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

In an effort to reassess the contribution of HLA-DRB1 polymorphisms to inter-individual variations of human longevity, we have compared their genotypic distributions 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.