored with
emphasis on the present data. However, within families, it is
conceivable that the relatives shared, beyond the genetic array, the
same environmental risk factors, BMI and smoking habit, being related
to CRP concentrations.13 Epidemiologists have drawn
attention to the importance of social class as an important risk factor
in determining health and illness.43 Differences in
socioeconomic status may explain, at least partially, the findings
obtained in the present cohort. To fully understand the relative
importance of genetic/environmental factors behind this association, it
would be necessary to evaluate the risk factors among relatives also.
We do not have data on these variables for the relatives at the
time of their myocardial infarction. Thus, it was not possible to
further address the importance of the relationships we found.
In a large population of first-degree relatives, these results showed an important link between raised levels of CRP and a family history of myocardial infarction. Such an association was independent of the established risk factors for myocardial infarction. The offspring of patients with severe coronary artery disease often exhibits an aggregation of risk factors.44 45 Whether an index combining measurements of CRP and risk factor(s) would be a better marker than either variable evaluated alone needs to be evaluated in prospective studies.
Received April 26, 1999; accepted July 1, 1999.
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