Gene Polymorphisms Predicting High Plasma

A Study in Centenarians

P.M. Mannucci, D. Mari, G. Merati, F. Peyvandi, L. Tagliabue, E. Sacchi, E. Taioli, P. Sansoni,

P.M. Mannucci, D. Mari, G. Merati, F. Peyvandi, L. Tagliabue, E. Sacchi, E. Taioli, P. Sansoni, S. Bertolini, C. Franceschi

Abstract Gene polymorphisms associated with the plasma levels of fibrinogen, factor VII, and plasminogen activator inhibitor 1 (PAI-1)—hemostasis proteins that help to predict the risk of atherothrombotic disease—were compared in 124 healthy individuals > 100 years old and 130 young, healthy indi viduals to identify genetic influences on extreme longevity. We investigated the restriction fragment length polymorphism G/A"455 located in the promoter of the p-fibrinogen gene, the guanine insertion/deletion polymorphism 4G/5G in the pro moter of the PAI-1 gene, and the R353Q substitution polymor phism in exon 8 of the factor VII gene. Alleles and genotypes associated with elevated plasma levels of fibrinogen and factor VII were found with similar frequencies in centenarians and in

the comparison group. However, in centenarians there was a sig nificantly higher frequency of the 4G allele and of the homozy gous 4G4G genotype associated with high PAI-1 levels. Since high PAI-1 is considered a predictor of recurrent myocardial infarction in young men, it is intriguing that the corresponding genetic marker is more frequent in centenarians who have escaped major age-related atherothrombotic disease and reached the extreme limits of human life. Homozygosity for the 4G allele, despite its association with impaired fibrinolysis, is com patible with successful aging. (Arterioscler Thromb Vase Biol. 1997;17:755-759.)

KeyWords • centenarians • fibrinogen • factor VII • plasminogen activator inhibitor 1 • gene polymorphisms

The purpose of this study was to evaluate the allele and genotype frequencies of polymorphisms influencing plasma levels of fibrinogen, factor VII, and PAI-1 in a cohort of Italian healthy centenarians, who are considered a natural model of extreme longevity and positive selection.7 Results obtained in these exceptional individuals, who have escaped age-related atherothrombotic disease and reached the extreme limits of life, were compared with those obtained in healthy individuals who were young enough that none of them would be lost from the study sample because of symptomatic atherothrombotic disease. We surmised that the study of genetic markers of hypercoagulability and hypofibrinoly- sis should establish whether or not successful aging is asso ciated with the predominance of genotypes predicting lower plasma levels of hemostasis proteins.

from http://ahajournals.org by on March 13, 2020

Common biallelic polymorphisms of the genes encod ing for fibrinogen, factor VII, and PAI-1 influence the plasma levels of these proteins.2 The polymorphic genotypes asso ciated with elevated plasma levels of these hemostasis com ponents might prove more reliable as predictors of the throm botic risk than the plasma levels. In the general population, plasma levels have a continuous distribution, and so it is difficult to establish cutoff values that can identify the indi viduals at risk. In addition, variation of plasma levels deter mined by environmental factors may further complicate risk assignment. To assess the value of genetic markers as risk predictors, studies have been carried out in relatively small groups of individuals with or without atherothrombotic dis ease, but the results have been conflicting. 3"6

Methods

Subjects

In Italy, there is currently a multicenter project on centenarians; it is coordinated by one of the authors (C.F.). The aim of thi sproj ect is to study the mechanisms of successful aging. Centenarians identified from the General Registry Offices are studied in special units, generally established in university departments. Approxi mately 2000 centenarians have been identified.7 Several biological systems of these individuals are being investigated by biochemical and molecular methods.

Received April 16, 1995; revision accepted July 31, 1996. From the Angelo Bianchi Bonomi Hemophilia and Center, Epidemiology Unit, IRCCS Maggiore Hospital and Unit, Institute of Internal Medicine, University of Milano D.M., G.M., F.P., L.T., E.S., E.T.); the Institute of Clinical Medicine, University of Parma (P.S.); the Department of Medicine, University of Genoa (S.B.); and the Department of Bio chemical Sciences, University of Modena (C.F.), Italy.

Received April

,

; revision accepted July

,

From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Epidemiology Unit, IRCCS Maggiore Hospital and Geriatric Unit, Institute of Internal Medicine, University of Milano (P.M.M., D.M., G.M., F.P., L.T., E.S., E.T.); the Institute of Clinical Medicine, University of Parma (P.S.); the Department of Internal Medicine, University of Genoa (S.B.); and the Department of Bio chemical Sciences, University of Modena (C.F.), Italy. Correspondence to Dr P.M. Mannucci, via Pace

,

Milano,

Study Design

The present study is part of the hemostasis DNA polymorphisms for two coagulation factors, factor VI1 and fibrinogen, and the fibrinolysis inhibitor PAI-1 were studied in 124 healthy centenarians from four metropolitan communities in north ern Italy (Milan, Modena, Parma, and Genoa). Allele and genotype frequencies were compared with those of 130 young, healthy

viduals recruited from the same communities and ethnically homo geneous with the centenarians but unrelated to them. Approval these studies was obtained from the Institutional Review Board the University of Milan, and informed consent was given after experimental nature of the studies had been explained.