title: A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.
abstract: Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.
authors.affiliation: Institute of Genetics & Pathology, Section for Medical Genetics, Rudbeck Laboratories, University of Uppsala, Dag Hammarsjölds väg 20, 751 85, Uppsala, Sweden.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina
authors.forename: Casimiro
authors.initials: C
authors.lastname: Castillejo-López
authors.forename: Fredrik
authors.initials: F
authors.lastname: Oberg
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Louise
authors.initials: L
authors.lastname: Berg
authors.forename: Veronica
authors.initials: V
authors.lastname: Magnusson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Brookes
authors.forename: Dmitry
authors.initials: D
authors.lastname: Tentler
authors.forename: Helga
authors.initials: H
authors.lastname: Kristjansdóttir
authors.forename: Gerdur
authors.initials: G
authors.lastname: Gröndal
authors.forename: Anne Isine
authors.initials: AI
authors.lastname: Bolstad
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lundberg
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönssen
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Lima
authors.forename: Jorge
authors.initials: J
authors.lastname: Alcocer-Varela
authors.forename: Roland
authors.initials: R
authors.lastname: Jonsson
authors.forename: Ulf B
authors.initials: UB
authors.lastname: Gyllensten
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Donato
authors.initials: D
authors.lastname: Alarcón-Segovia
authors.forename: Kristján
authors.initials: K
authors.lastname: Steinsson
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000483:Alleles; D019943:Amino Acid Substitution; D015703:Antigens, CD; D000954:Antigens, Surface / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002457:Cell Extracts; D002467:Cell Nucleus / Q000737:chemistry; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000166:cytology; D015810:Linkage Disequilibrium; D008126:Lod Score; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor; D011401:Promoter Regions, Genetic; D020080:Tandem Repeat Sequences; D014157:Transcription Factors
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D002457:Cell Extracts; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D014157:Transcription Factors