title: HLA B44 is associated with decreased severity of autoimmune lymphoproliferative syndrome in patients with CD95 defects (ALPS type Ia).
abstract: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis characterized by non-malignant lymphadenopathy and splenomegaly, expansion of T cells without either CD4 or CD8 surface markers, and increased incidence of autoimmune diseases and lymphoma. Most patients with ALPS have dominant, heterozygous mutations in tumor necrosis factor receptor superfamily member 6 (TNFRSF6), which encodes CD95, also known as Fas, a mediator of apoptosis. Penetrance and range of disease manifestations in ALPS are highly variable, even among family members who share the same dominant TNFRSF6 mutation. To evaluate HLA as a candidate modifier locus, we typed HLA A, B (including subtypes), and DQB alleles in 356 individuals from 63 unrelated families with defined TNFRSF6 mutations associated with ALPS. We also developed a quantitative severity score and performed statistical analysis. Among the healthier, mutation-bearing individuals, transmission of HLA B44 was significantly overrepresented (nominal P<0.0074) as compared to transmission in patients with severe clinical features of ALPS. The B44 allele may exert a protective role in ALPS.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Building 49, Room 4A14, Bethesda, MD 20892, USA.
authors.forename: Marla M
authors.initials: MM
authors.lastname: Vacek
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Roxanne E
authors.initials: RE
authors.lastname: Fischer
authors.forename: Janet K
authors.initials: JK
authors.lastname: Dale
authors.forename: Sharon
authors.initials: S
authors.lastname: Adams
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Straus
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D003627:Data Interpretation, Statistical; D005787:Gene Frequency; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D059948:HLA-B44 Antigen; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006650:Histocompatibility Testing; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D012720:Severity of Illness Index; D013577:Syndrome; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C040626:HLA-Dx antigen; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor