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ÍtemSolo MetadatosAssociation of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups(2011) Tan W.; Sunahori K.; Zhao J.; Deng Y.; Kaufman K.M.; Kelly J.A.; Langefeld C.D.; Williams A.H.; Comeau M.E.; Ziegler J.T.; Marion M.C.; Bae S.-C.; Lee J.H.; Lee J.-S.; Chang D.-M.; Song Y.W.; Yu C.-Y.; Kimberly R.P.; Edberg J.C.; Brown E.E.; Petri M.A.; Ramsey-Goldman R.; Vilá L.M.; Reveille J.D.; Alarcõn-Riquelme M.E.; Harley J.B.; Boackle S.A.; Stevens A.M.; Scofield R.H.; Merrill J.T.; Freedman B.I.; Anaya, Juan-Manuel; Criswell L.A.; Jacob C.O.; Vyse T.J.; Niewold T.B.; Gaffney P.M.; Moser K.L.; Gilkeson G.S.; Kamen D.L.; James J.A.; Grossman J.M.; Hahn B.H.; Tsokos G.C.; Tsao B.P.Objective T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac. Methods We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction. Results A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P = 3.8 × 10 -7). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ?2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P = 0.007). Conclusion Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians. Copyright © 2011 by the American College of Rheumatology.- ÍtemSolo MetadatosPhenotypic associations of genetic susceptibility loci in systemic lupus erythematosus(2011) Sanchez E.; Nadig A.; Richardson B.C.; Freedman B.I.; Kaufman K.M.; Kelly J.A.; Niewold T.B.; Kamen D.L.; Gilkeson G.S.; Ziegler J.T.; Langefeld C.D.; Alarcón G.S.; Edberg J.C.; Ramsey-Goldman R.; Petri M.; Brown E.E.; Kimberly R.P.; Reveille J.D.; Vilá L.M.; Merrill J.T.; Anaya, Juan-Manuel; James J.A.; Pons-Estel B.A.; Martin J.; Park S.-Y.; Bang S.-Y.; Bae S.-C.; Moser K.L.; Vyse T.J.; Criswell L.A.; Gaffney P.M.; Tsao B.P.; Jacob C.O.; Harley J.B.; Alarcón-Riquelme M.E.; Sawalha A.H.Objective: Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods: 4001 European-derived, 547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results: Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10-6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of and lt;0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion: Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.
- ÍtemSolo MetadatosAssociation of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus(2011) Adrianto I.; Wen F.; Templeton A.; Wiley G.; King J.B.; Lessard C.J.; Bates J.S.; Hu Y.; Kelly J.A.; Kaufman K.M.; Guthridge J.M.; Alarcón-Riquelme M.E.; Anaya, Juan-Manuel; Bae S.-C.; Bang S.-Y.; Boackle S.A.; Brown E.E.; Petri M.A.; Gallant C.; Ramsey-Goldman R.; Reveille J.D.; Vila L.M.; Criswell L.A.; Edberg J.C.; Freedman B.I.; Gregersen P.K.; Gilkeson G.S.; Jacob C.O.; James J.A.; Kamen D.L.; Kimberly R.P.; Martin J.; Merrill J.T.; Niewold T.B.; Park S.-Y.; Pons-Estel B.A.; Scofield R.H.; Stevens A.M.; Tsao B.P.; Vyse T.J.; Langefeld C.D.; Harley J.B.; Moser K.L.; Webb C.F.; Humphrey M.B.; Montgomery C.G.; Gaffney P.M.Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT and gt;A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10-8, odds ratio = 1.70) and Korean (P = 8.33 × 10-10, odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-?B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT and gt;A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE. © 2011 Nature America, Inc. All rights reserved.
