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,† Gregorio Enrico Hoffmann,† Giuseppina Colonna-Romano,* Domenico Lio,* Yael Shinar,‡ Claudio Franceschi,§ and Calogero Caruso*,1

*Gruppo di Studio sull’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, and †Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Universita` di Palermo, Italy; ‡Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer, Israel; and §Dipartimento di Sperimentale and Centro Interdipartimentale “L. Galvani,” Universita` di Bologna, and Istituto Nazionale di

gevity [1–4]. The Mediterranean fever gene MEFV is highly polymorphic among the Mediterranean populations and is pro- posed to play an important role in controlling the leukocyte- related inflammatory responses and apoptosis [5–8]. 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 mes- sage levels, whereas anti-inflammatory cytokines down-regu- late them [9–11]. 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.

contribute significantly to the risk of developing coronary heart disease (CHD). Conversely, the sus- ceptibility alleles to inflammatory disease should be infrequent in the genetic background favoring lon- gevity. In fact, in a modern environment, attain- ment of longevity is facilitated by an anti-inflam- matory 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 cente- narians, 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-repre- sented 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 environ- ment with reduced pathogen load and improved control of severe infections by antibiotics. All these data indicate a strong relationship among inflam- mation, genetics, CHD, and longevity. J. Leukoc. Biol. 79: 611–615; 2006.

fied. Current listings of all mutations and polymorphisms can be easily derived by visiting INFEVERS, a mutational data- base found at http://fmf.igh.cnrs.fr/infevers/. The most preva- lent mutations in the MEFV gene are ancient founder muta- tions, which are associated with familial Mediterranean fever (FMF) [6, 8]. The disease is an autosomal, recessive, inflam- matory 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

Words: AMI  inflammation  MEFV

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

INTRODUCTION

Genetic backgrounds promoting proinflammatory responses play an opposite role in cardiovascular diseases and in lon-

Received July 27, 2005; revised September 29, 2005; accepted November 3, 2005; doi: 10.1189/jlb.0705416.

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.

Men 111 (92%) Women 10 (8%) Age range 20–46 Positive familial history of coronary heart disease 70 (58%) t+ fi Current smokers (current former) 90 (74%; 108; 89%) History of Type 2 diabetes 21 (17%) History of obesity 41 (34%) Hypertension 35 (29%)   Blood cholesterol levels 220 mg/dl 74 (61%)   Triglycerides 160 mg/dl 52 (43%)

MATERIALS AND METHODS