Influence of HLA-G 3′ Untranslated Region Haplotypes and SNP +3422 Gene Variants […] During Acute and Post-Acute Phases […], 2024, Rohn+

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
Hana Rohn; Fynn Elischer; Louisa Larbig; Sarah Jansen; Sabine Schramm; Mona Otte; Margarethe Konik; Krystallenia Paniskaki; Peter Weber; Johanna Reinold; Anja Gäckler; Adalbert Krawczyk; Benjamin Wilde; Mirko Trilling; Rafael T. Michita; Birte Möhlendick; Winfried Siffert; Thorsten Brenner; Hannah Dinse; Eva M. Skoda; Peter A. Horn; Oliver Witzke; Vera Rebmann

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 SARSCoV-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.

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