HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity

Rayna Ivanova1, Nicolas Hénon2, Virginia Lepage1, Dominique Charron1, Eric Vicaut3 and François Schächter2,*

1Laboratoire d’Histocompatibilité, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France, 2Fondation Jean Dausset—CEPH, 27 rue Juliette Dodu, 75010 Paris, France and 3Laboratoire de Hôpital Fernand Vidal, 200 rue du Faubourg Saint Denis, 75010 Paris, France

Received August 5, 1997; Revised and Accepted November 21, 1997

In an effort to reassess the contribution of HLA-DRB1 polymorphisms to inter-individual variations of human longevity, we have compared their genotypic distribu- tions between longevous and adult control groups in the French population. The longevous groups included two independent cohorts totalling 533 centenarians, and 163 nonagenarian siblings. Allelic distributions were significantly different between controls and longevous groups. Three individual alleles were mostly responsible for these differences: DR7, DR11 and DR13. Multivariate logistic analyses were performed in order to sort out interactions between gender- and age-specific genetic effects. DR7 frequency was elevated in longevous men, in centenarians as well as nonagenarian siblings [OR = 1.72 (1.2–2.5)]. DR11’s influence on longevity displayed a significant interaction with sex, with an increase in women from longevous sibships [OR = 2.03 (1.4–3.0)]. DR13’s frequency was increased in centenarians of both genders [OR = 1.46 (1.2–1.75)]. These results are discussed in the context of other pathophysiological effects of the implicated alleles. Our data support 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 is an original finding for humans.

genotypes have strong influences on lifespan in mice (7,8). In the last 25 years, a fair number of studies have searched for the impact of polymorphic HLA genes on human longevity (9–16). These studies have yielded conflicting results so that, in spite of the impressive quantity of data generated on this issue, no clear consensus has been reached as to 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 consider- ing the large number of alleles examined; (ii) age cut-offs for inclusion differ from study to study and may not be old enough for the purpose of 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 that 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

INTRODUCTION

long-believed contention that there is a genetic component to inter-individual differences in human longevity (1,2). Genetic effects on human longevity were found at a few loci (3–5). The HLA locus, as the cradle of genetic polymorphism in humans, has been involved in associations with many diseases (6). MHC

*To whom correspondence should be addressed. Tel: +33 1 42 41 48 55; Fax: +33 1 41 16 71 59; Email: schachte@ccr.jussieu.fr

Overall distributions and allelic associations

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.