title: Combined linkage and association studies show that HLA class II variants control levels of antibodies against Epstein-Barr virus antigens.
abstract: 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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Laurène
authors.initials: L
authors.lastname: Syx
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Laboratory of Immunity and Infection, Institut National de la Santé et de la Recherche Médicale UMR-S 945, Université Pierre et Marie Curie Université Paris 6, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Guergnon
authors.affiliation: Service d'Onco-Hématologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Brice
authors.affiliation: Department of Medicine, Hôpital Gustave Roussy, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Fermé
authors.affiliation: Department of Medicine, Hôpital Gustave Roussy, Villejuif, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Carde
authors.affiliation: Service d'Hématologie adultes, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Laboratoire de Virologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Le-Pendeven
authors.affiliation: Laboratoire de Virologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Amiel
authors.affiliation: Assistance Publique-Hôpitaux de Paris, CHU Bicetre, Service d'Hématologie et Immunologie Biologiques, Le Kremlin-Bicetre, France, and Université Paris Sud, Faculte de Médecine, Le Kremlin-Bicetre, France, and Institut National de la Santé et de la Recherche Médicale U1012, Le Kremlin-Bicetre, France.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Taoufik
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.affiliation: Laboratory of Immunity and Infection, Institut National de la Santé et de la Recherche Médicale UMR-S 945, Université Pierre et Marie Curie Université Paris 6, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Theodorou
authors.affiliation: Assistance Publique-Hôpitaux de Paris, CHU Bicetre, Service d'Hématologie et Immunologie Biologiques, Le Kremlin-Bicetre, France, and Université Paris Sud, Faculte de Médecine, Le Kremlin-Bicetre, France, and Institut National de la Santé et de la Recherche Médicale U1012, Le Kremlin-Bicetre, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Besson
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood*; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005260:Female; D055106:Genome-Wide Association Study; D004854:Herpesvirus 4, Human / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D000949:Histocompatibility Antigens Class II