Despite considerable effort, and the development of vast databases of genetic information, very few associations between specific genetic variants and longevity replicate across study populations, and the effect sizes are near all small. Based on the evidence to date, we should expect the genetic contribution to longevity to be small for most people, and across a population to be made up of tiny, conditional effects from thousands of gene variants. In this landscape, any new longevity-associated variant that occurs in multiple study populations is an unusual discovery worthy of note, even if the effect size is modest and it acts to reduce the odds of survival in later life.
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. We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Subsequently, significant associations were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank.
Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity. 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.
In conclusion, 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.
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