Association between the MHC class I gene HFE polymorphisms and longevity: a study in the Sicilian population. D Lio, CR Balistreri, G Colonna-Romano, M Motta, C Franceschi, M Malaguarnera, G Candore, and C Caruso. 

The I and II human leukocyte antigens (HLA) genes encode highly polymorphic heterodimeric glycoproteins involved in 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 acquired the ability to form a 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 was studied in Sicilian centenarians and nonagenarians 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 were heterozygous for the C282Y or for S65C mutation. Twenty-six were heterozygous for the H63D mutation. Among the elderly subjects, 11 were heterozygous for the C282Y mutation or for H63D mutation. None were 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 as a whole. By analyzing polymorphisms according to gender, heterozygous subjects for C282Y were found both in old men and 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 women. Possession of the C282Y allele, known to be associated with an increase of iron uptake, significantly increases the possibility of women 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.

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 peptides intracellularly and emerge on the cell surface where processed peptides are presented to T cells, regulating T cell responses against specific antigens. HFE, the most 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 prevents peptide binding and presentation. The HFE protein, expressed in crypt enterocytes of the duodenum, regulates the iron uptake by intestinal cells because it has acquired the ability to form a complex with the receptor for iron-binding transferrin. Thus, it indirectly regulates 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.

The C282Y mutation (a cysteine to tyrosine mutation at amino acid 282) in this gene has been identified as the main genetic basis of hereditary hemochromatosis (HH). It destroys its ability to make up a heterodimer with an α2-microglobulin. The defective protein fails to associate with the transferrin receptor, and the complex cannot be transported to the surface of the duodenal crypt cells. As a consequence, in homozygous people, two to three times the normal amount of iron is absorbed from food by the intestine. The disease is characterized by progressive storage of iron in organs such as the liver, pancreas, pituitary gland, and heart that results in end-organ damage and reduced life expectancy. Two other mutations, H63D (a histidine to aspartate at amino acid 63) and S65C (a serine to cysteine at amino acid 65), appear to be associated with milder forms of HH. In fact, a small number of patients with HH were identified as homozygous for H63D or as compound heterozygous HIn men and women, we evaluated the prevalence of HFE mutations, including less common ones such as V53M, V59M, H63H, Q127H, E168Q, E168X, W169X and Q283P. Additionally, we analyzed the recently discovered haemochromatosis related transferrin receptor 2 (TFR2) Y250X mutation in 20 young and 20 elderly subjects, but found no instances of heterozygosity (data not shown).

Table 3 displays the allele frequencies for H63D HFE polymorphisms in 106 young (under 55 years) and 35 elderly (over 90 years) Sicilians, separated by gender. Among the young individuals, none were heterozygous for the C282Y or S65C mutation. However, twenty-six were found to be heterozygous for the H63D mutation. Among the elderly individuals, eleven were heterozygous for either the C282Y or H63D mutation. None were heterozygous for the S65C mutation. We did not find any compound heterozygous individuals (C282Y/H63D). A highly significant difference (P = 7.2 x 10^-7 by Fisher exact test) was observed in C282Y allele frequencies between young and oldest old subjects on the whole (Table 1).