We found a significant increase of HLA-DR11 in women belonging to long-lived sibships but not in centenarians. Lagaay et al. found that the association with DR5 in longevous women was entirely borne by DR11 when DR5 was split into its subtypes DR11 and DR12 (16). Our results may allow distinguishing between individual and familial longevity for the first time. Large-scale genealogic studies have demonstrated a correlation between fertility and longevity and shown that longevity is more correlated among siblings of the same sex, especially female siblings (57,58).

The prevalence of thyroid disorders is higher in females, and it is interesting that centenarians were found to have lower levels of thyroid auto-antibodies than elderly subjects in the 70-85 years range (43), which could be a clue to underlying genetic factors. Evolutionary considerations lead us to think that this clustering is not merely coincidental and that one may indeed expect epistasis between closely linked variants on life cycle traits, including lifespan (63). The challenge, typical of HLA associations, will be to distinguish primary effects from secondary associations due to linkage disequilibrium (64,65). Other loci are currently under investigation in the HLA region. The involvement of HLA in longevity may well turn out to be exemplary, in complexity as well as instructiveness.

Centenarians were individuals in their 100th year recruited in the French population solely on the 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 and >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 different regional immunology centers throughout the country, and genotypic data were kindly provided by these centers. HLA-DR allele distributions have been published for 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 components for familial and individual longevity, (ii) they merely reflect sampling fluctuations, or (iii) they arise from the age difference between the two groups. 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.

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, particularly 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 FrenchVersus 11%), DR11 is 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 is not affected in any gender (12.2% versus 12.8%). There is an increased homozygosity (15% versus 11.1%) and no difference in homozygosity (11.5% versus 11.1%).