Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease.
Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease.
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DOI：
10.1371/journal.pgen.1001195
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发表时间：
2010-12-02
期刊：
影响因子：
4.5
通讯作者：
Brown MA
中科院分区：
文献类型：
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作者：
Danoy P;Pryce K;Hadler J;Bradbury LA;Farrar C;Pointon J;Australo-Anglo-American Spondyloarthritis Consortium;Ward M;Weisman M;Reveille JD;Wordsworth BP;Stone MA;Spondyloarthritis Research Consortium of Canada;Maksymowych WP;Rahman P;Gladman D;Inman RD;Brown MA
强直性脊柱炎（AS）是一种常见的炎症性关节炎。约10%的AS患者发生明显的炎症性肠病（IBD），另外70%的AS病例可能有亚临床终末回肠炎。脊椎关节炎在IBD患者中也很常见。因此，我们测试了克罗恩病易感基因与AS的关联，旨在确定多效性与这两种疾病的遗传关联。使用Sequenom和Applied Biosystems TaqMan和OpenArray技术对选自30个克罗恩病相关基因组区域的53个标记进行基因分型。我们检测了一组白色欧洲血统的不相关个体病例（n = 2，773）和对照（n = 2，215）的基因型与AS的关系。 使用Cochran-Armitage检验对PLINK中的趋势进行统计分析。在靠近KIF21B的chr1q32处检测到强相关性（rs11584383，P = 1.6 × 10 − 10，比值比（OR）= 0.74，95%CI：0.68 - 0.82）。 STAT3中的2个变异体也与疾病相关（rs6503695，P = 4.6 × 10 − 4）。 OR = 0.86（95% CI：0.79 - 0.93）; rs744166，P = 2.6 × 10 − 5，OR = 0.84（95% CI：0.77 - 0.91））。 确认了与IL23R的相关性（rs11465804，P = 1.2 × 10 − 5，OR = 0.65（95% CI：0.54 - 0.79）），并检测到IL 12 B（rs10045431，P = 5.2 × 10 − 5，OR = 0.83（95% CI：0.76 - 0.91）），CDKAL 1（rs6908425，P = 1.1 × 10 - 4，OR = 0.82（95%CI：0.74 - 0.91））、LRRK2/MUC19（rs11175593，P = 9.9 × 10 − 5，OR = 1.92（95% CI：1.38 - 2.67））和chr13q14（rs3764147，P = 5.9 × 10 − 4，OR = 1.19（95%CI：1.08 - 1.31））。 排除临床IBD病例对这些结果无显著影响。本研究确定chr1q32和STAT3为强直性脊柱炎易感基因座。它还进一步证实了与IL23R的关联，并检测到与另外4个基因座的暗示关联。STAT3是Th17淋巴细胞分化途径中的关键信号分子，并进一步增强了该T淋巴细胞亚群在强直性脊柱炎中的主要作用。最后，这些发现表明AS和克罗恩病的共同病因途径，并进一步强调了多种疾病中常见风险变异的参与。强直性脊柱炎是一种常见的炎症性关节炎，主要影响脊柱和骨盆。该疾病具有高度遗传性（遗传率> 90%），并且该疾病的主要遗传等位基因HLA-B27占该疾病遗传风险的大约一半。强直性脊柱炎和炎症性肠病（克罗恩病和溃疡性结肠炎）经常发生在同一个家庭和个人，这表明他们有共同的危险因素。我们测试了与克罗恩病相关的基因是否也与强直性脊柱炎相关，并证实这两种疾病在染色体1q32靠近KIF21B，STAT3，IL12B，CDKAL1，LRRK2/MUC19和染色体13q14处共享关联。即使在没有临床炎症性肠病的强直性脊柱炎病例中也存在这些相关性。这些发现极大地扩展了我们对这些条件共同发生的原因的理解，并提供了人类疾病病理多效性的进一步证据。由于基因IL 23 R、STAT 3和IL 12 B都影响Th17淋巴细胞分化/活化，这提供了进一步的证据，表明Th17淋巴细胞亚群参与强直性脊柱炎的发病机制。
Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6×10−10, odds ratio (OR) = 0.74, 95% CI:0.68–0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6×10−4. OR = 0.86 (95% CI:0.79–0.93); rs744166, P = 2.6×10−5, OR = 0.84 (95% CI:0.77–0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2×10−5, OR = 0.65 (95% CI:0.54–0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2×10−5, OR = 0.83 (95% CI:0.76–0.91)), CDKAL1 (rs6908425, P = 1.1×10−4, OR = 0.82 (95% CI:0.74–0.91)), LRRK2/MUC19 (rs11175593, P = 9.9×10−5, OR = 1.92 (95% CI: 1.38–2.67)), and chr13q14 (rs3764147, P = 5.9×10−4, OR = 1.19 (95% CI: 1.08–1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases. Ankylosing spondylitis is a common inflammatory arthritis primarily affecting the spine and pelvis. The disease is highly heritable (heritability>90%), and the major genetic allele for the disease, HLA-B27, contributes approximately half the genetic risk for the condition. Ankylosing spondylitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis) frequently occur together in the same families and individuals, suggesting that they share common risk factors. We tested whether genes associated with Crohn's disease are also associated with ankylosing spondylitis and confirmed that the two diseases share associations at chromosome 1q32 near KIF21B, STAT3, IL12B, CDKAL1, LRRK2/MUC19, and chromosome 13q14. These associations were present even in ankylosing spondylitis cases with no clinical inflammatory bowel disease. These findings greatly expand our understanding of why these conditions co-occur and provide further evidence of pleiotropy in human disease pathology. As the genes IL23R, STAT3, and IL12B all influence Th17 lymphocyte differentiation/activation, this provides further evidence implicating the Th17 lymphocyte subset in the pathogenesis of ankylosing spondylitis.
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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：
--
作者：
LEIRISALOREPO, M;TURUNEN, U;SEPPALA, K
通讯作者：
SEPPALA, K
影响因子：
7.6
作者：
Orchard, T. R.;Holt, H.;Wordsworth, B. P.
通讯作者：
Wordsworth, B. P.
DOI：
10.1038/jid.2008.297
发表时间：
2009-03
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
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银屑病全基因组关联研究确定了 1q21 LCE 基因簇内的易感性变异。
影响因子：
30.8
作者：
Zhang, Xue-Jun;Huang, Wei;Liu, Jian-Jun
通讯作者：
Liu, Jian-Jun