Human Genetics

, Volume 115, Issue 5, pp 393–398

Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies

  • Dharambir K. Sanghera
  • Susan Manzi
  • Franklin Bontempo
  • Cara Nestlerode
  • M. Ilyas Kamboh
Original Investigation


Recently, a polymorphism in intron 4 (G/A) of the programmed cell death 1 (PDCD1) gene was shown to be associated with systemic lupus erythematosus (SLE) risk in familial and sporadic patients of European, European American, and Mexican origin. In this investigation, we examined the role of this polymorphism in 311 SLE patients (276 European Americans and 35 African Americans) and 390 age-matched healthy controls (359 European Americans and 31 African Americans). The frequency of the A allele was significantly higher in European American controls than in African American controls (0.107 vs. 0.048; P=0.046). There was no significant difference in the frequency of the A allele between SLE cases and controls in either the European American (0.107 vs. 0.129; P=0.84) or African American (0.048 vs. 0.100; P=0.25) cohort. However, after adjustment for the status of the antiphospholipid antibodies (APA) in the logistic regression analysis, the risk for SLE associated with the PDCD1 polymorphism was statistically significant. The APA-adjusted odds ratio (OR) between A allele carriers (AA + AG genotypes) versus the GG genotype showed a modest association with SLE risk in European Americans (OR=1.52, 95% CI: 1.02–2.27; P=0.039), African Americans (OR=2.89, 95% CI: 0.61–13.76; P=0.183), and the ethnicity-combined sample (OR=1.59, 95% CI: 1.08–2.34; P=0.019). Furthermore, we observed that the A allele carriers were protected against the occurrence of APA in both controls (OR=0.399, 95% CI: 0.19–0.82; P=0.0098) and SLE cases (OR=0.566, 95% CI: 0.32–1.01; P=0.054). Our data indicate polymorphism in intron 4 of the PDCD1 gene affects the occurrence of APA and may slightly modify the risk of sporadic SLE.


  1. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772PubMedGoogle Scholar
  2. Arnett FC (1997) The genetics of human lupus. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus erythematosus, 5th edn. Williams and Wilkins, Baltimore, pp 77–117Google Scholar
  3. Block SR (1993) Twin studies: genetic factors are important. Arthritis Rheum 36:135–136Google Scholar
  4. Bolstad AI, Eiken HG, Rosenlund B, Alarcon-Riquelme ME, Jonsson R (2003) Increase salivary gland tissue and expression of Fas, Fas ligand, cytotoxin T lymphocytes-associated antigen 4 and programmed cell death 1 in primary Sjogren’s syndrome. Arthritis Rheum 48:174–185CrossRefPubMedGoogle Scholar
  5. Chakraborty R, Kamboh MI, Nwankwo M, Ferrell RE (1992) Caucasian genes in American Blacks: new data. Am J Hum Genet 50:145–150PubMedGoogle Scholar
  6. Deapan D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burnman P, Walker A, Mack TM (1992) A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 35:311–318PubMedGoogle Scholar
  7. Finger LR, Pu J, Wasserman R, Vibhakar R, Louie E, Hardy RR, Burrows PD, Billips LG (1997) The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. Gene 197:177–187CrossRefPubMedGoogle Scholar
  8. Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ockenden TC, et al (1998) A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 95:14875–14879CrossRefPubMedGoogle Scholar
  9. Gaffney PM, Ortmann WA, Selby SA, Shark KB, Ockenden TC, Rohlf KE, Walgrave NL, Boyum WP, Malmgren ML, Miller ME, Kearns GM, Messner RP, King RA, Rich SS, Behrens TW (2000) 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 66:547–556CrossRefPubMedGoogle Scholar
  10. Graham RR, Ortmann WA, Langefeld CD, Jawaheer D, Selby SA, et al (2002) Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet 71:543–553CrossRefPubMedGoogle Scholar
  11. Gray-McGuire C, Moser KL, Gaffney PM, Kelly J, Yu H, Olson JM, Jedrey CM, Jacobs KB, Kimberly RP, Neas BR, Rich SS, Behrens TW, Harley JB (2000) Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2. Am J Hum Genet 67:1460–1469CrossRefPubMedGoogle Scholar
  12. Kamboh MI, Manzi S, Mehdi H, Fitzerald S, Sanghera DK, Kuller LH, Aston CE (1999) Genetic variation in apolipoprotein H (β2-glycoprotein 1) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus. Lupus 8:742–750CrossRefPubMedGoogle Scholar
  13. Kelly JA, Moser KL, Harley JB (2002) The genetics of systemic lupus erythematosus: putting the pieces together. Genes Immun 3(Suppl 1):71–85CrossRefPubMedGoogle Scholar
  14. Lindqvist AK, Steinsson K, Johanneson B, Kristjansdottir H, Arnasson A, et al (2000) A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun 14:169–178CrossRefPubMedGoogle Scholar
  15. Magnusson V, Lindqvist AK, Castillejo-Lopez C, Kristjansdottir H, Steinsson K, et al (2000) Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics 70:307–314CrossRefPubMedGoogle Scholar
  16. Manzi S, Wasco MCM (2000) Inflammation—mediated rheumatic diseases and atherosclerosis. Ann Rheum Dis 59:321–325CrossRefPubMedGoogle Scholar
  17. McMurray RW, May W (2003) Sex hormones and systemic lupus erythematosus: review and meta-analysis. Arthritis Rheum 48:2100–2110CrossRefPubMedGoogle Scholar
  18. Moser KL, Neas BR, Salmon JE, et al (1998) Genome scan of human systemic lupus erythematosus; evidence for linkage on chromosome 1q in African–American pedigrees. Proc Natl Acad Sci USA 95:14869–14874CrossRefPubMedGoogle Scholar
  19. Nath SK, Quintero-Del-Rio AI, Kilpatrick J, Feo L, Ballesteros M, Harley JB (2004) Linkage at 12q24 with systemic lupus erythematosus (SLE) is established and confirmed in Hispanic and European American families. Am J Hum Genet 74:73–82CrossRefPubMedGoogle Scholar
  20. Nishimura H, Hiebert SW (2001) PD-1: an inhibitory immuno-receptor involved in peripheral tolerance. Trends Immunol 22:265–268CrossRefPubMedGoogle Scholar
  21. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by distruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1:141–151CrossRefGoogle Scholar
  22. Petri M (2000) Epidemiology of the antiphospholipid syndrome. J Autoimmun 15:145–152CrossRefPubMedGoogle Scholar
  23. Prokunina L, Castillego-Lopez C, Oberg F, Gunnrsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism in the PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669CrossRefPubMedGoogle Scholar
  24. Sanghera DK, Nestlerode Cs, Ferrell RE, Kamboh MI (2001) Chimpanzee apolipoprotein H (β2-glycoprotein 1): report on the gene structure, a common polymorphism, and a high prevalence of aniphospholipid antibodies. Hum Genet 109:63–72CrossRefPubMedGoogle Scholar
  25. Selzer F, Sutton- Tyrrell K, Fitzgerald S, Tracy R, Kuller L, Manzi S (2001) Vascular stiffness in women with systemic lupus erythematosus. Hypertension 37:1075–1082PubMedGoogle Scholar
  26. Shai R, Quisnorio FR Jr, Li L, Kwon OJ, Morrison J, Wallace DJ, Neuwelf CM, Brautbar C, et al (1999) Genome-wide screen for SLE susceptibility genes in multiplex families. Hum Mol Genet 8:639–644CrossRefPubMedGoogle Scholar
  27. Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 23:704–706Google Scholar
  28. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277PubMedGoogle Scholar
  29. Tsao BP (2002) An update on genetic studies of systemic lupus erythematosus. Curr Rheumatol Rep 4:359–367PubMedGoogle Scholar
  30. Tsao BP, Cantor RM, Kalunian KC, Chen CJ, Badsha H, Singh R, Wallace DJ, Kitridou RC, Chen SL, Shen N, Song YW, Isenberg DA, Yu CL, Hahn BH, Rotter JI (1997) Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 99:725–731PubMedGoogle Scholar
  31. Tsuchiya N, Ohashi J, Tokunaga K (2002) Variations in immune response genes and their associations with multifactorial immune disorders. Immunol Rev 190:169–181CrossRefPubMedGoogle Scholar
  32. Vibhakar R, Juan G, Traganos F, Darzykiewiez Z, Finger LR (1997) Activation-induced expression of human programmed death 1 gene in T lymphocytes. Exp Cell Res 232:25–28CrossRefPubMedGoogle Scholar
  33. Vivier E, Daeron M (1997) Immunoreceptor tyrosine-based inhibitory motifs. Immunol Today 18:286–291CrossRefPubMedGoogle Scholar
  34. Vyse TJ, Kotzin BL (1998) Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 16:261–292CrossRefPubMedGoogle Scholar
  35. Wandstrat A, Wakeland E (2001) The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat Immunol 2:802–809CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Dharambir K. Sanghera
    • 1
  • Susan Manzi
    • 2
    • 3
  • Franklin Bontempo
    • 2
  • Cara Nestlerode
    • 1
  • M. Ilyas Kamboh
    • 1
  1. 1.Department of Human Genetics, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  2. 2.Department of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.Department of Epidemiology, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA

Personalised recommendations