HLA-DRB1*15:01 is associated with a reduced likelihood of longevity in northern European men.

Background: Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. Here, we addressed this gap by analysing the influence of HLA variation on longevity in Europeans.

Methods: We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Associations were evaluated with logistic regression, adjusting for multiple testing and population structure. Subsequently, significant associations (adjusted P ≤ 0.05) were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank. Furthermore, epitope binding and immunogenicity predictions were performed to detect potential mechanisms linking HLA alleles to longevity.

Results: Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity (adjusted P = 2.80 × 10^-2, odds ratio = 0.64, 95% CI: 0.48-0.82). In Germans, HLA-DRB1*15:01:01 was less frequent among male cases (10%) than controls (15%), whilst female cases exhibited no substantial decrease (14%), suggesting that men carrying this allele have a lower chance of becoming long-lived. This finding was replicated in the UK Biobank and found to be consistent in the Danish cohort. Computational predictions further revealed that HLA-DRB1*15:01 is more likely to trigger an immune response against an apolipoprotein B-100 (APOB-100) epitope than other HLA-DRB1 alleles. Furthermore, the overall predicted APOB-100 immunogenicity of all HLA-DRB1 alleles was significantly associated with longevity (estimate -0.11, SE = 0.03, P = 0.005).

Conclusions: The novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele. This hypothesis is based on prior research that has identified a male-specific association between HLA-DRB1*15:01:01 and AD. Additionally, it is likely that this link is mediated by increased immune reactivity against APOB-100, which is promoted by HLA-DRB1*15:01:01.