Influence of HLA‐G 3′ Untranslated Region Haplotypes and SNP +3422 Gene Variants as Host Genetic Factors on the Outcomes of SARS‐CoV‐2 Infection During Acute and Post‐Acute Phases in a German Cohort

ABSTRACT HLA‐G, an important immune‐checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS‐CoV‐2). Since specific single‐nucleotide polymorphisms (SNP) in the HLA‐G 3′untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA‐G expression, we analysed the contribution of these genetic variants as host factors in SARS‐CoV‐2 infection during acute and post‐acute phases. HLA‐G gene polymorphisms in the 3′UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID‐19) cohort during acute SARS‐CoV‐2 infection (N = 505) and in the post‐acute phase (N = 253). The HLA‐G 3′UTR haplotype known as UTR‐3 (p = 0.002) and the variant rs17875408 (also known as +3422) T variant (p = 0.004) are independent prognostic risk factors for fatal COVID‐19. The +3422T variant (p = 0.006) predicted also the early loss of neutralising SARS‐CoV‐2 antibodies. In addition, the HLA‐G 3′UTR haplotype UTR‐7 (p = 0.023) emerged as an independent prognostic factor for increased susceptibility to Long‐COVID symptoms after SARS‐CoV‐2 infection. Our study highlights that due to the variability of the 3′UTR genetic background, HLA‐G has the potential to contribute to the progression of SARS‐CoV‐2 infection, extending to the development of Long‐COVID symptoms, despite the likely alterations in the microenvironment and associated HLA‐G‐specific regulatory elements over the course of the disease. By spotlighting HLA‐G, the importance of the genetic background of IC and their pivotal role in modulating immune responses during and after COVID‐19 are emphasised.