Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ~1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10？26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10？28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.
References
[1]
Noel PJ, Boise LH, Thompson CB (1996) Regulation of T cell activation by CD28 and CTLA4. Adv Exp Med Biol 406: 209–217.
[2]
Tang AL, Teijaro JR, Njau MN, Chandran SS, Azimzadeh A, et al. (2008) CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis. J Immunol 181: 1806–1813.
[3]
Kavanagh B, O'Brien S, Lee D, Hou Y, Weinberg V, et al. (2008) CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 112: 1175–1183.
[4]
Axmann R, Herman S, Zaiss M, Franz S, Polzer K, et al. (2008) CTLA-4 directly inhibits osteoclast formation. Ann Rheum Dis.
[5]
Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, et al. (2007) TRAF1-C5 as a risk locus for rheumatoid arthritis–a genomewide study. N Engl J Med 357: 1199–1209.
[6]
Chang MC, Chang YT, Tien YW, Liang PC, Jan IS, et al. (2007) T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chem 53: 1700–1705.
[7]
Suppiah V, O'Doherty C, Heggarty S, Patterson CC, Rooney M, et al. (2006) The CTLA4+49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland. Exp Mol Pathol 80: 141–146.
[8]
Heggarty S, Suppiah V, Silversides J, O'Doherty C, Droogan A, et al. (2007) CTLA4 gene polymorphisms and multiple sclerosis in Northern Ireland. J Neuroimmunol 187: 187–191.
[9]
Downie-Doyle S, Bayat N, Rischmueller M, Lester S (2006) Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjogren's syndrome. Arthritis Rheum 54: 2434–2440.
Lei C, Dongqing Z, Yeqing S, Oaks MK, Lishan C, et al. (2005) Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population. Eur J Hum Genet 13: 823–828.
[12]
Karlson EW, Chibnik LB, Cui J, Plenge RM, Glass RJ, et al. (2007) Associations between HLA, PTPN22, CTLA4 genotypes and RA phenotypes of autoantibody status, age at diagnosis, and erosions in a large cohort study. Ann Rheum Dis 67: 358–363.
[13]
Barton A, Jury F, Eyre S, Bowes J, Hinks A, et al. (2004) Haplotype analysis in simplex families and novel analytic approaches in a case-control cohort reveal no evidence of association of the CTLA-4 gene with rheumatoid arthritis. Arthritis Rheum 50: 748–752.
[14]
Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, et al. (2005) Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 77: 1044–1060.
[15]
Brighton SW, de la Harpe AL, van Staden DJ, Badenhorst JH, Myers OL (1988) The prevalence of rheumatoid arthritis in a rural African population. J Rheumatol 15: 405–408.
[16]
Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, et al. (1993) Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 32: 903–907.
[17]
Moolenburgh JD, Moore S, Valkenburg HA, Erasmus MG (1984) Rheumatoid arthritis in Lesotho. Ann Rheum Dis 43: 40–43.
[18]
MacGregor AJ, Riste LK, Hazes JM, Silman AJ (1994) Low prevalence of rheumatoid arthritis in black-Caribbeans compared with whites in inner city Manchester. Ann Rheum Dis 53: 293–297.
[19]
Anaya JM, Correa PA, Mantilla RD, Jimenez F, Kuffner T, et al. (2001) Rheumatoid arthritis in African Colombians from Quibdo. Semin Arthritis Rheum 31: 191–198.
[20]
van der Helm-van Mil AH, Huizinga TW, de Vries RR, Toes RE (2007) Emerging patterns of risk factor make-up enable subclassification of rheumatoid arthritis. Arthritis Rheum 56: 1728–1735.
[21]
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31: 315–324.
[22]
Mikuls TR, Holers VM, Parrish L, Kuhn KA, Conn DL, et al. (2006) Anti-cyclic citrullinated peptide antibody and rheumatoid factor isotypes in African Americans with early rheumatoid arthritis. Arthritis Rheum 54: 3057–3059.
[23]
Hughes LB, Morrison D, Kelley JM, Padilla MA, Vaughan LK, et al. (2008) The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum 58: 349–358.
[24]
Kelly JA, Kelley JM, Kaufman KM, Kilpatrick J, Bruner GR, et al. (2008) Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun 9: 187–194.
[25]
Redden DT, Divers J, Vaughan LK, Tiwari HK, Beasley TM, et al. (2006) Regional admixture mapping and structured association testing: conceptual unification and an extensible general linear model. PLoS Genet 2: e137. doi:10.1371/journal.pgen.0020137.
[26]
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
[27]
Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, et al. (2007) Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 80: 867–875.
[28]
Tian C, Hinds DA, Shigeta R, Kittles R, Ballinger DG, et al. (2006) A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping. Am J Hum Genet 79: 640–649.
[29]
Bangalore S, Wang J, Allison D (2008) How accurate are the extremely small p-values used in genomic research: An evaluation of numerical libraries. Comp Stat Data Anal. In submission.
[30]
Collins-Schramm HE, Chima B, Operario DJ, Criswell LA, Seldin MF (2003) Markers informative for ancestry demonstrate consistent megabase-length linkage disequilibrium in the African American population. Hum Genet 113: 211–219.
[31]
Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75: 330–337.
[32]
Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, et al. (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34: 395–402.
[33]
Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, et al. (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35: 341–348.
[34]
Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K (2005) Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 50: 264–266.
[35]
Ueda H, Howson JM, Esposito L, Heward J, Snook H, et al. (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423: 506–511.
[36]
Verbinnen B, Billiau AD, Vermeiren J, Galicia G, Bullens DM, et al. (2008) Contribution of regulatory T cells and effector T cell deletion in tolerance induction by costimulation blockade. J Immunol 181: 1034–1042.
