Background Human leukocyte antigen (HLA) genes are key regulators of immune function and have been implicated in susceptibility to various diseases. However, their role in healthy longevity remains unclear. Here, we investigate the relationship between disease-associated HLA alleles and the likelihood of becoming a cognitively healthy centenarian (CHC).

Methods We imputed HLA genotypes using genetic data from 3,634 individuals, including 354 CHCs from the Dutch 100-plus Study and 3,269 middle-aged healthy individuals from multiple Dutch cohorts. We examined associations between 59 HLA alleles previously linked to 12 diseases—including Alzheimer’s disease (AD), ten autoimmune disorders, and SARS- CoV-2—and the likelihood of becoming a CHC. Logistic regression models were used to estimate odds ratios (ORs), adjusting for population structure. We then calculated centenarian effect ratios (CERs) to compare the effect sizes of HLA alleles on the chance of becoming a CHC relative to their known effects on disease susceptibility, assessing the directions of potential pleiotropic effects.

Results While the genomes of CHCs were not enriched with any specific HLA alleles, six alleles reduced the likelihood of becoming a CHC (ORs=0.59–0.74, FDR<0.1). These alleles clustered into three haplotypes based on linkage disequilibrium: a class II haplotype (HLA- DRB1*01:01, HLA-DQA1*01:01, HLA-DQB1*05:01), a class I haplotype (HLA-C*03:04, HLA-B*40:01), and an independent class I allele (HLA-A*02:01). We identified both synergistic and antagonistic pleiotropic relationships between autoimmune disease-associated HLA alleles and becoming a CHC, with similar magnitudes of effect sizes. HLA alleles associated with increased risk of AD consistently exhibited synergistic pleiotropies, with a 5- to 10-fold larger effect on decreased likelihood of healthy longevity.

Conclusions Our findings highlight a complex interplay between HLA alleles associated with autoimmune disease susceptibility and healthy longevity. The strongly increased effect sizes and synergistic pleiotropic relationships between the likelihood of becoming a cognitively healthy centenarian and HLA alleles previously associated with AD, highlight the involvement of immune-related mechanisms in longevity and neurodegeneration. Further studies, employing Next-Generation-Sequencing and Long-Read-Sequencing, preferably in diverse populations, are needed to map our findings to the full genetic resolution of the HLA region.

DAS, NT, MHul, AS, NvdS, MHui, YP, WvdF, ES, MR, SvdL declare that they have no competing interests. HH received consultancy fees from Retromer Therapeutics and Muna Therapeutics. BU received research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics.

Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. DAS is supported by a VIDI Award (received by HH; WO/ZonMW # 09150172010083). NT SvdL MR HH and WvdF are recipients of ABOARD. ABOARD is a public and private partnership receiving funding from ZonMW National Dementia program (#73305095007) and Health∼Holland Topsector Life Sciences & Health (PPP-allowance;#LSHM20106). More than 30 partners including de Hersenstichting (Dutch Brain Foundation) participate in ABOARD.

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