Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.
Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.
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DOI：
10.1002/art.30452
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发表时间：
2011-09
影响因子：
--
通讯作者：
Tsao, Betty P.
中科院分区：
文献类型：
--
作者：
Tan, Wenfeng;Sunahori, Katsue;Zhao, Jian;Deng, Yun;Kaufman, Kenneth M.;Kelly, Jennifer A.;Langefeld, Carl D.;Williams, Adrienne H.;Comeau, Mary E.;Ziegler, Julie T.;Marion, Miranda C.;Bae, Sang-Cheol;Lee, Joo Hyun;Lee, Ji-Seon;Chang, Deh-Ming;Song, Yeong Wook;Yu, Chack-Yung;Kimberly, Robert P.;Edberg, Jeffrey C.;Brown, Elizabeth E.;Petri, Michelle A.;Ramsey-Goldman, Rosalind;Vila, Luis M.;Reveille, John D.;Alarcon-Riquelme, Marta E.;Harley, John B.;Boackle, Susan A.;Stevens, Anne M.;Scofield, R. Hal;Merrill, Joan T.;Freedman, Barry I.;Anaya, Juan-Manuel;Criswell, Lindsey A.;Jacob, Chaim O.;Vyse, Timothy J.;Niewold, Timothy B.;Gaffney, Patrick M.;Moser, Kathy L.;Gilkeson, Gary S.;Kamen, Diane L.;James, Judith A.;Grossman, Jennifer M.;Hahn, Bevra H.;Tsokos, George C.;Tsao, Betty P.
SLE患者的T细胞表达PP2Ac量增加，这有助于降低IL-2的产生。由于IL-2在免疫应答的几个方面的调节中很重要，因此有人提出PP2Ac参与SLE的表达。本研究旨在确定PPP2AC的遗传变异是否与SLE的表达和特定临床表现有关，并解释PP2Ac表达增加的原因。我们进行了一项跨种族研究，包括来自四个不同祖先的8,695例SLE病例和7,308例对照。使用Illumina定制阵列对PPP2CA中的18个单核苷酸多态性（snp）进行基因分型。实时荧光定量PCR分析PPP2CA在SLE及对照T细胞中的表达。由PPP2CA的多个snp组成的32kb单倍型显示，西班牙裔美国人（HA）、欧洲裔美国人（EA）和亚洲人与SLE有显著关联，但与非洲裔美国人（AA）无显著关联。条件分析显示，在亚洲、EA和HA人群中，内含子1中的SNP rs7704116与SLE具有一致的强相关性（pmeta=3.8×10−7，OR=1.3[1.14-1.31]）。在EA（最大的种族数据集）中，rs7704116的风险等位基因A与肾脏疾病、抗dsdna和抗rnp抗体的存在相关。携带rs7704116 AG基因型的SLE患者的PPP2CA表达比携带GG基因型的患者高约2倍（p = 0.008）。我们的数据为T细胞中PPP2CA多态性与PP2Ac转录水平升高之间的关联提供了第一个证据，这暗示了EA、HA和亚洲人SLE易感性的新分子途径。
T cells from patients with SLE express increased amounts of PP2Ac which contribute to decreased production of 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 consisting of 8,695 SLE cases and 7,308 controls from four different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across the PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time PCR. A 32-kb haplotype comprised of multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans (HA), European Americans (EA) and Asians but not in African-Americans (AA). Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, EA and HA populations (pmeta=3.8×10−7, OR=1.3[1.14–1.31]). In EA, the largest ethnic dataset, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-dsDNA and anti-RNP antibodies. PPP2CA expression was approximately 2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying GG genotype (p = 0.008). Our data provide the first evidence for an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in EA, HA and Asians.
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影响因子：
13.6
作者：
Crispín JC;Liossis SN;Kis-Toth K;Lieberman LA;Kyttaris VC;Juang YT;Tsokos GC
通讯作者：
Tsokos GC
DOI：
10.1038/nrrheum.2010.176
发表时间：
2010-12
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
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影响因子：
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作者：
Brunner, Hermine I.;Gladman, Dafna D.;Silverman, Earl D.
通讯作者：
Silverman, Earl D.
影响因子：
5.6
作者：
Purev, E;Giordano, A;Soprano, KJ
通讯作者：
Soprano, KJ
6q23 上 TNFAIP3 附近的遗传变异与系统性红斑狼疮相关。
影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
通讯作者：
Gaffney, Patrick M.