Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.
Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.
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DOI：
10.1371/journal.pgen.1002091
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Martinez M
中科院分区：
文献类型：
--
作者：
Allanore Y;Saad M;Dieudé P;Avouac J;Distler JH;Amouyel P;Matucci-Cerinic M;Riemekasten G;Airo P;Melchers I;Hachulla E;Cusi D;Wichmann HE;Wipff J;Lambert JC;Hunzelmann N;Tiev K;Caramaschi P;Diot E;Kowal-Bielecka O;Valentini G;Mouthon L;Czirják L;Damjanov N;Salvi E;Conti C;Müller M;Müller-Ladner U;Riccieri V;Ruiz B;Cracowski JL;Letenneur L;Dupuy AM;Meyer O;Kahan A;Munnich A;Boileau C;Martinez M
系统性硬化症（SSc）是一种影响免疫系统和结缔组织的孤儿、复杂的炎性疾病。SSc是一种严重致残和危及生命的炎性风湿性疾病，其发病机制基本上未知。我们设计了一个两阶段的SSc全基因组关联研究，使用来自法国、意大利、德国和北方的病例对照样本。最初的全基因组扫描是在法国的564例病例和1,776例对照的质量控制后样本中进行的，使用了近500个K SNP。选择来自MHC区域的两个SNP以及具有至少一个P<10 - 5的SNP的MHC外的6个基因座用于后续分析。这些标记物在1，682例SSc病例和3，926例对照的QC后复制样本中进行基因分型。在HLA-DQB 1基因中，位于6p 21上的三个最高SNP处于强连锁不平衡状态：rs 9275224，P = 9.18×10−8，OR = 0.69，95%CI [0.60-0.79]; rs6457617，P = 1.14×10−7和rs 9275245，P = 1.39×10−7。 在MHC区域内，下一个最相关的SNP（rs3130573，P = 1.86×10−5，OR = 1.36 [1.18-1.56]）位于PSORS 1C 1基因中。 在MHC区域之外，我们的GWAS分析揭示了跨越6个独立基因组区域的7个顶级SNP（P<10−5）。对1,682名SSc和3,926名对照的独立样本中的17个顶级SNP的随访显示，PSORS 1C 1（总体P = 5.70×10−10，OR：1.25），TNIP 1（P = 4.68×10−9，OR：1.31）和RHOB位点（P = 3.17×10−6，OR：1.21）存在关联。 由于其生物学相关性，以及之前关于该位点与结缔组织疾病遗传相关性的报道，我们研究了TNIP 1的表达。TNIP 1基因及其蛋白产物的表达显着减少，观察无论是在皮损皮肤组织和培养的皮肤成纤维细胞从SSc患者。此外，TNIP 1在体外对炎性精氨酸诱导的胶原蛋白产生具有抑制作用。与TNIP 1变体相关的遗传信号，以及组织和细胞研究表明，该途径在调节自身免疫和SSc发病机制中具有关键作用。系统性硬化症（SSc）是一种结缔组织疾病，其特征是全身性微血管病、严重的免疫学改变和结缔组织中基质成分的大量沉积。流行病学调查表明，SSc遵循多因子遗传模式;然而，在多项研究中仅复制了少数位点。我们进行了一项两阶段的SSc全基因组关联研究，涉及8,800多名欧洲血统的个体。综合分析显示，在已知的HLA-DQB 1区域的独立关联，并揭示了在PSORS 1C 1，TNIP 1和RHOB基因座的关联，与强免疫遗传成分一致。由于它的生物学相关性，和以前的报告，在这个位点与其他结缔组织疾病的遗传关联，我们调查TNIP 1的表达。我们观察到该基因及其蛋白产物在SSc中的表达显著降低，以及其在控制细胞外基质合成中的潜在意义，为炎症/免疫和纤维化之间的联系提供了新的线索。
Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10−5 were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10−8, OR = 0.69, 95% CI [0.60–0.79]; rs6457617, P = 1.14×10−7 and rs9275245, P = 1.39×10−7. Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10−5, OR = 1.36 [1.18–1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10−5) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10−10, OR:1.25), TNIP1 (P = 4.68×10−9, OR:1.31), and RHOB loci (P = 3.17×10−6, OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis. Systemic sclerosis (SSc) is a connective tissue disease characterized by generalized microangiopathy, severe immunologic alterations, and massive deposits of matrix components in the connective tissue. Epidemiological investigations indicate that SSc follows a pattern of multifactorial inheritance; however, only a few loci have been replicated in multiple studies. We undertook a two-stage genome-wide association study of SSc involving over 8,800 individuals of European ancestry. Combined analyses showed independent association at the known HLA-DQB1 region and revealed associations at PSORS1C1, TNIP1, and RHOB loci, in agreement with a strong immune genetic component. Because of its biological relevance, and previous reports of genetic association at this locus with other connective tissue disorders, we investigated TNIP1 expression. We observed a markedly reduced expression of the gene and its protein product in SSc, as well as its potential implication in control of extra-cellular matrix synthesis, providing a new clue for a link between inflammation/immunity and fibrosis.
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影响因子：
30.8
作者：
Nair RP;Duffin KC;Helms C;Ding J;Stuart PE;Goldgar D;Gudjonsson JE;Li Y;Tejasvi T;Feng BJ;Ruether A;Schreiber S;Weichenthal M;Gladman D;Rahman P;Schrodi SJ;Prahalad S;Guthery SL;Fischer J;Liao W;Kwok PY;Menter A;Lathrop GM;Wise CA;Begovich AB;Voorhees JJ;Elder JT;Krueger GG;Bowcock AM;Abecasis GR;Collaborative Association Study of Psoriasis
通讯作者：
Collaborative Association Study of Psoriasis
影响因子：
27.4
作者：
Dieude, P.;Guedj, M.;Allanore, Y.
通讯作者：
Allanore, Y.
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影响因子：
30.8
作者：
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通讯作者：
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影响因子：
4.5
作者：
Fan X;Yang S;Huang W;Wang ZM;Sun LD;Liang YH;Gao M;Ren YQ;Zhang KY;Du WH;Shen YJ;Liu JJ;Zhang XJ
通讯作者：
Zhang XJ
影响因子：
30.5
作者：
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通讯作者：
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