title: Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.
abstract: Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Prithvi
authors.initials: P
authors.lastname: Raj
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.|School of Biotechnology, Shri Mata Vaishno Devi University, Katra, India.
authors.forename: Ekta
authors.initials: E
authors.lastname: Rai
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Ran
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Wakeland
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Kasthuribai
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Carlos
authors.initials: C
authors.lastname: Arana
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Ferdicia
authors.initials: F
authors.lastname: Carr-Johnson
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, United States.
authors.forename: Mitja
authors.initials: M
authors.lastname: Mitrovic
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
authors.forename: Graham B
authors.initials: GB
authors.lastname: Wiley
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Pole de pathologies rhumatismales, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Bruxelles, Belgium.
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Lauwerys
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State Medical School, Hershey, United States.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Olsen
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Cotsapas
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.|Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Garcia
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States.|Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, United States.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.affiliation: Cincinnati VA Medical Center, Cincinnati, United States.|Cincinnati Children's Hospital Medical Center, Cincinnati, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, United States.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Pasare
authors.affiliation: Rheumatic Diseases Division, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Karp
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Quan Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Edward K
authors.identifier: http://orcid.org/0000-0002-7107-0992
authors.initials: EK
authors.lastname: Wakeland
mesh_terms: D015551:Autoimmunity; D003713:Dendritic Cells / Q000737:chemistry; D005060:Europe; D005786:Gene Expression Regulation; D006681:HLA-D Antigens / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis; D011110:Polymorphism, Genetic; D014481:United States; D044465:White People
chemical_list: D006681:HLA-D Antigens; D008565:Membrane Proteins
keywords: HLA; LD; SLE risk; evolutionary biology; genomics; haplotype; human; human biology; medicine; risk allele; targeted sequencing