Combined Linkage and Association Studies Show that HLA Class II Variants Control Levels of Antibodies against Epstein-Barr Virus Antigens

Vincent Pedergnana (1, 2) , Laurène Syx (1, 2) , Aurélie Cobat (1, 2) , Julien Guergnon (3) , Pauline Brice (4) , Christophe Fermé (5) , Patrice Carde (5, 6) , Olivier Hermine (7) , Catherine Le-Pendeven (8) , Corinne Amiel (8) , Yassine Taoufik (9, 10) , Alexandre Alcaïs (1, 2) , Ioannis Theodorou (3) , Caroline Besson (9, 10) , Laurent Abel (1, 2, 11)

1 Inserm U980 - Génétique Humaine des Maladies Infectieuses
2 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
3 Immunité et Infection
4 Service d'hématologie-oncologie adultes
5 IGR - Institut Gustave Roussy
6 Département d'hématologie [Gustave Roussy]
7 Hôpital Necker - Enfants Malades [AP-HP]
8 CHU Tenon [AP-HP]
9 Régulation de la réponse immune, infection VIH-1 et autoimmunité
10 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
11 Rockefeller University [New York]

Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infection is associated with the development of several cancers, including Hodgkin lymphoma (HL). Elevated levels of anti-EBV antibodies have been associated with increased risk of HL. There is growing evidence that genetic factors control the levels of antibodies against EBV antigens. Here, we conducted linkage and association studies to search for genetic factors influencing either anti-viral capsid antigen (VCA) or anti-Epstein Barr nuclear antigen-1 (EBNA-1) IgG levels in a unique cohort of 424 individuals of European origin from 119 French families recruited through a Hodgkin lymphoma (HL) patient. No major locus controlling anti-VCA antibody levels was identified. However, we found that the HLA region influenced anti-EBNA-1 IgG titers. Refined association studies in this region identified a cluster of HLA class II variants associated with anti-EBNA-1 IgG titers (e.g. p = 5×10(-5) for rs9268403). The major allele of rs9268403 conferring a predisposition to high anti-EBNA-1 antibody levels was also associated with an increased risk of HL (p = 0.02). In summary, this study shows that HLA class II variants influenced anti-EBNA-1 IgG titers in a European population. It further shows the role of the same variants in the risk of HL.

Domains: Cancer; Hematology; Infectious diseases; Adaptive immunology; Human genetics

Vincent Pedergnana, Laurène Syx, Aurélie Cobat, Julien Guergnon, Pauline Brice, et al.. Combined Linkage and Association Studies Show that HLA Class II Variants Control Levels of Antibodies against Epstein-Barr Virus Antigens. PLoS ONE, 2014, 9 (7), pp.e102501. ⟨10.1371/journal.pone.0102501⟩. ⟨hal-03684734⟩