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Background <p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a wide-range of clinical outcomes, which have been extensively studied through genome-wide association studies (GWAS).</p> Methods <p>Starting from lead genetic variants associated with COVID-19 infection and severity, we identified a subset of non-coding candidate variants with potential regulatory functions. We combined bioinformatics analysis and functional screening in three cell lines to provide evidence for regulatory activity. We then performed a genetic study to test the association of our selected candidates with disease susceptibility followed by the functional validation of the risk haplotype. </p> Results <p>We prioritized two <i>DPP9</i> variants within a haplotype that increases the risk of severe COVID-19. This haplotype exhibited increased regulatory activity and altered transcription factor binding, suggesting its role in influencing COVID-19 severity by modulating DPP9 expression in immune and lung cell types.</p> Conclusions <p>The interest of our study lies in the functional characterization of regulatory variants responsible for increased levels of DPP9 and lung damage observed in patients with severe COVID-19. These findings advance our understanding of genetic risk factors for COVID-19 and highlight functional SNPs that may guide future therapeutic research.</p>

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Identification and functional characterization of regulatory variants in DPP9 associated with COVID-19 severity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Gaëlle Farah,
  • Magali Torres,
  • Leo Henches,
  • Hugues Aschard,
  • Jade Ghosn,
  • Xavier Duval,
  • Laurent Abel,
  • Andres Alcover,
  • Philippe Bousso,
  • Nollaig Bourke,
  • Petter Brodin,
  • Pierre Bruhns,
  • Nadine Cerf-Bensussan,
  • Ana Cumano,
  • Christophe D’Enfert,
  • Caroline Demangel,
  • Ludovic Deriano,
  • Marie-Agnès Dillies,
  • James Di Santo,
  • Gérard Eberl,
  • Jost Enninga,
  • Jacques Fellay,
  • Ivo Gomperts-Boneca,
  • Milena Hasan,
  • Gunilla Karlsson Hedestam,
  • Serge Hercberg,
  • Molly A. Ingersoll,
  • Olivier Lantz,
  • Rose Anne Kenny,
  • Mickaël Ménager,
  • Hugo Mouquet,
  • Cliona O’Farrelly,
  • Etienne Patin,
  • Antonio Rausell,
  • Frédéric Rieux-Laucat,
  • Lars Rogge,
  • Magnus Fontes,
  • Anavaj Sakuntabhai,
  • Olivier Schwartz,
  • Benno Schwikowski,
  • Spencer Shorte,
  • Frédéric Tangy,
  • Antoine Toubert,
  • Mathilde Touvier,
  • Marie-Noëlle Ungeheuer,
  • Christophe Zimmer,
  • Matthew L. Albert,
  • Darragh Duffy,
  • Lluis Quintana-Murci,
  • Amal Abrous,
  • Delphine Bachelet,
  • Marie Bartoli,
  • Lila Bouadma,
  • Minerva Cervantes-Gonzalez,
  • Anissa Chair,
  • Charlotte Charpentier,
  • Sandrine Couffin-Cadiergues,
  • Nathalie De Castro,
  • Diane Descamps,
  • Hang Doan,
  • Céline Dorival,
  • Hélène Esperou,
  • Aline-Marie Florence,
  • François Goehringer,
  • Maxime Goyat,
  • Ikram Houas,
  • Isabelle Hoffmann,
  • Salma Jaafoura,
  • Simon Jamard,
  • Nadhem Lafhej,
  • Cédric Laouénan,
  • Soizic Le Mestre,
  • France Mentré,
  • Christelle Paul,
  • Aurélie Papadopoulos,
  • Marion Schneider,
  • Coralie Tardivon,
  • Sarah Tubiana,
  • Aurélie Wiedemann,
  • Pascal Rihet,
  • Salvatore Spicuglia,
  • Sandrine Marquet

摘要

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to a wide-range of clinical outcomes, which have been extensively studied through genome-wide association studies (GWAS).

Methods

Starting from lead genetic variants associated with COVID-19 infection and severity, we identified a subset of non-coding candidate variants with potential regulatory functions. We combined bioinformatics analysis and functional screening in three cell lines to provide evidence for regulatory activity. We then performed a genetic study to test the association of our selected candidates with disease susceptibility followed by the functional validation of the risk haplotype.

Results

We prioritized two DPP9 variants within a haplotype that increases the risk of severe COVID-19. This haplotype exhibited increased regulatory activity and altered transcription factor binding, suggesting its role in influencing COVID-19 severity by modulating DPP9 expression in immune and lung cell types.

Conclusions

The interest of our study lies in the functional characterization of regulatory variants responsible for increased levels of DPP9 and lung damage observed in patients with severe COVID-19. These findings advance our understanding of genetic risk factors for COVID-19 and highlight functional SNPs that may guide future therapeutic research.