Download Genetics and heritability of coronary artery disease and myocardial

Clin Res Cardiol 95:1–7 (2006)
DOI 10.1007/s00392-006-0447-y
B. Mayer
J. Erdmann
H. Schunkert
REVIEW
Genetics and heritability
of coronary artery disease
and myocardial infarction
A positive family history is frequently reported by
patients with coronary artery disease (CAD) or myocardial infarction. For risk stratification, it is crucial
to distinguish between accidental reoccurrence of
sporadic cases and cases with a true heritable component of the conditions. A familial predisposition is
assumed when a myocardial infarction is diagnosed
by a male first degree relative before the 55th year of
life or a female first degree relative before the 65th
year of life. The current manuscript reviews major
studies from which a familial risk of CAD or myocardial infarction can be inferred. Moreover, a brief
overview summarizes the current results of molecular genetic research on chromosomal loci and genes
relevant for CAD and myocardial infarction.
n Key words Myocardial infarction –
coronary artery disease – heritability – genetics
Received: 8 May 2006
Accepted: 11 August 2006
Published online: 10 October 2006
Dr. Björn Mayer, MD ()) · Jeanette Erdmann, PhD
Heribert Schunkert, MD
Universitätsklinikum Schleswig-Holstein (UKSH)
Campus Lübeck
Medizinische Klinik II
Ratzeburger Allee 160
23538 Lübeck, Germany
Fax: +49-4 51 / 5 00 23 63
Tel.: +49-4 51 / 5 00 24 21
E-Mail: [email protected]
Epidemiology of CAD and myocardial
Within Europe, the incidence of myocardial infarction
shows a prominent north-south gradient. Whereas
500 cases per year out of 100 000 inhabitants are observed in Finland, only 125/100 000 cases are recorded
in South Eastern Europe [1]. Differences in life style,
e.g., dietary and smoking habits as well as climate
are thought to be responsible for this regional distribution [1]. In addition, the prevalence of lipid metabolism disorders is increased in Scandinavian countries [2]. The INTERHEART Study concluded that vascular risk factors explain just under 90% of the risk of
myocardial infarction. This may imply that significance of the hereditary risk is low [3]. However, this
apparently high figure neglects to consider that risk
factors such as hypertension, hypercholesterolemia,
diabetes mellitus and even addictive behavior (smoking) are crucially affected by genetic factors [4–6].
Moreover, multiethnic comparisons may largely underestimate factors that are of relevance for the variability within an ethnic group.
Thus, the variability in the manifestation of MI
and CAD cannot be explained exclusively in terms
of the variations in the frequency of vascular risk
factors [7–14], indicating the high clinical importance of ethnic or genetic differences in the pathogenesis of the conditions [1].
The familial risk of CAD
and myocardial infarction
In the setting of a large epidemiological survey 35%
of all patients with CAD fulfilled the criteria for a
positive family history of the disease. This high
prevalence underscores the quantitative significance
of this risk factor [15].
2
Clinical Research in Cardiology, Volume 95, Number a (2006)
© Steinkopff Verlag 2006
Fig. 1 The relative increase in risk of myocardial
infarction/CAD is shown in relation to different
familial susceptibilities. The risk for identical and
nonidentical twins is based on the hypothesis
that the partner twin had died of myocardial infarction at an age of 55 years
The Framingham Heart Study demonstrated that
a positive family history of a parent or a sibling is a
risk factor for CAD [16, 17]. The excessive risk related to a positive family history was independent of
all other risk factors tested. Moreover, the familial
risk was found to be greater the lower the age at
first manifestation of disease was in the affected
family members [18]. The analysis of a genealogical
data bank from Utah (USA), in which data from
more than 2.2 million persons were collected over
the past 100 years, revealed a significantly raised
risk of myocardial infarction even when second degree relatives were affected before the 65th year of
life [19]. The associated relative increase in risk of
myocardial infarction is lower than for first degree
relatives, but again not explained by traditional risk
factors [19].
In families with a repeated occurrence of CAD,
vascular risk factors are also found with increased
frequency [20]. Furthermore, lifestyle habits associated with a raised incidence of CAD (e.g., smoking) are more frequently encountered in the families
[7]. The 2nd Northwick Park Heart Study (NPHS-II)
documented that a positive family history of CAD
entails an increase in risk by the factor 1.65 even
after adjustment for multiple risk factors [15, 18].
Likewise, the Reykjavik Cohort Study on 10 062
women and 9328 men showed that the increase in
risk in terms of the positive family history remains
high with a factor of 1.5 to 1.8 even after adjustment
of multiple risk factors [21].
The Swedish Twin Study broadens our knowledge
concerning the heritability of myocardial infarction
by comparing the 10-year risk between monozygotic
and dizygotic twins [22]. The relative increase in
risk for an apparently healthy twin to die from myocardial infarction was 2.6 in dizygotic twins who can
be regarded genetically as siblings. The risk increased by the factor 8.1 if a monozygotic, i.e., genetically identical, twin was affected (Fig. 1).
Heritability of left main disease
We recently demonstrated that the heritability estimates of CAD depend, in part, on the pattern of coronary morphology. Particularly, left main disease
and proximal coronary stenoses were observed to carry a high risk for reoccurrence in affected sibling pairs
(Fig. 2) [23]. A highly significant heritability was
found for ostial and proximal coronary stenoses, respectively (h2 = 0.32; p = 0.008 and h2 = 0.30; p = 0.01),
Fig. 2 Heritability of coronary morphology in myocardial infarction of sibling
pairs in different cardiac vessel regions – regions with significant heritability
are marked
B. Mayer et al.
Genetics and heritability of coronary artery disease and myocardial infarction
3
whereas a distal involvement did not show any heritability.
In addition, significant heritability of extraluminal calcification and the ectatic form of coronary
sclerosis was demonstrated in the sibling pairs with
CAD [23]. Further investigations of our group replicated these results in a second sample [24] and substantiate familial risk prediction on the basis of the
coronary morphology findings.
Molecular genetics of CAD
and myocardial infarction
Genes associated with complex human diseases such
as CAD or myocardial infarction may be grouped
into two major categories: susceptibility genes and
disease-causing genes. Susceptibility genes are genes
that increase or decrease the risk of disease manifestation. These genes may or may not contribute to
the variability of the disease in the context of other
genetic and environmental factors. Genetic variants
of these genes are present, albeit with different frequency, in both, apparently healthy and affected individuals within a population. Disease-causing genes
are the genes that are, if mutated, directly responsible for the pathogenesis of disease. In this case, mutations can be clearly defined as the primary cause
of the disease. An unequivocal diagnosis can be
made for such mutations on the basis of a molecular
analysis (as a rule, identification of the nucleotide
sequence of the gene). However, the search and subsequent detailed sequence analysis of a disease causing gene is more difficult than screening for frequent
variants in susceptibility genes. Moreover, on the
population level disease causing genes for myocardial infarction may be extremely rare, whereas susceptibility genes may be highly prevalent. Certain
genetic variants of these genes entail a higher risk of
disease, but do not automatically induce disease,
since further genetic and non-genetic factors also
modulate the risk of disease. The investigation of
only one susceptibility gene is hence not sufficient
in order to fully appraise the risk of disease.
In the case of myocardial infarction, it must be
assumed that several predisposing susceptibility factors located in one or several genes interact. Such interactions may or may not result in the manifestation of disease in conjunction with corresponding
environmental factors in an insidious process. Myocardial infarction can thus be considered as a multifactorial polygenic disease (Fig. 3). The effect of a
single variant may be small. This gives rise to major
difficulties in the identification and clinical weighting of possibly contributing gene defects or genetic
Fig. 3 Schematic representation of the multifactorial genesis of myocardial
infarction caused by vascular risk factors, environmental factors and various
genetic factors
variants. On the one hand, respective molecular-genetic analyses must be carried out in enormously
large populations to identify functional variants
which may affect the risk of myocardial infarction or
CAD. On the other hand, the cardiovascular risk
profile certainly varies from subject to subject
further complicating the analysis. Likewise, genetic
risk alleles for hypercholesterolemia, hypertension,
and diabetes mellitus may interact in a complex
fashion further complicating the scenario [25–27].
Analyses of candidate genes
in myocardial infarction and CAD
Candidate genes are usually chosen on the basis of
pathophysiological considerations. For example, the
link between a polymorphism in the gene of the angiotensin-converting enzyme and myocardial infarction initiated this field in the year 1992 [28]. Since
then, multiple investigators have tested the functional
relevance of this variant [29, 30]. The conclusion of
these studies is that an ACE I/D polymorphism may
result in a small risk increase for myocardial infarction and left ventricular hypertrophy [31, 32].
Up to now, nearly 5000 studies have analyzed candidate genes in relation to myocardial infarction and
CAD (pubmed search by myocardial infarction and
association study, myocardial infarction and polymorphism, and coronary artery disease and polymorphism in December 2005). According to this
search a total of 329 variants from 152 candidate
genes have been analyzed. Positive and reproducible
findings were shown for 192 polymorphisms from
102 genes in at least two independent populations
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Clinical Research in Cardiology, Volume 95, Number a (2006)
© Steinkopff Verlag 2006
Fig. 4 Total number of studies analyzing candidate genes in relation to myocardial infarction
and CAD since 1990 (left side). Definition of reproducible findings (right side)
Fig. 5 Schematic representation of the human
genome. Chromosomal CAD/myocardial infarction
gene regions (red) and myocardial infarction
genes (green) identified so far by genome-wide
analyses
(Fig. 4). These genes represent different signal transduction cascades. Most studies have investigated the
renin-angiotensin system [28], lipid metabolism
[33], inflammation [34–37] and the clotting cascade
[38]. However, both positive and negative associations were found for nearly all variants. Some of the
discrepant results can be explained by relatively
small study populations with the possibility of false
positive association. Moreover, ethnic variation must
be taken into consideration in the appraisal of divergent results. Finally, the functional relevance of most
polymorphisms still needs demonstration since, alternatively, these variants may only display association with disease because of their close neighborhood or linkage disequilibrium, with responsible
mutations. According to present-day knowledge,
none of these candidate gene variants allows genetic
risk prediction with sufficient reproducibility for
myocardial infarction or CAD in the clinical setting.
Genome-wide analyses
in myocardial infarction and CAD
The approach in genome-wide analysis is free of any
hypothesis as to whether any given gene may predispose to the phenotype. By analyzing genetic markers
located at short intervals throughout the entire human
genome, regions can be identified in which a gene
causing disease is localized with a high probability.
In a study conducted by our group a locus on human
chromosome 14 was identified [8]. Figure 5 shows a
schematic overview of the entire human genome. Regions displaying linkage for CAD or myocardial infarction and the genes so far identified with this methodological approach are marked [39]. These chromosomal loci require further studies in order to identify
the disease causing genes.
B. Mayer et al.
Genetics and heritability of coronary artery disease and myocardial infarction
5
Fig. 6 Examples of myocardial infarction extended families of the German MI family
study; men are encoded with squares, women
with circles, affected individuals in black, unaffected individuals are bordered and deceased persons are crossed through
Autosomal dominant inheritance
of myocardial infarction
Wang and co-workers recently succeeded in identifying a mutation in the gene of the transcription factor MEF2A in a family with an autosomal-dominant
form of myocardial infarction. For the first time, a
familial genetic defect was shown to give rise to
myocardial infarction in humans [40]. A 21-bp deletion in the gene appeared to result in alterations of
the coronary walls, thus favoring plaque deposition,
which ultimately may lead to myocardial infarction.
Interestingly, the same pathway is crucial in preventing apoptosis in endothelial cells and death due to
vascular obstruction in mice [41]. However, at the
present time the significance of this gene with respect to the heritability in humans is still unclear
given the multifactorial background of the disease
[42–44].
In everyday clinical routine, extremely raised incidences of myocardial infarction are often recorded
in the history of multiple families. With the exception of the family studied by Wang et al. [28], many
of such families could not be systematically analyzed
genetically due to the high lethality of the disease.
In the German myocardial infarction family study,
we specifically looked for myocardial infarction in
large families with at least four surviving affected individuals. We succeeded in systematically interviewing members of 19 such families and investigating
them in detail [45]. On the basis of family pedigree
analysis and statistical simulations, the presence of
an autosomal dominant inheritance pattern was
probable in all cases. The family pedigrees will
hopefully extend the knowledge of genes involved in
myocardial infarction (Fig. 6).
Outlook
Myocardial infarction and CAD are diseases which
occur with increased frequency in certain families.
About one – third of all patients with myocardial infarction or CAD fulfill the criteria of a positive family history of the disease. In clinical practice this important information needs to be included for risk
stratification particularly in unaffected individuals,
as suggested by the PROCAM score [46]. Moreover,
the information on coronary morphology might become an important additional characteristic for disease prediction in families with CAD or premature
myocardial infarction.
It is obvious that multiple genetic factors make a
crucial contribution to the pathogenesis of the conditions. However, current scientific knowledge is not
sufficient to recommend routine use of genetic test
procedures for prediction of risk. Nevertheless, the
technical possibilities for genetic testing are increasing with enormous speed. In fact, it is now feasible
to analyze 500 000 gene variants on a single DNA
chip within minutes. As soon as the functional relevance of some of these polymorphisms can be estimated, the prediction of CAD or myocardial infarction may improve considerably. Such test procedures
which were regarded as visionary years ago now appear conceivable for the near future provided that
molecular genetics continues its rapid technological
development. The European commission and the
NIH currently stimulating the field by enormous
funding (http://fp6.cordis.lu/).
n Acknowledgment We wish to thank all participants of the German MI registry. The work on the genetics of coronary artery disease and myocardial infarction is supported by the Deutsche For-
Clinical Research in Cardiology, Volume 95, Number a (2006)
© Steinkopff Verlag 2006
6
schungsgemeinschaft (DFG Schu 672/9-1, 672/10-1, 672/12-1, 672/
14-1, DFG He1921/9-1), the Ernst- and Berta-Grimmke-Stiftung,
the Wilhelm-Vaillant-Stiftung, the Deutsche Stiftung für Herzforschung and the Bundesministerium für Bildung und Forschung
(National Genome Network 2; 01GS0418). Moreover, we wish to
thank the European Union (Sixth Framework Programme) and
the NIH for enormous funding.
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