# Genetic differences in the HLA region contribute to the variability in SARS‐CoV‐2 vaccine responsiveness of older persons: the Doetinchem Cohort Study

## TL;DR

This study finds that genetic differences in the HLA region affect how older people respond to SARS-CoV-2 vaccines, with some variants linked to weaker antibody responses.

## Contribution

The study identifies HLA region genetic variants as a key contributor to vaccine response variability in older individuals.

## Key findings

- Genetic variants on Chromosome 5 and HLA region on chromosome 6p21 are linked to SARS-CoV-2 vaccine antibody responses.
- Polygenic scores explain up to 9% of the variance in antibody responses after vaccination.
- HLA genes are associated with lower anti-SARS-CoV-2 IgG antibody responses and immune-related pathways.

## Abstract

Older persons generally have weaker antibody responses to vaccines than younger individuals, but heterogeneity is large. We aimed to identify genetic variants associated with primary SARS‐CoV‐2 vaccine‐induced antibody responses in older persons that might contribute to this heterogeneity.

Demographic and genotype data were collected in the Doetinchem Cohort Study prior to the COVID‐19 pandemic. Antibody responses were measured 1 month after the first and second SARS‐CoV‐2 vaccinations, and genome‐wide association analysis was performed in 842 and 890 individuals respectively. Polygenic scores were calculated and tested in an independent sample, and the variance explained by the scores was estimated using a bootstrap procedure. Genes were mapped to genome‐wide suggestive (P < 1 × 10−5) loci, and gene set enrichment was performed using the hypergeometric test.

Antibody responses 1 month after the first and second SARS‐CoV‐2 vaccinations were linked to genome‐wide significant (P < 5 × 10−8) loci on Chromosome 5. Polygenic scores related to these antibody responses could explain 9% (95% CI P1: [−4% to 21%], 95% CI P2: [−4% to 24%]) of the variance. Genome‐wide suggestive loci related to the responses after two vaccinations could be mapped to several genes in the human leukocyte antigen (HLA) region on chromosome 6p21.

Genetic variation is suggested to play a role in the primary vaccine‐induced IgG antibody responses to SARS‐CoV‐2 in older persons. The most prominent source of variation was found to lie in HLA genes, which are enriched in several immune pathways and immune‐mediated diseases.

We identified genetic variants that contribute to the heterogeneity in primary SARS‐CoV‐2 vaccine‐induced antibody responses in older persons. Most prominently were genetic variants in the HLA region that were associated with lower anti‐SARS‐CoV‐2‐S1 IgG antibody responses and could be linked to various immune pathways and immune‐mediated diseases.