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Originally published online as doi:10.1189/jlb.0705416 on December 30, 2005

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(Journal of Leukocyte Biology. 2006;79:611-615.)
© 2006 by Society for Leukocyte Biology

Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population

Maria Paola Grimaldi*, Giuseppina Candore*, Sonya Vasto*, Marco Caruso{dagger}, Gregorio Caimi{dagger}, Enrico Hoffmann{dagger}, Giuseppina Colonna-Romano*, Domenico Lio*, Yael Shinar{ddagger}, Claudio Franceschi§ and Calogero Caruso*,1

* Gruppo di Studio sull’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, and
{dagger} Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Università di Palermo, Italy;
{ddagger} Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer, Israel; and
§ Dipartimento di Patologia Sperimentale and Centro Interdipartimentale "L. Galvani," Università di Bologna, and Istituto Nazionale di Riposo e Cura per Anziani, Ancona, Italy

1 Correspondence: Gruppo di Studio sull’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, 90134 Palermo, Italy. E mail: marcoc{at}unipa.it


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ABSTRACT
 
A proinflammatory genotype seems to contribute significantly to the risk of developing coronary heart disease (CHD). Conversely, the susceptibility alleles to inflammatory disease should be infrequent in the genetic background favoring longevity. In fact, in a modern environment, attainment of longevity is facilitated by an anti-inflammatory status. To evaluate whether inflammatory alleles of pyrin, the gene responsible for familial Mediterranean fever (FMF) may play an opposite role in CHD and in longevity, we examined three FMF-associated mutations, M694V (A2080G), M694I (G2082A), and V726A (T2177C), encoded by the FMF gene (MEFV) in 121 patients affected by acute myocardial infarction (AMI), in 68 centenarians, and in 196 age-matched controls from Sicily. None of the Sicilian subjects studied carried the V726A and the M694I FMF-related mutations. The proinflammatory M694V (A2080G) mutation was the only one we found, which was over-represented significantly in CHD patients and under-represented in oldest old, and intermediate values were in healthy, young controls. After adjustment for well-recognized AMI risk factors, the M694V allele still predicted a significant risk to develop AMI. So, according to these results, we suggest that carrying the proinflammatory M694V pyrin allele may increase the risk to develop AMI. Conversely, the wild-type pyrin genotype may predispose to a greater chance to live longer in a modern environment with reduced pathogen load and improved control of severe infections by antibiotics. All these data indicate a strong relationship among inflammation, genetics, CHD, and longevity.

Key Words: AMI • inflammation • MEFV


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INTRODUCTION
 
Genetic backgrounds promoting proinflammatory responses play an opposite role in cardiovascular diseases and in longevity [1 2 3 4 ]. The Mediterranean fever gene MEFV is highly polymorphic among the Mediterranean populations and is proposed to play an important role in controlling the leukocyte-related inflammatory responses and apoptosis [5 6 7 8 ]. The MEFV gene encodes for pyrin, a basic protein of 781 amino acids, expressed in the cytosol of neutrophils, eosinophils, and activated monocytes. Although its exact mode of function is not known, its N-terminal, similar in secondary structure to the death protein domains, is capable of binding to key molecules in inflammatory gene transcription and cytokine secretion [8 ]. Proinflammatory activators up-regulate leukocyte MEFV message levels, whereas anti-inflammatory cytokines down-regulate them [9 10 11 ]. So far, the role of MEFV in cardiovascular diseases has not been demonstrated formally (see below), and its effect on longevity has not yet been studied.

Over 40 different MEFV mutations have now been identified. Current listings of all mutations and polymorphisms can be easily derived by visiting INFEVERS, a mutational database found at http://fmf.igh.cnrs.fr/infevers/. The most prevalent mutations in the MEFV gene are ancient founder mutations, which are associated with familial Mediterranean fever (FMF) [6 , 8 ]. The disease is an autosomal, recessive, inflammatory disorder, characterized by fever attacks combined with abdominal, chest, or joint pain, erysipelas-like erythema, and infiltration of affected tissues by large numbers of neutrophils [9 ]. FMF is an ethnically restricted genetic disease, found commonly among Mediterranean populations such as Jews, Turks, Arabs, and Armenians. However, in the course of time, as a result of several migrations, the Mediterranean MEFV alleles reached Western Europe, spreading throughout Italy, France, and Spain. Further, FMF is also found in Ashkenazi Jews (Eastern European origin), although less frequently [12 , 13 ].

Most of the missense mutations in the MEFV gene described to date, including the M694V mutation, are clustered in exon 10, corresponding to the carboxyl terminal of pyrin protein [9 , 14 ]. Several studies about patients affected by FMF have identified the M694V mutation in a homozygous genotype as the most deleterious [14 ]. Although the molecular effects of these mutations are not yet known, they appear to be effective, even in the heterozygous state [15 16 17 18 ]. Hence, the presence of high carrier frequencies for these mutations in several geographically related populations as well as above-normal levels of the acute-phase proteins C-reactive protein and serum amyloid A in obligate carriers in FMF families [17 , 18 ] suggests that people bearing pyrin mutations may have a selective advantage, possibly because of heightened resistance to pathogen(s) [15 , 16 ]. It has also been postulated that the low-grade inflammation in carriers, especially those carrying the M694V mutation [17 ], may well worsen clinical symptoms of immune-inflammatory diseases [17 , 18 ]. Thus, we hypothesized that MEFV mutations may increase the risk of acute myocardial infarction (AMI) when interacting with ongoing atherosclerosis disease.

According to this aim, we have studied the frequency of three MEFV mutations commonly seen in the Mediterranean area, M694V, M694I and V726A [19 , 20 ], in patients affected by AMI and age-matched controls from Sicily. First, to improve the power of our study, we selected genetically loaded cases having early AMI onset (<46 years) [21 ]. Second, we have studied a third group of subjects, consisting of a cohort of Sicilian centenarians, as in our previous studies, we have demonstrated that the achievement of longevity is facilitated by an anti-inflammatory status [22 23 24 25 ], and centenarians are a suitable control group for complex, age-related, inflammatory diseases, such as coronary heart disease (CHD) [1 2 3 4 ].

To date, the lifespan of MEFV mutation carriers or FMF patients has not been a matter of study. Langevitz et al. [26 ] have reported a similar incidence of CHD in patients with FMF treated with colchicine, their spouses, and the general population. It is well known, however, that before the introduction of colchicine, amyloidosis occurred in 60% of FMF patients over 40 years of age, being the main cause of death [9 ]. Moreover, Langevitz et al. [26 ] also reported on higher prevalence of CHD in families of FMF patients than in controls (their spouses), yet this observation was not attributed to the high probability of mutation carriers among these family members, and therefore, their genotype was not pursued.


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MATERIALS AND METHODS
 
We enrolled 121 young patients admitted at the Cardiac Unit of Palermo University Hospital (Italy), as they were affected by AMI. The diagnosis of AMI was based on typical electrocardiographic changes and increased serum activities of relevant enzymes and confirmed by echocardiography and coronary angiography. The healthy, age-matched control group of 196 subjects was recruited amongst students or staff personnel who were checked and judged to be in good health based on their clinical history and on blood tests (complete blood cell count, erythrocyte sedimentation rate, glucose, urea nitrogen, creatinine, electrolytes, C-reactive protein, liver function tests, iron, proteins, cholesterol, triglycerides). The second control group consisted of 68 Sicilian centenarians, whose age (>99 years) was verified by archival records at the City Hall and/or church registries. We paid particular attention to the concordance between reported age and personal chronologies (age of marriage and of military service for men; age of first and last pregnancy for women; age of children, among others). The characteristics of patient and control groups are reported in Table 1 . The Sicilian ethnicity of the participants at the study was established by confirming that all four grandparents were born in Sicily; immigration and intermarriage have historically been rare. The University Hospital Ethics Committee approved the project, and an informed consent was obtained from each individual.


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  		Table 1. Characteristics of AMI Patients (Number and Percentage)

Blood specimens were collected in tripotassium EDTA sterile tubes, DNA-extracted, and processed for genotyping of three common FMF mutations: the M694V mutation, where G replaces A at position 2080 of the MEFV DNA (rs28940577); the M694I mutation, where A replaces G at position 2082 (rs28940578); and the V726A mutation, where C replaces T at position 2177 (rs28940479). The genotyping was performed by the amplification-refractory mutation system method according to published protocols [27 ], and random samples were genotyped again using restriction enzymes site analyses at the Heller Institute, Sheba Medical Center (Tel Hashomer, Israel), to confirm the results [20 ].

Allele and genotypic frequencies were evaluated by gene count and differences in frequency among the groups. The {chi}2 test (2x2 and 3x2 tables, where appropriate) and ODD ratio (OR) with confidence interval (CI) were calculated. The data were tested for the goodness of fit between the observed and expected genotype frequencies according to the Hardy-Weinberg equilibrium (HWE) by {chi}2 test. In male patients and controls, we performed a logistic regression analysis to test the association of genotypes with AMI after adjustment for smoking habits, family history of CHD, and the presence of Type 2 diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia. The OR (with CI) was calculated as exponential of regression coefficient and its standard error.


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RESULTS
 
None of the Sicilian subjects carried the M694I or the V726A mutations. The proinflammatory M694V mutation, however, was present in all three cohorts of study. It was most frequent in AMI patients (12%), intermediate in healthy, young controls (6%), and less frequent in centenarians (4%; Table 2 , P=0.0033). All the genotypes were in HWE. As expected from the HWE of M694V genotypes, all subjects with the M694V mutation were heterozygous. The heterozygous genotype was also significantly overexpressed in AMI patients (30/121) and underexpressed in centenarians (5/68) compared with young controls (121/196; Table 3 , P=0.0019).


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  		Table 2. Frequency of Proinflammatory Alleles of Pyrin in 121 AMI Patients, 196 Controls, and 68 Centenarians from Sicily


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  		Table 3. Prevalence of the Heterozygous M694V Genotype in 121 AMI Patients, 196 Controls, and 68 Centenarians from Sicily

By performing a series of 2 x 2 separate comparisons, high significance for the different frequencies of M694V genotypes and alleles was obtained between AMI patients and age-matched and centenarian controls. The frequency of M694V proinflammatory genotype and allele in centenarians was lower (but not significantly) than that observed in young, healthy controls. Finally, we performed a logistic regression analysis to test the association of genotypes with AMI after adjustment for smoking habits, family history of CHD, and the presence of Type 2 diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia. As a result of the different number of women in the groups under study, logistic regression was performed only in men. Taking into account the risk factors, significant differences in genotype frequency persisted between male AMI patients and male young controls and between male AMI patients and male centenarians (Table 4 ). These results indicate that the M694V genotype is an independent risk factor for developing AMI in the Sicilian population.


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  		Table 4. 2 x 2 Comparisons between the Different Groups with OR and CI


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DISCUSSION
 
The role of inflammatory responses in mediating all stages of atherosclerosis and CHD has been well established. Atherosclerosis begins as a focal process at specific regions of the vasculature, so-called lesion-prone areas, where hemodynamic flow is altered. The arterial endothelium expresses numerous adhesion molecules. The specific up-regulation of adhesion molecules suggests that they may regulate leukocyte adhesion in early atherogenesis. Moreover, adhesion molecules on the leukocyte membrane are increased in patients with AMI with respect to control subjects, causing the recruitment of neutrophils and monocytes to the involved myocardial region [28 29 30 ].

The aim of this report was to investigate whether the proinflammatory mutations of the MEFV gene play an opposite role in AMI and longevity. To this purpose, all the subjects were screened for M694V, V726A, and M694I, which are the most frequent FMF-associated mutations. Also, a fourth mutation, E148Q, is quite frequent in the Mediterranean area, but its penetrance is low [19 , 20 ]. We found that only the M694V mutation, which is the most frequent in all Mediterranean populations, was present in all the groups studied [19 , 20 ]. This proinflammatory mutation was over-represented significantly in patients with AMI and under-represented in centenarians. The differences between patients and age-related controls are significant but relatively small, as demonstrated by OR values. However, as AMI is a multifactorial disease, any single mutation will only provide a small or modest contribution to risk, also depending on interaction with a particular environment [31 ].

From literature, several case-control studies show that MEFV mutations do not seem to predispose toward inflammatory diseases such as Crohn’s disease, multiple sclerosis, or rheumatoid arthritis, but patients having that inflammatory burden and at the same time, carrying one MEFV mutation appear to be highly susceptible to develop a more severe disease [17 , 32 , 33 ]. So, it may be possible that MEFV mutations are not increasing the susceptibility to develop atherosclerosis, but they might affect its severity and complications, enhancing AMI occurrence.

Taking into account that several mechanisms have been proposed to explain the anti-inflammatory role of pyrin [7 , 8 , 34 , 35 ], it may be intriguing to suggest a mechanism by which the mutated MEFV gene could be responsible for this process. One option is that the mutated pyrin allele is not able to limit the migration of neutrophils and activated monocytes into the site of inflammation, and although failing to down-regulate the inflammatory response of monocytes, instead augments the secretion of inflammatory molecules. Several findings are consistent with this role. First, the inflammatory attacks of FMF are prevented with colchicine, an agent that disrupts microtubules by blocking polymerization of tubulin [11 ]. Second, the wild-type pyrin is considered anti-inflammatory, as by inducing apoptosis of neutrophils and monocytes, it down-regulates the recruitment toward the inflammatory sites [7 ]. Moreover, recent studies have demonstrated that white blood cell (WBC) count is a strong predictor of infarction, as CHD patients with elevated WBC counts show a higher risk of developing AMI [29 ]. A possible link, which is working to increase procoagulant activity of circulating leukocytes, has been proposed between the inflammation and thrombosis in CHD patients [29 ]. Thus, the presence of mutations in the gene of pyrin, causing the survival of leukocytes, which would otherwise be direct to the apoptosis pathway, might account for the association with inflammation and AMI. However, it must be pointed out that until now, there are no reports showing the association between MEFV mutations and CHD but only studies regarding the absence of disease in FMF patients treated with colchicine [26 ] (see also Introduction).

In conclusion, the present results add another piece of evidence to our hypothesis that people genetically predisposed to a weak inflammatory activity have less of a chance to develop CHD and therefore, a greater chance to live longer in a modern environment with reduced pathogen load and improved control of severe infections by antibiotics [1 2 3 4 , 22 23 24 25 , 31 , 36 ]. In any case, all these data point out the strong relationship among inflammation, genetics, CHD, and longevity. Finally, our comparison with centenarians may help to elucidate the role of genetics in age-associated inflammatory diseases characterized by a multifactorial etiology.


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ACKNOWLEDGEMENTS
 
This work was supported by grants from the Italian Ministry of Education, University and Research to G. Candore, D. L., G. C-R., and C. C. Funds from Italian Ministry of Health (genetic and nongenetic factors of health in elderly) to C. F. and G. C-R. are also acknowledged. M. P. G. and S. V. are Ph.D. students of the Pathobiology Ph.D. course (directed by C. C.) of Palermo University, and this work is in partial fulfillment of the requirement for the Ph.D. Statistical advise of Prof. C. Cammà is acknowledged.

Received July 27, 2005; revised September 29, 2005; accepted November 3, 2005.


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