A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.
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.
Prokunina
Ludmila
L
Institute of Genetics & Pathology, Section for Medical Genetics, Rudbeck Laboratories, University of Uppsala, Dag Hammarsjölds väg 20, 751 85, Uppsala, Sweden.
Castillejo-López
Casimiro
C
Oberg
Fredrik
F
Gunnarsson
Iva
I
Berg
Louise
L
Magnusson
Veronica
V
Brookes
Anthony J
AJ
Tentler
Dmitry
D
Kristjansdóttir
Helga
H
Gröndal
Gerdur
G
Bolstad
Anne Isine
AI
Svenungsson
Elisabet
E
Lundberg
Ingrid
I
Sturfelt
Gunnar
G
Jönssen
Andreas
A
Truedsson
Lennart
L
Lima
Guadalupe
G
Alcocer-Varela
Jorge
J
Jonsson
Roland
R
Gyllensten
Ulf B
UB
Harley
John B
JB
Alarcón-Segovia
Donato
D
Steinsson
Kristján
K
Alarcón-Riquelme
Marta E
ME
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
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