HLA-DR alleles have sex-dependent effects on survival and can differentiate between individual and familial longevity. The study compared the genotypic distributions of HLA-DRB1 polymorphisms between longevous and adult control groups in the French population. The longevous groups included two independent cohorts with 533 centenarians and 163 nonagenarian siblings. The allelic distributions were significantly different between the controls and longevous groups. Three individual alleles, DR7, DR11, and DR13, were mainly responsible for these differences.

Multivariate logistic analyses were performed to sort out interactions between gender- and age-specific genetic effects. DR7 frequency was higher in longevous men, in centenarians as well as nonagenarian siblings [OR = 1.72 (1.22-5)]. DR11's influence on longevity displayed a significant interaction with sex, with an increase in women from longevous sibships [OR = 2.03 (1.43-3.0)]. DR13's frequency was higher in centenarians of both genders [OR = 1.46 (1.21-1.75)]. These results are discussed concerning other pathophysiological effects of the implicated alleles.

The data supported the direct involvement of three HLA-DR alleles in survival at very old ages. Two allele-specific effects on longevity appear to depend on gender, and one on familial status for aggregation of this trait—the latter being an original finding for humans.

Genotypes have strong influences on lifespan in mice (7,8). In the last 25 years, many studies have searched for the impact of polymorphic HLA genes on human longevity (9-16). These studies have yielded conflicting results so that no clear consensus has been reached concerning the role of genetic variation at the HLA locus in longevity.

Major methodological problems account for the confusion in this field: (i) sample sizes are often insufficient to reach statistically significant conclusions considering the large number of alleles examined; (ii) age cut-offs for inclusion differ from study to study and may not be old enough for finding genetic effects on survival; (iii) sex is not always taken into account; (iv) matching between the old and the control populations is not always checked; and (v) the loci investigated within the HLA region differ from study to study.

Drawing examples from three studies that reported no effect of HLA loci on survival, one examined 182 individuals aged 70-93 years with no mention of sex (10), another included 18 males and 41 females >80 years old, of whom three males and seven females were >90 years (11), and a third examined 228 subjects aged 58-86 years with a median age of 68 and no mention of sex (14).

Proust et al. looked at HLA-A, -B, -C, and -DR specificities in 55 male and 100 female nonagenarians from France with mean ages >93 (12). They found that certain HLA-C alleles were increased in either male or female nonagenarians, and a haplotype bearing DR3 was increased in male nonagenarians. No difference could be detected without taking sex into account.

Takata et al. looked at HLA-A, -B, -C, -DR, and -DQ specificities in 82 centenarians and 20 nonagenarians from Japan comprising 22 males and 80 females (15). They found a decrease of DR9 and an increase of DR1 alleles in longevous individuals.

Lagaay et al. included 964 subjects >85 years old from Leiden, comprising 278 males and 686 females in what remains the largest-scale study to this date (16). These were compared with a control group, composed of 2444 young adults, for HLA-A, -B, -C, -DR, and -DQ specificities. The only emerging results were a decrease in B40 and an increase in DR5 in the 85+ women.

Altogether, it appears that effects on survival beyond age 90 of genetic variation at the HLA-DR locus were found whenever sex was taken into account, whereas they went undetected when sex was not considered. It may be relevant that in mice, where MHC effects on survival were first documented (7,17), MHC haplotypes have strong influences on fertility, fecundity, anatomy of reproductive organs and reproductive senescence (18). Therefore, there were strong grounds a priori to discriminate according to sex in the analysis.

There are no sex-related differences in HLA-DR allele frequencies in control populations, a fact well-established and directly verified here for the Paris and Strasbourg groups (P > 0.7 in a c2-test comparing the distributions between genders in a group totaling 1302 individuals).

Genotyped for HLA-DRB1 alleles, the following work pertains to the 13 generic DRB1 alleles, which are simply named after the generic DR specificities, such as DR3. Genotypes were gathered from adult blood donors (aged 20-60) in seven regions of France, totaling 2950 controls. The allele distributions for the different populations are given in Table 1. Fluctuations of certain allele frequencies occurred in several regions, but there was no significant overall heterogeneity among the distributions in control populations (P > 0.4 for a c2 test, df = 84). Therefore, genotypic data for controls were pooled in all subsequent calculations. In contrast, a comparison between centenarians and pooled controls revealed significant heterogeneity in the HLA-DR allele distributions (P < 0.05, c2 = 24 for df = 12). Four sets of longevous individuals were distinguished: male or female centenarians (VIE), male or female nonagenarian siblings (SIB).

Table 1 shows HLA-DRB1 allele frequencies in different regions of France. Subjects were genotyped at the DNA level in all groups except Marseille and Montpellier, for which results were from serotyping. For these last two groups, allele frequencies were computed from antigenic frequencies, whereas they were directly provided for other groups.