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Association between HFE mutations and longevity: a study in the Sardinian population

a, a a, b Ciriaco Carru*, Giovanni Mario Pes, Luca Deiana*, Giovannella Baggio, c,d e e e Claudio Franceschi, Domenico Lio, Carmela Rita Balistreri, Giuseppina Candore, e e Giuseppina Colonna-Romano, Calogero Caruso

a AKEA Project, Cattedra di Biochimica Clinica, Universita` di Sassari, viale S. Pietro 43/b, Sassari, Italy b AKEA Project, Unita` operativa di Medicina Generale, Azienda Ospedaliera di Padova, Padova, Italy c Istituto Nazionale di Riposo e Cura per Anziani, Ancona, Italy d AKEA Project, Dipartimento di Patologia Sperimentale, Universita` di Bologna, Bologna, Italy

Received 25 June 2002; accepted 20 December 2002

Abstract

Hereditary hemochromatosis is an HLA-linked inherited disease characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The cysteine-to-tyrosine substitution at codon 282 of the HFE encoding gene sequence is responsible for the disease, although other variants such as H63D and S65C may modify the affinity of the protein for transferrin receptors. We have recently reported that C282Y mutation is significantly increased in very old (≥90 years) Sicilian women, suggesting a role in attainment of longevity. In addition, an increase of H63D polymorphism was also observed in these women but the difference was not significant. To validate and extend these results, we investigated the distribution of these three common HFE gene mutations in Sardinian centenarians and controls. DNA samples obtained from 61 controls and 57 centenarians were typed for HFE polymorphisms using sequence-specific primers. Among the controls, none was heterozygous for the C282Y mutation, 15 were heterozygous for H63D mutation, and one for S65C. Among the centenarians, none was heterozygous for the C282Y mutation, whereas 25 were heterozygous for H63D mutation and four for the S65C mutation. No significant differences were observed in frequencies of the different alleles between young and centenarians both on the whole and when the data were analyzed according to gender. However, there was a trend for an increased frequency of H63D allele in centenarian women (24 vs. 17%, i.e., 19/80 vs. 13/78). It is noteworthy that the cumulative frequency of H63D mutations in centenarian and very old women from Sardinia and Sicily is 22 vs. 11%, i.e., 30/136 vs. 23/210, P<0.008. These findings are consistent with the hypothesis that there may be a survival difference for centenarian women among carriers and non-carriers of alleles involved in iron sparing.

#2003 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Centenarians; HFE; Longevity

1. Introduction

Hereditary hemochromatosis is an HLA-linked inherited disease characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The HLA class I gene product HFE localized at 6p21.3/p22 no longer participates in immunity because it has lost its ability to bind peptides due to a definitive closure of the antigen-binding cleft. This protein, instead, has acquired the ability to form a complex with the receptor for iron-binding transferrin, thus regulating iron uptake. It indirectly regulates immune responses too because iron availability plays a role in specific and non-specific immune responses. A cysteine-to-tyrosine substitution at codon 282 of the HFE encoding gene sequence is responsible for the disease. However, other variants such as H63D and S65C may modify the affinity of the protein for transferrin receptors. The distribution of these mutations differs in different populations (Feder et al.).

2. Materials and methods