- Email: [email protected]
Association between the HFE mutations and longevity: a study in Sardinian population
Mechanisms of Ageing and Development 124 (2003) 529 /532 www.elsevier.com/locate/mechagedev
Association between the HFE mutations and longevity: a study in Sardinian population Ciriaco Carru a,*, Giovanni Mario Pes a, Luca Deiana a,*, Giovannella Baggio b, Claudio Franceschi c,d, Domenico Lio e, Carmela Rita Balistreri e, Giuseppina Candore e, Giuseppina Colonna-Romano e, Calogero Caruso e 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 e Gruppo di Studio dell’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Universita` di Palermo, Palermo, Italy Received 25 June 2002; accepted 20 December 2002
Abstract Hereditary hemochromatosis is an HLA-linked inherited disease characterised 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, 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 analysed 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 characterised by inappropriately high absorption of iron by the gastrointestinal mucosa. The HLA class I gene product HFE, localised at 6p21.3 / p22, no longer participates in immunity because it has
* Corresponding authors. Tel.: /39-079-228-276; fax: /39-079228-120. E-mail address: [email protected] (L. Deiana).
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 complex with the receptor for iron-binding transferrin, so by regulating iron uptake. Thus, 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, 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
0047-6374/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0047-6374(03)00032-0
530
C. Carru et al. / Mechanisms of Ageing and Development 124 (2003) 529 /532
al., 1996; Merryweather-Clarke et al., 1997; Andrews, 1999; Mura et al., 1999; Rochette et al., 1999; Klein and Sato, 2000; Salter-Cid et al., 2000; Oppenheimer, 2001; Campo et al., 2001). We have recently reported that C282Y mutation may confer a selective advantage in term of longevity to Sicilian women. As matter of the fact, C282Y mutation was significantly increased both in very old men and women, but by comparing the allele frequencies to those of young people significance was attained only in very old women. Interestingly in these subjects an increase of H63D polymorphism was also observed but the difference was not significant (Lio et al., 2002). To validate and extend these results, in this study, we investigated the distribution of these three common HFE gene mutations C282Y, H63D, S65C in Sardinian centenarians and controls.
2. Materials and methods Genomic DNA samples for this study were obtained through AKEA (the name ‘AKEA’ is derived from an expression in the Sardinian language that means ‘health and life for 100 years!’) study of Sardinian centenarians (Deiana et al., 1999). At the time of the present study, DNA samples for HFE typing were available from 57 centenarians (age range from 100 to 105; 17 men and 40 women) and from 60 controls (60 years old; 21 men and 39 women). Samples were typed for C282Y, H63D and S65C alleles using polymerase chain reaction and sequence specific primers as previously reported (Lio et al., 2002). HFE allelic and genotypic frequencies were compared by Monte-Carlo x2-test implemented in SPSS package (SPSS, Chicago, Illinois).
3. Results Among the young individuals, none was heterozygous for the C282Y mutation. Fifteen subjects 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 (Table 1) and when the data were analysed according to gender (data not shown). However, there was a trend for an increased frequency of H63D mutation in centenarians. In particular, the frequency of H63D allele was higher in centenarian women than in control women (24 vs. 17%, i.e. 19/80 vs. 13/78).
4. Discussion In the present study, we have not been able to confirm in Sardinian centenarians the increase of C282Y mutation observed in Sicilian oldest old women. This datum is not surprising because the frequency of C282Y mutation is very low in the Mediterranean basin (Merryweather-Clarke et al., 1997; Campo et al., 2001; Lucotte, 2001; Balistreri et al., 2002). Besides Sardinian population is an ancient genetic isolate with a gene pool characterized by polymorphisms that are rare elsewhere, so the HLA ancestral haplotype 7.1. that usually carries this mutation is virtually absent in the Sardinian population (Contu et al., 1992; Rendine et al., 1998; Dawkins et al., 1999; Klein and Sato, 2000). However, we observed an increase of the other two mutations. This trend was not significant, but it is noteworthy that the cumulative frequency of H63D mutations in centenarian and very old women from Sardinia and Sicily (Lio et al., 2002) was 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 very old women, among carriers and non-carriers of alleles involved in iron sparing. It is well known that heterozygotes for mutations in HFE have a higher iron content (Burt et al., 1998; Steinberg et al., 2001), but it has until now been assumed that this was without significant influence on morbidity and mortality rates. Our study does not shed light on which mechanisms are behind this longer life expectancy. However, it is tempting to suggest that the difference is owing to accumulation of iron, but this should be further investigated. In the previous report on Sicilian population, considering the historical and social contest in which the generation of women under study lived, we have suggested that the possession of iron sparing alleles significantly increases women possibility to reach longevity. For instance, in Sicily as well in Sardinia and in other pre-industrial countries, a lot of pregnancies and an iron-poor diet, consisted mainly in grains, vegetables and fruits, were yet the rule for the women born at the beginning of last century (Shorter, 1982). Future research needs to elucidate this point by analysing other populations. It is seemingly puzzling that HFE mutations have been suggested to be involved in unsuccessful ageing too. In fact, these mutations have been suggested to be involved in Alzheimer disease, in chronic liver diseases, and coronary heart disease (Bathum et al., 2001; Balistreri et al., 2002; Candore et al., 2002). However, it is not surprising that HFE mutations are associated both with longevity and diseases affecting life span. In fact, available data from genetics of longevity (Caruso et al., 2000, 2001) show that longevity may be associated with alleles with increased risk to a variety of diseases in the younger phases of life (antagonistic pleiotropy). This
C. Carru et al. / Mechanisms of Ageing and Development 124 (2003) 529 /532
531
Table 1 Allele frequencies for HFE polymorphisms in 60 controls ( /60 years) and 57 centenarians ( /100 years) from Sardinia C282Y
/60 years /100 years
H63D
S65C
Wild type
Allele
Wild type
Allele
Wild type
Allele
120 (100%) 114 (100%)
0 (0%) 0 (0%)
99 (82.5%) 87 (76.3%)
21 (17.5%) 27 (23.7%)
119 (99.2%) 110 (96.5%)
1 (0.8%) 4 (3.5%)
theory is also a possible explanation for the apparent discrepancy with a recent study performed in Denmark. In a C282Y mutation high-carrier frequency population as Denmark (Lucotte 2001; Bathum et al., 2001), this mutation shows an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy. The observed reduction in C282Y mutation carrier frequency persists until age 95 years; however, the frequency in the centenarian group was the same as that in the youngest group for both men and women (Bathum et al., 2001). So, in that study heterozygosity for C282Y has a higher mortality rate in the younger groups but becomes beneficial in the oldest old. All together present and previous reports seem to strongly suggest that longevity is the results of interaction between genetic and environmental factors that in different age, gender and population may result in a successful or unsuccessful ageing.
Acknowledgements The authors are grateful to Dr Alessandra Errigo for the help in patient recruitment and in blood samples processing. The ‘AKEA Project’ coordinated by Professor L. Deiana was funded by grants from the Regione Autonoma della Sardegna and MIUR (ex 40% and ex 60%). The ‘Gruppo di Studio sull’immunosenescenza’ coordinated by Professor C. Caruso was funded by grants from MIUR, Rome (ex 40%, to CC and DL; ex 60% to GC and GCR). The collaboration between this group and the Istituto Nazionale di Riposo e Cura per Anziani was enhanced by a cooperation contract (Longevity and elderly disability biological markers) and by the EU thematic network program ImAginE (QLK6CT-1999-02031).
References Andrews, N.C., 1999. Disorders of iron metabolism. N. Engl. J. Med. 341 (26), 1986 /1995. Balistreri, C.R., Candore, G., Almasio, P., Colonna Romano, G., Craxi, A., Motta, M., Piazza, G., Malaguarnera, M., Lio, D., Caruso, C., 2002. Analysis of Haemochromatosis gene mutations in the Sicilian Population: implications for survival and longevity, Arch. Gerontol. Geriatr. 58, 35 /42.
Bathum, L., Christiansen, L., Nybo, H., Ranberg, K.A., Gaist, D., Jeune, B., Petersen, N.E., Vaupel, J., Christensen, K., 2001. Association of mutations in the hemochromatosis gene with shorter life expectancy. Arch. Intern. Med. 161, 2441 /2444. Burt, M.J., George, P.M., Upton, J.D., Collett, J.A., Frampton, C.M., Chapman, T.M., Walmsley, T.A., Chapman, B.A., 1998. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 43, 830 /836. Campo, S., Restuccia, T., Villari, D., et al., 2001. Analysis of haemochromatosis gene mutations in a population from the Mediterranean Basin. Liver 21, 233 /236. Candore, G., Licastro, F., Chiappelli, M., Franceschi, C., Lio, D., Balistreri, C.R., Piazza, G., Colonna-Romano, G., Grimaldi, L.H., Caruso, C., 2003. Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer’s disease patients from Northern Italy. Mech. Ageing Dev. 124, 525 /528. Caruso, C., Candore, G., Colonna Romano, G., Lio, D., Bonafe, M., Valensin, S., Franceschi, C., 2000. HLA, aging and longevity a critical reappraisal. Human Immunol. 61, 942 /949. Caruso, C., Candore, G., Colonna Romano, G., Lio, D., Bonafe, M., Valensin, S., Franceschi, C., 2001. Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data. Mech. Ageing Dev. 122, 445 /462. Contu, L., Arras, M., Carcassi, C., La Nasa, G., Mulargia, M., 1992. HLA structure of the Sardinian population: a haplotype study of 551 families. Tissue Antigens 40, 165 /174. Dawkins, R., Leelayuwat, C., Gaudieri, S., et al., 1999. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunol. Rev. 167, 275 /304. Deiana, L., Ferrucci, L., Pes, G.M., Carru, C., Delitala, G., Ganau, A., Mariotti, S., Nieddu, A., Pettinato, S., Putzu, P., Franceschi, C., Baggio, G., 1999. AKEntAnnos. The sardinia study of extreme longevity. Aging Clin. Exp. Res. 11, 142 /149. Feder, J.N., Gnirke, A., Thomas, W., et al., 1996. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399 /408. Klein, J., Sato, A., 2000. The HLA system. Second of two parts. N. Engl. J. Med. 343, 782 /790. Lio, D., Balistreri, C.R., Colonna-Romano, G., Motta, M., Franceschi, C., Malaguarnera, M., Candore, G., Caruso, C., 2002. Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population. Genes Immunity 3, 20 /24. Lucotte, G., 2001. Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Mol. Dis. 27 (2), 549 /556. Merryweather-Clarke, A.T., Pointon, J.J., Shearman, J.D., Robson, K.J.H., 1997. Global prevalence of putative haemochromatosis mutations. J. Med. Genet. 34, 275 /278. Mura, C., Raguenes, O., Ferec, C., 1999. HFE mutations analysis in 711 hemochromatosis probands evidence for S65C implication in mild form of hemochromatosis. Blood 1593, 2502 /2505. Oppenheimer, S.J., 2001. Iron and its relation to immunity and infectious disease. J. Nutr. 131, 616S /633S.
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Rendine, S., Borelli, I., Barbanti, M., Sacchi, N., Roggero, S., Curtoni, E.S., 1998. HLA polymorphisms in Italian bone marrow donors: a regional analysis. Tissue Antigens 52, 135 /146. Rochette, J., Pointon, J., Fisher, J., et al., 1999. Multicentric origin of hemochromatosis gene (HFE) mutations. Am. J. Hum. Genet. 64, 1056 /1062. Salter-Cid, L., Peterson, P.A., Yang, Y., 2000. The major histocompatibility complex-encoded HFE in iron homeostasis and immune function. Immunol. Res. 22, 43 /59.
Shorter, E., 1982. A History of Women’s Bodies. Basic books, Inc, New York. Steinberg, K.K., Cogswell, M.E., Chang, J.C., Caudill, S.P., McQuillan, G.M., Bowman, B.A., Grummer-Strawn, L.M., Sampson, E.J., Khoury, M.J., Gallagher, M.L., 2001. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. J. Am. Med. Assoc. 285 (17), 2216 /2222.
Association between the HFE mutations and longevity: a study in Sardinian population Ciriaco Carru a,*, Giovanni Mario Pes a, Luca Deiana a,*, Giovannella Baggio b, Claudio Franceschi c,d, Domenico Lio e, Carmela Rita Balistreri e, Giuseppina Candore e, Giuseppina Colonna-Romano e, Calogero Caruso e 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 e Gruppo di Studio dell’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Universita` di Palermo, Palermo, Italy Received 25 June 2002; accepted 20 December 2002
Abstract Hereditary hemochromatosis is an HLA-linked inherited disease characterised 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, 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 analysed 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 characterised by inappropriately high absorption of iron by the gastrointestinal mucosa. The HLA class I gene product HFE, localised at 6p21.3 / p22, no longer participates in immunity because it has
* Corresponding authors. Tel.: /39-079-228-276; fax: /39-079228-120. E-mail address: [email protected] (L. Deiana).
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 complex with the receptor for iron-binding transferrin, so by regulating iron uptake. Thus, 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, 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
0047-6374/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0047-6374(03)00032-0
530
C. Carru et al. / Mechanisms of Ageing and Development 124 (2003) 529 /532
al., 1996; Merryweather-Clarke et al., 1997; Andrews, 1999; Mura et al., 1999; Rochette et al., 1999; Klein and Sato, 2000; Salter-Cid et al., 2000; Oppenheimer, 2001; Campo et al., 2001). We have recently reported that C282Y mutation may confer a selective advantage in term of longevity to Sicilian women. As matter of the fact, C282Y mutation was significantly increased both in very old men and women, but by comparing the allele frequencies to those of young people significance was attained only in very old women. Interestingly in these subjects an increase of H63D polymorphism was also observed but the difference was not significant (Lio et al., 2002). To validate and extend these results, in this study, we investigated the distribution of these three common HFE gene mutations C282Y, H63D, S65C in Sardinian centenarians and controls.
2. Materials and methods Genomic DNA samples for this study were obtained through AKEA (the name ‘AKEA’ is derived from an expression in the Sardinian language that means ‘health and life for 100 years!’) study of Sardinian centenarians (Deiana et al., 1999). At the time of the present study, DNA samples for HFE typing were available from 57 centenarians (age range from 100 to 105; 17 men and 40 women) and from 60 controls (60 years old; 21 men and 39 women). Samples were typed for C282Y, H63D and S65C alleles using polymerase chain reaction and sequence specific primers as previously reported (Lio et al., 2002). HFE allelic and genotypic frequencies were compared by Monte-Carlo x2-test implemented in SPSS package (SPSS, Chicago, Illinois).
3. Results Among the young individuals, none was heterozygous for the C282Y mutation. Fifteen subjects 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 (Table 1) and when the data were analysed according to gender (data not shown). However, there was a trend for an increased frequency of H63D mutation in centenarians. In particular, the frequency of H63D allele was higher in centenarian women than in control women (24 vs. 17%, i.e. 19/80 vs. 13/78).
4. Discussion In the present study, we have not been able to confirm in Sardinian centenarians the increase of C282Y mutation observed in Sicilian oldest old women. This datum is not surprising because the frequency of C282Y mutation is very low in the Mediterranean basin (Merryweather-Clarke et al., 1997; Campo et al., 2001; Lucotte, 2001; Balistreri et al., 2002). Besides Sardinian population is an ancient genetic isolate with a gene pool characterized by polymorphisms that are rare elsewhere, so the HLA ancestral haplotype 7.1. that usually carries this mutation is virtually absent in the Sardinian population (Contu et al., 1992; Rendine et al., 1998; Dawkins et al., 1999; Klein and Sato, 2000). However, we observed an increase of the other two mutations. This trend was not significant, but it is noteworthy that the cumulative frequency of H63D mutations in centenarian and very old women from Sardinia and Sicily (Lio et al., 2002) was 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 very old women, among carriers and non-carriers of alleles involved in iron sparing. It is well known that heterozygotes for mutations in HFE have a higher iron content (Burt et al., 1998; Steinberg et al., 2001), but it has until now been assumed that this was without significant influence on morbidity and mortality rates. Our study does not shed light on which mechanisms are behind this longer life expectancy. However, it is tempting to suggest that the difference is owing to accumulation of iron, but this should be further investigated. In the previous report on Sicilian population, considering the historical and social contest in which the generation of women under study lived, we have suggested that the possession of iron sparing alleles significantly increases women possibility to reach longevity. For instance, in Sicily as well in Sardinia and in other pre-industrial countries, a lot of pregnancies and an iron-poor diet, consisted mainly in grains, vegetables and fruits, were yet the rule for the women born at the beginning of last century (Shorter, 1982). Future research needs to elucidate this point by analysing other populations. It is seemingly puzzling that HFE mutations have been suggested to be involved in unsuccessful ageing too. In fact, these mutations have been suggested to be involved in Alzheimer disease, in chronic liver diseases, and coronary heart disease (Bathum et al., 2001; Balistreri et al., 2002; Candore et al., 2002). However, it is not surprising that HFE mutations are associated both with longevity and diseases affecting life span. In fact, available data from genetics of longevity (Caruso et al., 2000, 2001) show that longevity may be associated with alleles with increased risk to a variety of diseases in the younger phases of life (antagonistic pleiotropy). This
C. Carru et al. / Mechanisms of Ageing and Development 124 (2003) 529 /532
531
Table 1 Allele frequencies for HFE polymorphisms in 60 controls ( /60 years) and 57 centenarians ( /100 years) from Sardinia C282Y
/60 years /100 years
H63D
S65C
Wild type
Allele
Wild type
Allele
Wild type
Allele
120 (100%) 114 (100%)
0 (0%) 0 (0%)
99 (82.5%) 87 (76.3%)
21 (17.5%) 27 (23.7%)
119 (99.2%) 110 (96.5%)
1 (0.8%) 4 (3.5%)
theory is also a possible explanation for the apparent discrepancy with a recent study performed in Denmark. In a C282Y mutation high-carrier frequency population as Denmark (Lucotte 2001; Bathum et al., 2001), this mutation shows an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy. The observed reduction in C282Y mutation carrier frequency persists until age 95 years; however, the frequency in the centenarian group was the same as that in the youngest group for both men and women (Bathum et al., 2001). So, in that study heterozygosity for C282Y has a higher mortality rate in the younger groups but becomes beneficial in the oldest old. All together present and previous reports seem to strongly suggest that longevity is the results of interaction between genetic and environmental factors that in different age, gender and population may result in a successful or unsuccessful ageing.
Acknowledgements The authors are grateful to Dr Alessandra Errigo for the help in patient recruitment and in blood samples processing. The ‘AKEA Project’ coordinated by Professor L. Deiana was funded by grants from the Regione Autonoma della Sardegna and MIUR (ex 40% and ex 60%). The ‘Gruppo di Studio sull’immunosenescenza’ coordinated by Professor C. Caruso was funded by grants from MIUR, Rome (ex 40%, to CC and DL; ex 60% to GC and GCR). The collaboration between this group and the Istituto Nazionale di Riposo e Cura per Anziani was enhanced by a cooperation contract (Longevity and elderly disability biological markers) and by the EU thematic network program ImAginE (QLK6CT-1999-02031).
References Andrews, N.C., 1999. Disorders of iron metabolism. N. Engl. J. Med. 341 (26), 1986 /1995. Balistreri, C.R., Candore, G., Almasio, P., Colonna Romano, G., Craxi, A., Motta, M., Piazza, G., Malaguarnera, M., Lio, D., Caruso, C., 2002. Analysis of Haemochromatosis gene mutations in the Sicilian Population: implications for survival and longevity, Arch. Gerontol. Geriatr. 58, 35 /42.
Bathum, L., Christiansen, L., Nybo, H., Ranberg, K.A., Gaist, D., Jeune, B., Petersen, N.E., Vaupel, J., Christensen, K., 2001. Association of mutations in the hemochromatosis gene with shorter life expectancy. Arch. Intern. Med. 161, 2441 /2444. Burt, M.J., George, P.M., Upton, J.D., Collett, J.A., Frampton, C.M., Chapman, T.M., Walmsley, T.A., Chapman, B.A., 1998. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 43, 830 /836. Campo, S., Restuccia, T., Villari, D., et al., 2001. Analysis of haemochromatosis gene mutations in a population from the Mediterranean Basin. Liver 21, 233 /236. Candore, G., Licastro, F., Chiappelli, M., Franceschi, C., Lio, D., Balistreri, C.R., Piazza, G., Colonna-Romano, G., Grimaldi, L.H., Caruso, C., 2003. Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer’s disease patients from Northern Italy. Mech. Ageing Dev. 124, 525 /528. Caruso, C., Candore, G., Colonna Romano, G., Lio, D., Bonafe, M., Valensin, S., Franceschi, C., 2000. HLA, aging and longevity a critical reappraisal. Human Immunol. 61, 942 /949. Caruso, C., Candore, G., Colonna Romano, G., Lio, D., Bonafe, M., Valensin, S., Franceschi, C., 2001. Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data. Mech. Ageing Dev. 122, 445 /462. Contu, L., Arras, M., Carcassi, C., La Nasa, G., Mulargia, M., 1992. HLA structure of the Sardinian population: a haplotype study of 551 families. Tissue Antigens 40, 165 /174. Dawkins, R., Leelayuwat, C., Gaudieri, S., et al., 1999. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunol. Rev. 167, 275 /304. Deiana, L., Ferrucci, L., Pes, G.M., Carru, C., Delitala, G., Ganau, A., Mariotti, S., Nieddu, A., Pettinato, S., Putzu, P., Franceschi, C., Baggio, G., 1999. AKEntAnnos. The sardinia study of extreme longevity. Aging Clin. Exp. Res. 11, 142 /149. Feder, J.N., Gnirke, A., Thomas, W., et al., 1996. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399 /408. Klein, J., Sato, A., 2000. The HLA system. Second of two parts. N. Engl. J. Med. 343, 782 /790. Lio, D., Balistreri, C.R., Colonna-Romano, G., Motta, M., Franceschi, C., Malaguarnera, M., Candore, G., Caruso, C., 2002. Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population. Genes Immunity 3, 20 /24. Lucotte, G., 2001. Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Mol. Dis. 27 (2), 549 /556. Merryweather-Clarke, A.T., Pointon, J.J., Shearman, J.D., Robson, K.J.H., 1997. Global prevalence of putative haemochromatosis mutations. J. Med. Genet. 34, 275 /278. Mura, C., Raguenes, O., Ferec, C., 1999. HFE mutations analysis in 711 hemochromatosis probands evidence for S65C implication in mild form of hemochromatosis. Blood 1593, 2502 /2505. Oppenheimer, S.J., 2001. Iron and its relation to immunity and infectious disease. J. Nutr. 131, 616S /633S.
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