Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population

D Lio1, CR Balistreri1, G Colonna-Romano1, M Motta2, C Franceschi3,4, M Malaguarnera2, G Candore1 and C Caruso1

1Dipartimento di Biopatologia e Metodologie Biomediche, Universita` di Palermo, Palermo, Italy; 2Dipartimento di Scienze della Senescenza, Urologiche e Neurourologiche, Universita` di Catania, Catania, Italy; 3Dipartimento di Patologia Sperimentale, Universita` di Bologna, Bologna, Italy; 4Istituto Nazionale di Riposo e Cura per Anziani di Ancona, Ancona, Italy

I and II human leukocyte antigens (HLA) genes encode highly polymorphic heterodimeric glycoproteins involved the control of immune responses. The HLA class I gene HFE seemingly no longer participates in immunity because it lost its ability to bind peptides and it has acquired the ability to form complex with the receptor for iron-binding by regulating iron uptake by intestinal cells. Thus, it indirectly regulates immune responses too, because iron plays a role in specific and non-specific immune responses. The distribution of HFE polymorphisms in Sicilian

in the control of immune responses. The HLA class I gene HFE seemingly no longer participates in immunity because it has lost its ability to bind peptides and it has acquired the ability to form complex with the receptor for iron-binding transferrin by regulating iron uptake by intestinal cells. Thus, it indirectly regulates immune responses too, because iron availability plays a role in specific and non-specific immune responses. The distribution of HFE polymorphisms in Sicilian centenarians and nonagenarians was studied to evaluate if HFE alleles might be represented differently in people selected for longevity. DNA samples were obtained from 106 young controls (age range from 22 to 55 years; 40 men and 66 women) and 35 elderly subjects (age range from 91 to 105 years; seven men and 28 women). Samples were typed for C282Y, H63D and S65C alleles using polymerase chain reaction and sequence specific primers. Among the young individuals, none was heterozygous for the C282Y or for S65C mutation. Twenty-six were heterozygous for H63D mutation. Among the elderly subjects, 11 were heterozygous for the C282Y mutation or for H63D mutation. None was heterozygous for the S65C mutation. No compound heterozygous individuals (C282Y/H63D) were found. A highly significant difference was observed in frequencies of C282Y alleles between the young and the elderly subjects on the whole. By analysing polymorphisms according to gender, heterozygous subjects for C282Y were found both in old men and in old women, but by comparing the allele frequencies to those of young people significance was attained only in women. Concerning H63D polymorphisms, no significant differences were observed, between old and young people, both in men and in women. Possession of C282Y allele, known to be associated with an increase of iron uptake, significantly increases women possibility to reach longevity. Thus, present data adds another piece of evidence to the complex puzzle of genetic and environmental factors involved in control of lifespan expectancy in humans. Genes and Immunity (2002) 3, 20–24. DOI: 10.1038/sj/gene/6363823

Keywords: HLA; longevity; HFE; centenarians; immune response

tides intracellularly and emerge on the cell surface where processed peptides are presented to T cells, regulating T cell responses against specific antigens.1,2 HFE, the most Mais telomeric HLA class I gene, codes for a class I chain, which seemingly no longer participates in immunity, because it has lost its ability to bind peptides owing to a definitive closure of the antigen binding cleft that pre- vents peptide binding and presentation. The HFE pro- tein, expressed in crypt enterocytes of the duodenum, regulates the iron uptake by intestinal cells because it has acquired the ability to form complex with the receptor for iron-binding transferrin.3–6 Thus, it indirectly regu- lates immune responses, because iron availability plays a role in specific and non-specific immune responses. In fact, iron deficiency may be associated with reversible abnormalities of immune function, although it is difficult to demonstrate the severity and relevance of these in observational studies.6–8

Introduction

The human leukocyte antigens (HLA) complex contains over 200 genes divided into three classes. Most HLA genes involved in the immune response fall into classes I and II, which encode highly polymorphic heterodimeric glycoproteins. These molecules take up antigenic pep-

Correspondence: Prof. C Caruso, Laboratorio di Immunopatologia, Dipart- imento di Biopatologia e Metodologie Biomediche, Corso Tukory 211,

imento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, yfc@u 90134 Palermo, Italy. E-mail: marcoc unipa.it These studies have been supported by grants from MURST, Rome (ex 40%, Immunogenetics of Longevity, coordinated by Professor Calogero Caruso, to CC and DL), ex 60% to CC and GC, from Min- istery of Health Project “Pharmacogenomics of Alzheimer’s Dis- ease” and by a cooperation contract between the Dipartimento di Biopatologia e Metodologie Biomediche dell’Universita` di Palermo and the Istituto Nazionale di Riposo e Cura per Anziani di Ancona (Longevity and elderly disability biological markers). Received 6 September 2001; revised 22 October 2001; accepted 22 October 2001

The C282Y mutation (a cysteine to tyrosine mutation at amino acid 282) in this gene has been identified as the

Table 1 Allele frequencies for HFE polymorphisms in 106 young ((cid:3) 55 years) and 35 elderly ((cid:4) 90 years) Sicilians