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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 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.

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Figure 1: Structure of the predicted binding sites in the intronic enhancer within PDCD1.
Figure 2: Electrophoretic mobility shift, super-shift and competition assays with Jurkat nuclear cell extract and allelic variants of SNP PD-1.3.

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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.

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Correspondence to Marta E. Alarcón-Riquelme.

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Competing interests

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.

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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).

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