Genetic polymorphisms of inflammatory cytokines and

myocardial infarction in the elderly

Fabiola Olivieri a,*, Roberto Antonicelli b, Maurizio Cardelli a, Francesca Marchegiani a,Luca Cavallone a, Eugenio Mocchegiani c, Claudio Franceschi a,d,e

a Centre of Genetic and Molecular Biology, Research Department, Italian National Research Centre on Aging (INRCA), Ancona, Italyb Coronary Care Unit, INRCA Hospital, Ancona, Italy

c Centre of Immunology (Sect: Nutrition, Immunity, Ageing), Research Department, INRCA, Ancona, Italyd Department of Experimental Pathology, University of Bologna, Bologna, Italy

e CIG, Interdipartimental Centre ‘‘L. Galvani’’, University of Bologna, Bologna, Italy

Available online 6 March 2006

Abstract

Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing

burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially

in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent

up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory

diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and

environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk

factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms

associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might

play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in

association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these

polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important

inflammatory cytokines (IL-6, TNF-a, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of

MI, with a special focus in ageing population.

# 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Myocardial infarction; IL-6; IL-10; TNF-a; Polymorphism; Ageing

www.elsevier.com/locate/mechagedev

Mechanisms of Ageing and Development 127 (2006) 552–559

1. Introduction

Cardiovascular diseases (CVD) and their compliances, such

as myocardial infarction (MI) are the leading worldwide causes

of morbidity and death in Western societies contributing to

large sections of morbidity and mortality in old people. The

prevention of this disease is one of the most important public

health goal. MI is caused by the interactions between genetic

and environmental factors (Marenberg et al., 1994). Although

many epidemiological studies have suggested that several

genetic variants increased the risk of MI, the context

* Corresponding author. Tel.: +39 071 8004322; fax: +39 071 206791.

E-mail address: b.molecolare@inrca.it (F. Olivieri).

0047-6374/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.mad.2006.01.013

dependency, i.e. the importance of environmental factors (life

style, physical activity, smoking and dietary habits, traffic

noise) in influencing genetic risk, is now becoming evident

(Babisch et al., 2005; Hergens et al., 2005; Nanchahal et al.,

2005). The main objective of genetic research into MI is to

provide a complete risk assessment, complementing the well-

studied traditional clinical and biochemical risk factors. In fact

the incidence of MI increases additively in function of the

number of conventional risk factors, including arterial

hypertension, diabetes mellitus (DM) and hypercholesterole-

mia. Although each risk factor itself is partially under genetic

control, several studies suggest the existence of additional

susceptibility genes (Broeckel et al., 2002; Wang, 2005).

Unravelling the role played by functional gene polymorphisms

in determining MI risks, it is possible to better understand the

F. Olivieri et al. / Mechanisms of Ageing and Development 127 (2006) 552–559 553

key metabolic and physiology pathways involved in the

appearance of some diseases or to escape them, in particular in

old age because CVD and MI are the major cause of disability

and mortality in elderly. Moreover, the identification of new

molecules (implicated in the relevant metabolic pathways) may

in turn lead to identify the potential targets for therapeutic

interventions or preventions. Thus, a possible innovative

approach for MI prevention is to identify disease-susceptibility

genes and the interaction between genes and environmental

factors, providing the basis for personalized lifestyle modifica-

tion and improved pharmacological therapy.

There is growing evidence that inflammation plays a central

role in the pathogenesis of atherosclerosis, coronary artery

disease (CAD) and its compliances, such as MI, which are in

turn widely considered to be related to an inflammatory process

(Ross, 1999; Lindahl et al., 2000; Frangogiannis et al., 2002).

The inflammation appears to be involved in all stages of

atherosclerotic developments, including oxidative damage

(Berliner et al., 1995), cell proliferation and plaque evolution

and destabilization (Buja and Willerson, 1994; Mauriello et al.,

2005; Ingelsson et al., 2005; Maier et al., 2005). The

pathogenetic role of inflammatory gene polymorphisms in

the most severe complication of atherosclerosis, such as MI, is

still under investigation. In spite of mounting evidence

implicating a group of inflammation-related markers and MI,

the interactions with environmental factors as well as their

mechanisms are still poorly understood (Woods et al., 2000;

Wannamethee et al., 2005). While the inflammation in the

vessel wall may be a consequence of some environmental

factors (bacterial or viral infection, tissue injury, dietary habits,

etc.), it is also possible that genetic factors may contribute to an

abnormal or exaggerated inflammatory response, as it occurs in

aging process.

Some years ago, we proposed to call this peculiar chronic

inflammatory status present during aging as ‘‘inflamm-aging’’,

which is characterised by the up-regulation of a variety of anti-

stress responses at cellular and molecular levels (Franceschi

et al., 2000). This phenomenon is the consequence of the ability

of the body to adapt to and counteract the effects of a variety of

stressors, which causes the accumulation of molecular and

cellular scars (De Martinis et al., 2005). ‘‘Inflamm-aging’’ is

considered the common and most important driving force of

age-related pathologies, such as atherosclerosis, neurodegen-

eration, DM and sarcopenia, among others, all of them share an

inflammatory pathogenesis. ‘‘Inflamm-aging’’ appears to be

under genetic control, is detrimental for longevity and is more

evident in men than in women (Franceschi et al., 2000, 2005;

De Martinis et al., 2005; Licastro et al., 2005).

Recent study in elderly people showed that some

inflammatory cytokines (IL-6, TNF-a and IL-10) were

predictors for cardiovascular outcome (Kritchevsky et al.,

2005; Antonicelli et al., 2005a,b; Stephens and Humphries,

2003). These observations suggest a potential genetic

component of inflammatory cardiovascular risk factors

especially in the aged people. In fact, polymorphisms

apparently neutral in young age may play an important role

in old and very old age, especially in phenomena related to the

production of pro- and anti-inflammatory cytokines (IL-6, IL-

10 and TNF-a) as well as to those ones involved in the

capability of cells to cope with oxidative stress and to undergo

apoptosis (Bonafe et al., 2001, 2004). Furthermore, the genetic

background of inflammatory genes may influence the longevity

of human species by affecting inflammatory responses

associated to some age-related diseases, such as CHD (Bonafe

et al., 2001).

Although a large number of studies of pro- and anti-

inflammatory gene variants in association with MI exists, the

emerging data are quite conflicting and do not provide

definitive evidence for a role of these gene variants in the

pathogenesis of MI.

In this paper we review the evidence for a possible role of

genetic polymorphisms of most important inflammatory

markers in the physiopathology of MI in order to better

understand the causes of MI and subsequently to develop more

aggressive therapies in elderly subjects, reducing disability and

mortality (Kritchevsky et al., 2005), and at the same time, to

locate specific inflammatory genes that may be of a great

benefit in young–adult-age and dangerous in elderly (antagonist

pleiotropy theory of ageing) (Franceschi et al., 2000). As a final

result, favourable inflammatory genes for healthy ageing and

longevity may be also found.

2. IL-6

IL-6 is a cytokine with both pro- and anti-inflammatory

effects acting both at local and systematic levels. IL-6 acts on

proliferation and differentiation of B and T lymphocytes and

affects the hepatic acute phase response, including CRP, PAI-1

and fibrinogen production (Xing et al., 1998). IL-6 activates the

endothelium, provokes leukocytes recruitment to the vessel

wall and stimulates vascular smooth muscle cell proliferation:

all effects that lead to plaque growth and/or instability in

atherosclerosis (Woods et al., 2000; Lindmark et al., 2001).

The genetic background of IL-6 may be helpful in

identifying subjects with increased or decrease risk in

developing MI. One of several polymorphic sites in IL-6 locus

was frequently used for genetic association studies. The

biallelic G to C polymorphism, located in the promoter region

at position �174 (IL-6 �174 G > C), results in different IL-6

transcription rate in vitro and circulating IL-6 levels in vivo

(Fishman et al., 1998; Bonafe et al., 2001; Olivieri et al., 2002).

Since elevated IL-6 plasma levels have been implicated in the

pathogenesis of CHD, this functional polymorphism was

analysed in several groups of patients affected by MI. Some

groups have showed the influence of this IL-6 polymorphism as

predictor for death or plaque instability in old patients affected

by CHD or for longevity (Bonafe et al., 2001; Cesari et al.,

2003).

A recent our study reports that the IL-6 �174 GG genotype

is a strong predictor of cardiovascular death after one year of

follow-up in old male patients affected by acute coronary

syndrome (ACS), such as MI and unstable angina (Antonicelli

et al., 2005a,b). Taking into account that the atherosclerosis

process is generally the pathologic background for the

F. Olivieri et al. / Mechanisms of Ageing and Development 127 (2006) 552–559554

appearance of MI (Ross, 1999), old atherosclerotic patients

with IL-6 �174 GG genotype showed a higher degree of

inflammation (increased IL-6 and TNF-a and decreased IL-10),

enhanced stress related protein production and a major risk for

plaque rupture, and therefore possible appearance of MI, when

compared to patients with the CC or CG (C+) genotypes

(Giacconi et al., 2004).

Moreover, elderly and long-lived healthy men had similar

G allele frequency, whilst the frequency of G allele was

decreased in centenarian males, who display a higher IL-6

serum levels with respect to C+ subjects. This finding suggests

that old individuals, i.e. GG men, genetically predisposed to

produce high levels of IL-6 had a reduced capacity to reach the

extreme limits of human life-span (Bonafe et al., 2001). From

a demographic point of view, the decreased proportion of GG

men in centenarians could be thus attributed to a higher

mortality of GG men for CHD (Franceschi et al., 2005).

Thus, the chronic inflammation by high and persistent levels

of IL-6 observed in old men with IL-6 �174 GG genotype is

associated with a higher risk of atherosclerosis and its

complications, such as MI, which is in turn detrimental for

longevity.

However, a general consensus does not exist in promoting

IL-6 �174 GG carriers patients as more at risk for MI. Some

papers report that C allele is associated with mild or moderate

increase risk of MI (Jenny et al., 2002; Georges et al., 2001).

Moreover, it was documented that the rare IL-6 �174C allele

showed a regional difference in its frequency. Indeed, one study

reports that subjects living in the North of Europe and carrying

IL-6�174C allele display a more reduced risk of MI than those

ones living in the South of Europe (Kelberman et al., 2004).

Conversely, several papers report no association between IL-6

�174 G > C polymorphism and risk of CAD or MI (Burzotta

et al., 2001; Yamada et al., 2002; Nauck et al., 2002; Bennermo

et al., 2004; Latkovskis et al., 2004; Lieb et al., 2004).

Moreover, some authors have reported that the IL-6 �174

G > C polymorphism in ACS condition did not influence the

increased inflammatory profile by higher levels of IL-6, despite

of elevated numbers of white blood cells (WBCs) (Byrne et al.,

2004).

All these discrepancies may be largely due to the ethnic

differences or environmental undefined factors among patients

enrolled in different European Countries (Franceschi et al.,

2005). The discrepancies may be also related to the study of

single polymorphism rather than the association of more

polymorphisms of proteins related to IL-6 and inflammation.

Indeed it has bee reported that the association of more

polymorphisms of genes involved in the same regulatory

network gives a more complete picture of ‘‘robust gene’’ both

for longevity and for the appearance of age-related diseases

(Carlson et al., 2004). Indeed, a study performed with the

association of more polymorphisms has revealed that subjects

with the IL-6 �174C allele, IL-1b C allele and APOEe 4 allele

display a mild or moderate increased risk of MI, suggesting the

existence of a functional interaction among IL-6, IL-1b and

APOE in affecting the immuno-pathogenetic mechanisms of

MI in elderly men (Licastro et al., 2004).

An interesting point related to IL-6 �174 C > G poly-

morphism is the different responsiveness to pharmacological

treatment in MI patients. A treatment with Pravastatin, which is

an effective drug in reducing CHD patients morbidity and

mortality, in CC homozygotes subjects reduced significantly

the risk of MI (Basso et al., 2002; Reiner et al., 2005).

However, despite all these controversial data regarding the

clinical relevance of IL-6 gene polymorphisms, several studies

have assigned to IL-6 a pivotal role in controlling the magnitude

of the inflammatory status in presence of cardiovascular

diseases, including MI (Lindmark et al., 2001; Biasucci et al.,

1999; Bennermo et al., 2004). Anyway, more studies are still

required because of the great inter-individual genetic variability

in IL-6 production in affecting MI susceptibility and the

subsequent prognosis as well as therapeutical intervention. In

this context, an intriguing point is related to the discovery

showing IL-6�174 polymorphism in affecting IL-6 gene at

transcriptional level in selected cell type (Terry et al., 2000).

This last finding is very relevant for future research because

some effects of IL-6 gene are mediated by specific transcrip-

tional factors, including nuclear factor kB (NF-kB) (Fishman

et al., 1998; Terry et al., 2000). Therefore, the discrepancy

observed in the association between IL-6 �174 polymorphism

and MI may be related to the genetic differences in IL-6

transcriptional factors (Hegazy et al., 2001).

In conclusion, the reason for the discrepancy of the data

regarding the association between the incidence or the

prognosis of MI and IL-6 �174 G > C polymorphism, is

unclear. The ethnic difference as well as the lifestyle and

cultural difference among the different population analysed in

the different studies could play a role, as well as other

unidentified factors. Large scale studies on many ethnic

population are needed to clarify this important topic.

3. TNF-a

Tumor necrosis factor (TNF) is another relevant cytokine in

the course of the inflammation process in CHD. This cytokine

has been localized in atheromatous plaques (Barath et al., 1990)

whereby it is thought to contribute to the progression of

atheroma by augmenting the local inflammatory response

(Vaddi et al., 1994). Further, TNF-a systemically affects a

number of mediators of atherosclerotic process, altering the

lipid homeostasis, enhancing insulin resistance and promoting

endothelial dysfunction (Fernandez-Real and Ricart, 2003).

High TNF-a plasma levels are associated with an increased risk

of CHD (Pai et al., 2004) and may be predictors of

cardiovascular events in older persons (Cesari et al., 2003).

Moreover, enhanced TNF-a gene expression is associated with

development of post-transplant CHD (Ueland et al., 2003).

A biallelic polymorphism within the promoter of TNF-a

locus, at the position �308, has been identified (Wilson et al.,

1992). This polymorphism plays an important functional role,

via zinc-dependent AP-2 transcription factor, because the TNF-

a �308 A allele is associated with higher constitutive and

inducible TNF-a levels (Wilson et al., 1997). Moreover the

TNF-a�308 locus has been found to be associated with several

F. Olivieri et al. / Mechanisms of Ageing and Development 127 (2006) 552–559 555

diseases, i.e. DM, in which the inflammation plays a

predominant role (Heijmans et al., 2002).

Recently, we analysed the TNF-a �308 polymorphism in

elderly patients affected by MI with ST-Elevation (STEMI) and

without ST-Elevation (NSTEMI). The TNF-a �308 AG + AA

genotypes (A + carriers) are more significantly represented in MI

patients affected by STEMI than in NSTEMI patients and healthy

controls. Furthermore, patients carrying TNF-a�308 AG + AA

genotypes displayed significant enhanced levels of the most

relevant biochemical myocardial ischaemia markers (Troponin I,

Creatine Kinase, Lactate Dehydrogenase and Mioglobin)

(Antonicelli et al., 2005a,b). These findings suggest that TNF-

a�308 polymorphism could play a key role in the pathogenesis

of cardiac ischaemic damage in old patients because more severe

ischaemic damages are observed in A + carriers.

Other authors suggested that the �308 TNF-a gene

polymorphism might contribute to CHD risk when associated

with some environmental factors (smoking habit, obesity and

dyslipidemia) (Padovani et al., 2000) or with DM (Vendrell

et al., 2003).

When TNF-a and -b polymorphisms were associated with

MI, some authors report that only TNF-b polymorphism is

linked to MI in a comprehensive genome-scan linkage analysis

in Japanese individuals but not in German population (Porto

et al., 2005). By contrast, other studies failed to find a

significant association between MI and TNF-a locus (Keso

et al., 2001; Koch et al., 2001). Although the emerging data also

for TNF gene locus, as reported above for IL-6, are quite

contradictory and do not provide definitive evidence for a

specific role of its genetic variants in MI pathogenesis, a recent

paper reports that TNF-a receptor 1 is one of the major

predictors both for mortality and new-onset of heart failure in

MI patients, confirming the importance of TNF-a and its

receptors in the pathogenesis and in the prognosis of MI

(Valgimigli et al., 2005).

However, also in this case, such as reported for IL-6, further

studies are required in order to give a solid conclusion.

4. IL-10

Interleukin-10 (IL-10) is a cytokine with anti-inflammatory

activity, limiting the inflammatory signal from monocytes and

macrophages, as well as B-cell-stimulating role (Moore et al.,

2001). IL-10 is expressed in human atherosclerotic plaques and

has several antiatherogenic effects. Among them, it inhibits the

adhesion of low density lipoproteins (LDL) to endothelium, and

down regulates the fibrinogen biosynthesis (Tedgui and Mallat,

2001). Of interest, IL-10 serum level decreases in ACS patients

(Smith et al., 2001; Tziakas et al., 2003; Wojakowski et al.,

2004) and it is inversely related to future events in patients with

MI (Seljeflot et al., 2004), suggesting an important anti-

inflammatory role in counterbalancing the pro-inflammatory

response (Okopien et al., 2002).

A functional polymorphism in the promoter region of IL-10

gene, such as IL-10�1082 G > A, was associated with the gene

expression and plasma levels of IL-10 (Turner et al., 1997; Kube

et al., 2001). However, few data exist regarding to the association

of this polymorphism with MI (Lio et al., 2004; Donger et al.,

2001). Recently, IL-10 �1082 G > A polymorphism was

investigated in a group of MI old male Italian patients, in

comparison with a control group and centenarian people (Lio

et al., 2004). The frequency of�1082 GG genotype carriers was

lower in old MI patients than in control subjects and oldest old

peoples. In particular, IL-10�1082 GG genotype as well as IL-

10 increased production are protective for MI and associated with

longevity, especially in men, suggesting that centenarians

possess some protective factors against cardiovascular diseases

(Lio et al., 2004). On the whole, increased IL-10 levels associated

with IL-10 �1082 GG genotype, might better control the

inflammatory response induced by chronic vessel damage and at

the same time reduced the risk of atherogenetic complication. As

a result, an increased chance of long life occurs (Lio et al., 2004).

A quite similar result was recently reported in patients

affected by systemic lupus erithemathosus (SLE), which is

pathology with an inflammatory background (Fei et al., 2004).

In SLE patients, the IL-10 �1087 GG genotype, associated

with a higher capacity in IL-10 production, is protective for

coronary vessels diseases (CVD) (Fei et al., 2004).

However, these last results contrast with previous papers

reporting no association of the IL-10 polymorphism with an

increased risk of MI (Donger et al., 2001), even when

functional polymorphisms for TNF-a and TNF-b are asso-

ciated (Koch et al., 2001; Koch et al., 2003).

Anyway, the association of IL-10 and TNF-a polymorph-

isms has been reported as fundamental for the longevity (Lio

et al., 2004). Therefore, even if few data are still available for

the IL-10 polymorphisms in CHD, there is no doubt of their

influence on the longevity, especially when associated with

TNF-a polymorphisms, confirming the pivotal role of IL-10 in

controlling the degree of the inflammatory status and

subsequently to reach health longevity (Lio et al., 2004).

5. CD 14 receptor and toll-like receptor 4 (TLR4)

The CD14 receptor is a pattern of recognition molecules

involved in the innate immune response against micro-

organisms and other exogenous and endogenous stress factors

(Finberg et al., 2004). The most important CD14 signalling co-

receptor is the toll-like receptor 4 (TLR4), which is a trans-

membrane receptor that mediates inflammatory responses by

bacterial endotoxins, and activates the nuclear factor kappaB

(NF-kappaB) pathway (Sabroe et al., 2005). Besides its role in

innate immunity and host defence, the proinflammatory

cytokines expressed upon TLR4/NF-kappaB pathway activa-

tion exert also proatherogenic effects. The CD14 receptor�260

C > T promoter and TLR4 299 A > G functional polymorph-

isms have been recently implicated in the development of

cardiovascular events, including MI, suggesting that the

genetically determined inflammatory response against patho-

gens or antigens may have a key role in atherogenesis and

subsequent acute cardiovascular events (Andreotti et al., 2002;

Arroyo-Espliguero et al., 2005). Different groups have reported

an association between CD14 receptor �260 C > T poly-

morphism and CHD (Arroyo-Espliguero et al., 2005). A recent

F. Olivieri et al. / Mechanisms of Ageing and Development 127 (2006) 552–559556

still unpublished study has shown that CD14 receptor�260 TT

old atherosclerotic subjects display an increased risk to develop

cerebral ischaemia and MI with respect to CC plus CT carriers.

Moreover, the CD14 �260 TT CHD patients showed increased

pro-inflammatory cytokines (IL6 and TNF-a) cholesterol levels

(Giacconi and Mocchegiani, unpublished results). These

findings altogether suggest that the CD 14 receptor poly-

morphism is implicated in the risk of worsening atherosclerosis

especially in elderly. However, some authors have reported no

association between CD14 receptor polymorphism and the risk

of MI (Zee et al., 2005; Longobardo et al., 2003).

Regarding to TLR4, recent studies found an association

between TLR4 genotype and risk of MI, suggesting that TLR4

genetic variants could potentially affect the susceptibility to MI

and, at the same time, the innate immunity, which is in turn

implicated in the pathogenesis of MI (Balistreri et al., 2004). It

was recently report that the frequency of TLR4 gene 299G

locus was decreased in a group of MI young patients respect to

healthy controls and oldest old people. As a consequence, the

TLR4 gene variant is of protection for MI and consequently for

health longevity (Balistreri et al., 2004). However, some

authors were not agree with this last results, suggesting that the

TLR4 299G allele is at risk of MI. Anyway, these papers focus

on the importance of environmental factors (pharmacological

treatments or smoking habit) in affecting TLR4 genetic variants

for MI. In particular, the TLR4 299G allele reduces the effect of

statin treatments against MI (Holloway et al., 2005) and

increases the risk of MI in smoking men (Edfeldt et al., 2004).

On the contrary, others studies failed to find a significant

association between TLR4 gene variant and risk of MI (Zee

et al., 2005).

In conclusion, the emerging data regarding the association

between TLR4 and CD 14 receptor polymorphisms and the

incidence and the prognosis of MI are still controversial.

However, the inflammatory status is at the base in controlling

the pathogenesis and the prognosis of MI. Further studies are

necessary in order to better clarify the specific role played by

these two polymorphisms in the assessment of the risk of MI

associated to environmental factors and to immune response.

6. Conclusion and future perspectives

Inflammation appears to be involved in all stages of

atherosclerotic development and compliances, including MI.

With advancing age, the inflammatory/immune response

Table 1

Polymorphisms associated or not with MI from different studies in the elderly

Polymorphism Association with MI

IL-6 �174 G > C Georges et al. (2001), Basso et al. (2002),

(2002), Kelberman et al. (2004), Licastro e

Reiner et al. (2005), Antonicelli et al. (200

TNF-a �308 G > A Padovani et al. (2000), Vendrell et al. (200

Antonicelli et al. (2005a,b)

IL-10 �1082 G > A Lio et al. (2004)

CD14 �260 C > T Arroyo-Espliguero et al. (2005)

TLR4 299 G > A Holloway et al. (2005), Edfeldt et al. (2004

becomes over-activated probably as consequence of an

increased exposure to infectious agents or cumulative damage

to tissues, leading both to ageing and chronic diseases. In CVD,

conventional risk factors remain important, but differential

baselines in inflammatory status may modulate the severity of

the pathological processes. On the other hand, controlling

inflammatory status may enhance individual chance of

achieving ‘successful’ ageing. So, major findings that report

a relationship between cytokine polymorphisms and longevity

suggest that individuals who are genetically predisposed to

produce low levels of inflammatory cytokines or high levels of

anti-inflammatory cytokines may have an increased capacity to

reach the extreme limit of human life-span escaping CVD and

its compliance.

The emerging data regarding the association between the

most important inflammatory cytokines (IL-6, TNF-a, IL-10)

and immune molecules (CD 14 receptor and TLR-4)

polymorphisms and the incidence or the prognosis of MI are

still conflicting (Table 1). The reasons for these discrepancies

are unclear. However, some important differences appear in the

different studies, e.g. different study design, different pharma-

cological treatment, variable linkage disequilibrium among

different populations, different hetnic origin, age, lifestyle,

environmental factors (nutritional factors) as well as other

unidentified factors.

Moreover, recent literature suggests that the analysis of a lot

of polymorphic genetic markers is more informative than the

analysis of a single polymorphism. A large number of patients

affected by MI must be enrolled in future studies for well

defining the relevance of the genetic control in CVD. Future

large scale studies are also necessary to focus on the gene–

environmental interaction in determining the inter-individual

variability to CHD susceptibility, and for understanding the key

metabolic pathways both in the CHD and in the disease-free

state, such as in healthy centenarian peoples who escape the

major age-related diseases, especially CHD. The identification

of genes and/or molecules implicated in the pro-anti

inflammatory pathways may subsequently suggest the key

gene targets for therapeutic intervention or prevention

especially in old people. At the same time, some relevant

inflammatory genes may be found in order to reach healthy

ageing and longevity. Furthermore future studies must be

encouraged to focus on the clinical relevance of cytokines gene

polymorphisms in the assessment of the single patients MI risk

profile and/or of the prognostic value after MI.

No association with MI

Jenny et al.

t al. (2004),

5a,b)

Burzotta et al. (2001), Yamada et al. (2002),

Nauck et al. (2002), Bennermo et al. (2004),

Latkovskis et al. (2004), Lieb et al. (2004)

3), Keso et al. (2001), Koch et al. (2001)

Donger et al. (2001), Koch et al. (2001, 2003)

Zee et al. (2005), Longobardo et al. (2003)

) Zee et al. (2005)

F. Olivieri et al. / Mechanisms of Ageing and Development 127 (2006) 552–559 557

Acknowledgements

This paper was supported by EU Commission GEHA project

(contract no. LSHM-CT-2004-503270), Coordinator: Prof.

Claudio Franceschi and ZINCAGE project (contract no.

FOOD-CT-2004-506850), Coordinator: Dr. Eugenio Mocche-

giani, Emilia-Romagna Project ‘‘ER-GenTech’’, FP6 EU

Project ‘‘T-CIA’’ and by University of Bologna ‘‘Pallotti’’

Research Funds.

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