Taken together, these data provide compelling evidence for direct influences on survival of three HLA-DR variants, taking sex- specific effects into account. Common features may be observed concerning the two variants that display sex-dependent effects: they are associated with sex-specific pathologies, in particular with lymphoproliferative diseases. Their associations with longevity may provide interesting examples of antagonistic pleiotropy (55), whereby the same allele has negative and positive effects on survival, the latter taking the edge very late in life. It is anecdotal that the oldest male centenarian in our cohort, who lived to 111 years, was homozygous for DR7.

MATERIALS AND METHODS

Subjects

Centenarians were individuals in their 100th year recruited in the French population on the mere basis of chronological age: >99 years on the day of blood collection (3) (mean age: 100.9 ± 0.35, 101.25 ± 0.21, 101.2 ± 0.18 for male, female and overall groups, respectively). These figures are the average for the complete cohort of 533 centenarians: the first cohort of 325 centenarians comprises samples collected from 1991 to 1994, while samples from the second cohort of 208 centenarians were collected later. Longevous siblings were recruited according to our set criterion for familial longevity: at least two longevous members in the sibship, i.e. >90 years old for men, >95 years old for women (mean age: 93.4 ± 0.78, 95.7 ± 1.05 and 94.7 ± 0.69 for male, female and overall groups, respectively). The 229 nonagenarians that compose our SIB group belong to 127 different sibships. Control adults had donated blood at the different regional immunology centres throughout the country and genotypic data were kindly provided by these centres. HLA-DR allele distributions have been published for the Marseille (66) and Bretagne (67) populations.

Differences between the long-lived groups VIE and SIB are summarized in Table 6. Three alternative interpretations of these differences are possible: (i) they indicate different genetic compo- nents for familial and individual longevity; (ii) they merely reflect sampling fluctuations; or (iii) they arise from the age difference between the two groups. The third alternative would imply that an astonishingly strong selection on HLA-DR alleles occurs between ages 95 and 100. It is all the more unlikely that in the subset of SIB-centenarians, DR11 frequency was 22% in 50 women (versus 12% in female VIE) and DR3 frequency was 15.6% in 16 men (versus 6.7% in male VIE). The second alternative cannot be dismissed until an independent SIB cohort is examined. If the familial effect holds true, it may even be underestimated here for want of reliable information on the families of most centenarians in the VIE group. For example, our oldest centenarian, subject J.C. who lived to the ripe age of 122, was DR11/DR15. A genealogic study of her ancestry revealed a highly significant longevity trend up to the

Table 6. Differences between the two long-lived groups SIB and VIE

VIE SIB DR3 decreased in males (6.7% versus 11%) DR3 increased in males (13.4% versus 11%) DR11 not affected in females (11.8% versus 13.1%) DR11 increased in females (23.4% versus 13.1%) DR13 increased in both genders (17.7% versus 12.8%) DR13 not affected in any gender (12.2% versus 12.8%) Increased homozygosity (15% versus 11.1%) No difference in homozygosity (11.5% versus 11.1%)

Toro, A.I. and Ossa, J. (

) PCR activity of CMV in healthy CMV-sero- positive individuals: does latency need a redefinition? Res. Virol.,

,

–

Smith, G.S. and Walford, R.L. (

) Influence of the main histocompatibil- ity complex on ageing in mice. Nature,

,

–

Yunis, E.J. and Salazar, M. (

) Genetics of life span in mice. Genetica,

,

–

Macurova, H., Ivanyi, P., Sajdlova, H. and Trojan, J. (

) HLA antigens in aged persons. Tissue Antigens,

,

–

Drouet, E., Colimon, R., Michelson, S., Fourcade, N., Niveleau, A., Ducere, C., Boibieux, A., Chevallier, M. and Denoyel, G. (

) Monitoring levels of human cytomegalovirus DNA in blood after liver transplantation. J. Clin. Microbiol.,

,

–

Yarnell, J.W., St Leger, A.S., Balfour, I.C. and Russell, R.B. (

) The distribution, age effects and disease associations of HLA antigens and other blood group markers in a random sample of an elderly population. J. Chron. Dis.,

,

–

Proust, J., Moulias, R., Fumeron, F., Bekkhoucha, F., Busson, M., Schmid, M. and Hors, J. (

) HLA and longevity. Tissue Antigens,

,

–

Gerkins, V.R., Ting, A. and Menck, H.T. (

) HLA heterozygosity as a genetic marker of long-term survival. J. Natl Cancer Inst.,

,

–

Blackwelder, W.C., Mittal, K.K., M

amara, P.M. and Payne, F.J. (

) Lack of association between HLA and age in an aging population. Tissue Antigens,

,

–

Takata, H., Suzuki, M., Ishii, T., Sekiguchi, S. and Iri, H. (

) Influence of major histocompatibility complex region genes on human longevity among Okinawan-Japanese centenarians and nonagenarians. Lancet,

–

Lagaay, A.M., D’Amaro, J., Ligthart, G.J., Schreuder, G.M., Van Rood, J.J. and Hijmans, W. (

) Longevity and heredity in humans. Association with the human leukocyte antigen phenotype. Ann. NY Acad. Sci.,

,

–

Yunis, E.J., Watson, A., Gelman, S.L., Sylvia, S.L., Bronson, R. and Dorf, D.E. (

) Traits that influence longevity in mice. Genetics,

,

–

Lerner, S.P. and Finch, C.E. (

) The major histocompatibility complex and reproductive functions. Endocrine Rev.,

,

–

Gozlan, J., Laporte, J.P., Lesage, S., Labopin, M., Najman, A.G. and Petit, J.C. (

) Monitoring of cytomegalovirus infection and disease in bone marrow recipients by reverse transcription-PCR and comparison with PCR and blood and urine cultures. J. Clin. Microbiol.,

,

–

Grundy, J.E., Ehrnst, A., Einsele, H., Emery, V.C., Hebart, H., Prentice, H.G. and Ljungman, P. (

) A three-center European external quality control study of PCR detection of cytomegalovirus DNA in blood. J. Clin. Microbiol.,

,