Sequence-based HLA genotyping identifies six candidate alleles associated with human longevity in Germans

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Aims: Human leukocyte antigen (HLA) polymorphism influences immunity by balancing protection against pathogens with the preservation of self-tolerance. This balance has been proposed to affect longevity, and associations with HLA variants have been reported. However, studies in this field have often yielded inconsistent findings due to small sample sizes and low-resolution genotyping methods. We aimed to identify HLA alleles linked to longevity while overcoming these previous limitations. Methods: We performed high-resolution HLA genotyping using targeted sequencing (HLA-seq) in 1,265 long-lived individuals (long-lived individuals (LLI); ≥ 94 years) from Germany and compared their HLA allele frequencies with those of a large control population of 3.4 million individuals from the German Bone Marrow Donor Registry (DKMS) using χ2 (chi-square) tests. Results: Six HLA alleles were significantly associated with longevity. Of those, two exhibited the most robust associations: A*01:01g (odds ratio (OR) = 0.87; 95% confidence interval (CI): 0.80-0.95; adj. P = 0.02) and DRB1*13:02g (OR = 1.24; 95% CI: 1.10-1.41; P = 0.01). DRB1*13:02g was replicated in the UK Biobank after Bonferroni correction, whereas A*01:01g showed directionally concordant nominal support but did not remain significant after multiple-testing correction. Conclusion: Both DRB1*13:02g and A*01:01g have previously been implicated in dementia-related phenotypes. These observations support the hypothesis that HLA variation may influence longevity partly through pathways linked to neurodegeneration. This study provides a high-resolution (2-field) HLA dataset for a longevity cohort, which should be valuable for future investigations.

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