Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women1,2,3,4. 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 identified5,6,7,8,9. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families9,10. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease11,12,13,14. 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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gudmundsson, S. & Steinsson, K. Systemic lupus erythematosus in Iceland 1975 through 1984. A nationwide epidemiological study in an unselected population. J. Rheumatol. 17, 1162–1167 (1990).
Lawrence, R.C. et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 41, 778–799 (1998).
Ståhl-Hallengren, C., Jönsen, A., Nived, O. & Sturfelt, G. Incidence studies of systemic lupus erythematosus in Southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J. Rheumatol. 27, 685–691 (2000).
Arnett, F.C. & Reveille, J.D. Genetics of systemic lupus erythematosus. Rheum. Dis. Clin. North Am. 18, 865–892 (1992).
Moser, K.L. et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc. Natl Acad. Sci. USA 95, 14869–14874 (1998).
Gaffney, P.M. et al. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc. Natl Acad. Sci. USA 95, 14875–14879 (1998).
Gaffney, P.M. et al. Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families. Am. J. Hum. Genet. 66, 547–566 (2000).
Shai, R. et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum. Mol. Genet. 8, 639–644 (1999).
Lindqvist, A.K. et al. A susceptibility locus for systemic lupus erythematosus (hSLE1) in chromosome 2q. J. Autoimmun. 14, 169–178 (2000).
Magnusson, V. et al. Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics 70, 307–314 (2000).
Shinohara, T., Taniwaki, M., Ishida, Y., Kawaichi, M. & Honjo, T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 23, 704–706 (1994).
Finger, L.R. et al. The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. Gene 197, 177–187 (1997).
Vibhakar, R., Juan, G., Traganos, F., Darzynkiewicz, Z. & Finger, L.R. Activation-induced expression of human programmed death-1 gene in T-lymphocytes. Exp. Cell Res. 232, 25–28 (1997).
Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).
Thomson, G. Mapping disease genes: family-based association studies. Am. J. Hum. Genet. 57, 487–498 (1995).
Lutterbach, B. & Hiebert, S.W. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 245, 223–235 (2000).
Wong, H.K., Kammer, G.M., Dennis, G. & Tsokos, G.C. Abnormal NF-κ B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. J. Immunol. 163, 1682–1689 (1999).
Nishimura, H. & Honjo, T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 22, 265–268 (2001).
Goodnow, C.C. Pathways for self-tolerance and the treatment of autoimmune diseases. Lancet 357, 2115–2121 (2001).
Hugot, J.P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).
Tan, E.M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).
Lichter, P., Cremer, T., Borden, J., Manuelidis, L. & Ward, D.C. Delineation of individual human chromosomes in metaphase and interphase cells by in situ suppression hybridization using recombinant DNA libraries. Hum. Genet. 80, 224–234 (1988).
Howell, W.M., Jobs, M., Gyllensten, U. & Brookes, A.J. Dynamic allele-specific hybridization (D.A.S.H.). Nature Biotechnol. 17, 87–88 (1999).
Prince, J.A. et al. Robust and accurate single-nucleotide polymorphism genotyping by dynamic allele-specific hybridization (D.A.S.H.): design criteria and assay validation. Genome Res. 11, 152–162 (2001).
Andrews, N.C. & Faller, D.V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 19, 2499 (1991).
Bombardier, C., Gladman, D.D., Urowitz, M.B., Caron, D. & Chang, C.H. Derivation of the SLEDAI - a disease activity index for lupus patients. Arthritis Rheum. 35, 630–640 (1992).
Lathrop, M. Estimating genotype relative risk. Tissue Antigens 22, 160–166 (1983).
Martin, E.R., Monks, S.A, Warren, L.L. & Kaplan, N.L. The pedigree disequilibrium test. Am. J. Hum. Genet. 67, 146–154 (2000).
We gratefully acknowledge support from the European Commission, the Swedish Science Council, King Gustav V 80th-year Jubilee Foundation, the Swedish Association against Rheumatism, the US National Institutes of Health, the Lupus Multiplex Registry and Repository and the Genome Programme of the Swedish Foundation for Strategic Research (to L.P.). We thank the affected individuals and their families for their participation.
L.P. and M.E.A.-R. are shareholders in EVERYGENE AB (Uppsala, Sweden), which has filed patent applications for the results presented here, and have personal financial interests that may be affected by the publication of this article.
About this article
Cite this article
Prokunina, L., Castillejo-López, C., Öberg, F. et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32, 666–669 (2002). https://doi.org/10.1038/ng1020
Cell and Tissue Research (2021)
Programmed cell death-1 single-nucleotide polymorphism rs10204525 is associated with human immunodeficiency virus type 1 RNA viral load in HIV-1-infected Moroccan subjects
Medical Microbiology and Immunology (2021)
Cellular and Molecular Life Sciences (2021)
Nature Medicine (2021)
Inflammation and Regeneration (2020)