Dataset Information

Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.

ABSTRACT: 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.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.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).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.

SUBMITTER: Tan W

PROVIDER: S-EPMC3163110 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.

Tan Wenfeng W Sunahori Katsue K Zhao Jian J Deng Yun Y Kaufman Kenneth M KM Kelly Jennifer A JA Langefeld Carl D CD Williams Adrienne H AH Comeau Mary E ME Ziegler Julie T JT Marion Miranda C MC Bae Sang-Cheol SC Lee Joo Hyun JH Lee Ji-Seon JS Chang Deh-Ming DM Song Yeong Wook YW Yu Chack-Yung CY Kimberly Robert P RP Edberg Jeffrey C JC Brown Elizabeth E EE Petri Michelle A MA Ramsey-Goldman Rosalind R Vilá Luis M LM Reveille John D JD Alarcón-Riquelme Marta E ME Harley John B JB Boackle Susan A SA Stevens Anne M AM Scofield R Hal RH Merrill Joan T JT Freedman Barry I BI Anaya Juan-Manuel JM Criswell Lindsey A LA Jacob Chaim O CO Vyse Timothy J TJ Niewold Timothy B TB Gaffney Patrick M PM Moser Kathy L KL Gilkeson Gary S GS Kamen Diane L DL James Judith A JA Grossman Jennifer M JM Hahn Bevra H BH Tsokos George C GC Tsao Betty P BP Alarcón Graciela S GS

Arthritis and rheumatism 20110901 9

<h4>Objective</h4>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 ...[more]

PMID: 21590681

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Project description:BackgroundA number of observational studies have been conducted to investigate the association of the IL-10 gene polymorphisms with systemic lupus erythematosus (SLE) susceptibility. However, their results are conflicting.MethodWe searched published case-control studies on the IL-10 polymorphisms and SLE in PubMed, EMBASE and Chinese Biomedical Literature Database. A meta-analysis was conducted using a fixed-effect or random-effect model based on between-study heterogeneity.ResultsA total of 42 studies with 7948 cases and 11866 controls were included in this meta-analysis. Among Caucasians, the CA27 allele of the IL10.G microsatellites (OR 2.38, 95% CI 1.01-5.62), the G allele of the IL-10 -1082G/A polymorphism (G vs. A: OR 1.21, 95% CI 1.02-1.44; GG vs. AA: OR 1.45, 95% CI 1.16-1.82; GG+GA vs. AA: OR 1.16, 95% CI 1.03-1.29) and its associated haplotype -1082G/-819C/-592C (OR 1.25, 95% CI 1.10-1.42) were associated with increased SLE susceptibility without or with unimportant between-study heterogeneity. Removing studies deviating from Hardy-Weinberg equilibrium (HWE) hardly changed these results. Among Asians, the CA21 allele of the IL-10.G microsatellites (OR 1.28, 95% CI 1.02-1.60) and the -1082G/-819C/-592C haplotype (OR 1.24, 95% CI 1.00-1.53) were associated with increased SLE susceptibility, but with substantial between-study heterogeneity or sensitive to HWE status. Removing studies deviating from HWE also produced statistically significant associations of the IL-10 -1082G/A (GG vs. AA: OR 3.21, 95% CI 1.24-8.28; GG vs. AA+GA: OR 2.85, 95% CI 1.19-6.79) and -592C/A polymorphisms (CC+CA vs. AA: OR 0.69, 95% CI 0.51-0.94) with SLE among Asians.ConclusionThis meta-analysis showed that the IL10.G microsatellites, the IL-10 -1082G/A and -592C/A polymorphisms and the haplotype -1082G/-819C/-592C are associated with SLE susceptibility. Besides, this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings.

Project description:Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10(-4), Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18-1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30-1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10(-4), Pc = 0.037, OR 1.53, 95%CI 1.19-1.96) and rs62339994 (dominant model, P = 9.0×10(-4), Pc = 0.043, OR 1.46, 95%CI 1.17-1.82). The haplotype carrying both of the risk alleles (rs66801661A-rs62339994A) was significantly increased in SLE (P = 9.9×10(-4)), while the haplotype constituted by both of the non-risk alleles (rs66801661G-rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10(-4)). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2.

Dataset Information

Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.

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Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.

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