We found that homozygotes were significantly more frequent in centenarians of both genders than in controls and that they also exceeded the proportion expected under the assumption of Hardy– Weinberg equilibrium: these results suggest the existence of a homozygous advantage at the HLA-DR locus, at least very late in life. Data have been apparently conflicting concerning the effect of heterozygosity at the HLA locus on survival. Several studies have reported a survival advantage for heterozygotes (9,13,19,20), while others have not confirmed this observation (10,11,14,16). All reports of a heterozygous advantage bear on HLA-B or HLA-A alleles. One exception is Dorak et al. (21), who found that a haplotype between a DQ gene in the class II region and the HSP70 gene in the class III region progressively disappears with age in males. We are not aware of published data mentioning an increased heterozygosity at the HLA-DR locus in association with ageing. On the contrary, Takata et al. noted an increase of HLA-DR homozy- gotes in their centenarians (15). It has been remarked that a bias for homozygosity may stem from imperfect matching between centen- arians and controls, the former coming from a more rural background and a less admixed population. Although this may be the case, we note that the rate of homozygosity was not increased in the nonagenarian SIB group, for which the same argument would apply.

We found a significant increase of HLA-DR11 in women belonging to long-lived sibships, but not in centenarians. Most relevant to this result is the finding of Lagaay et al. that the association with DR5 in longevous women was entirely borne by DR11, when DR5 was split into its subtypes DR11 and DR12 (16). Their population from Leiden included 681 women older than 85. HLA-DR11 has been associated with Graves’ disease only in

tenth generation and she had a brother who died at the age of 97 [(56), and unpublished data]. In fact, she would have qualified as a SIB-centenarian, long before she was included in our study. Our results may allow, for the first time, to distinguish between individual and familial longevity. In this respect, 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).

Spanish population (42). The prevalence of thyroid disorders is higher in females and the latter study did not mention the sex of their patients. In this regard, 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. DR11 has been associated with alopaecia areata (44) and with hairy cell leukaemia (45), which affects mostly men above 40. The only suspected protective effect of HLA-DR11 is in IDDM, since a decrease of this allele has been reported in two independent populations of patients, from Sardinia and Belgium (46,47).

Walford and other gerontologists view the whole MHC as a region involved in the control of mammalian longevity (59,60). This view is based on substantial work in mice, showing the differential longevity of congenic mice differing at the MHC locus (7,17). The MHC region displays unique features: it contains one of the highest density of genes in the genome, packing >70 functional genes within ~ 4 Mb (61); several of these genes present the highest degree of polymorphism; yet, extended haplotypes are so well conserved that they are used in anthropological history.

longevity in both male and female centenarians. DR13 has been identified as protective against two major infectious diseases in West Africans: malaria parasitic and HBV infections (48,49). Functional data on peptide binding specificities suggest a molecular basis for these associations (50). DR13 confers a greater resistance to HIV infection in newborns from different ethnic groups (51). Negative associations of DR13 with cervical carcinoma have been reported in Hispanic and French women (52,53). DR13 was also negatively associated with mutiple sclerosis in Iceland (54). Therefore, this allele appears as protective in the context of both infectious and autoimmune diseases as well as neoplasia. Our findings are in agreement with these data, and suggest that HLA-DR13 imparts a survival advantage at very advanced ages.

Going one step further, it may be seen that this exceptional region contains genes involved in several aspects of the life cycle: fertility, endocrine controls—and lifespan (62). 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). So the direct impact of some HLA-DR alleles on longevity does not preclude other such genetic effects to be unravelled in this region. On the contrary: 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.