Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis.
Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis.
复制标题
DOI：
10.1371/journal.pone.0007154
复制
发表时间：
2009-09-28
期刊：
影响因子：
3.7
通讯作者：
Franchimont D
中科院分区：
文献类型：
--
作者：
Villani AC;Lemire M;Louis E;Silverberg MS;Collette C;Fortin G;Nimmo ER;Renaud Y;Brunet S;Libioulle C;Belaiche J;Bitton A;Gaudet D;Cohen A;Langelier D;Rioux JD;Arnott ID;Wild GE;Rutgeerts P;Satsangi J;Vermeire S;Hudson TJ;Franchimont D
家族性地中海热（FMF）基因（MEFV）编码pyrin， pyrin是控制caspase-1激活和IL-1β加工的炎性体平台的主要调节因子。Pyrin已被证明与NLRP3基因产物NALP3/cryopyrin相互作用，NALP3/cryopyrin也是炎症小体的重要活性成员。最近有报道称NLRP3区域与克罗恩病（CD）易感性相关。因此，我们试图评估MEFV作为炎症性肠病（IBD）易感基因。MEFV结肠粘膜基因表达在实验性结肠炎小鼠模型（TNBS p<0.0003; DSS p<0.006）、CD活检（p<0.02）和重度溃疡性结肠炎（UC）患者（p<0.008）中显著升高。在比利时探索性样本集（440个CD三胞胎、137个UC三胞胎、239个CD病例、96个UC病例和107个健康对照）中对MEFV区域进行综合遗传筛查，发现位于MEFV 5 '单倍型块的snp与UC显著相关（rs224217; p = 0.003；等位基因频率：56%病例，45%对照），而未观察到CD相关。测序和随后的基因分型发现，位于MEFV外显子2的三个同义变体（D102D/rs224225、G138G/rs224224、A165A/rs224223）和一个非同义变体（R202Q/rs224222）与UC显著相关（rs224222: p = 0.0005；等位基因频率：病例32%，对照组23%）。在其他加拿大（256例CD三人组，91例UC三人组）和苏格兰（495例UC， 370例对照）样本组中未观察到一致的关联。我们注意到rs224222在加拿大样本中显示出边际关联（p = 0.012； G等位基因频率：82%病例，70%对照组），但风险等位基因不同。在比利时-加拿大UC样本中，NLRP3常见变异均未与UC相关，并且未观察到NLRP3与MEFV之间的显著相互作用，这可以解释rs224222风险等位基因的突变。在样本集之间观察到的关联水平的差异可能是不同的创始人效应或本研究中评估的队列相对较小的样本量的结果。然而，结果表明，MEFV区域的常见变异与CD和UC易感性无关。
The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1β processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene. MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5′ haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian-Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele. The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility.
登录
查看更多内容
DOI：
10.1073/pnas.88.16.7276
发表时间：
1991-08-01
影响因子：
11.1
作者：
HOLLAND, PM;ABRAMSON, RD;GELFAND, DH
通讯作者：
GELFAND, DH
影响因子：
30.8
作者：
Fisher, Sheila A.;Tremelling, Mark;Anderson, Carl A.;Gwilliam, Rhian;Bumpstead, Suzannah;Prescott, Natalie J.;Nimmo, Elaine R.;Massey, Dunecan;Berzuini, Carlo;Johnson, Christopher;Barrett, Jeffrey C.;Cummings, Fraser R.;Drummond, Hazel;Lees, Charlie W.;Onnie, Clive M.;Hanson, Catherine E.;Blaszczyk, Katarzyna;Inouye, Mike;Ewels, Philip;Ravindrarajah, Radhi;Keniry, Andrew;Hunt, Sarah;Carter, Martyn;Watkins, Nick;Ouwehand, Willem;Lewis, Cathryn M.;Cardon, Lon;Lobo, Alan;Forbes, Alastair;Sanderson, Jeremy;Jewell, Derek P.;Mansfield, John C.;Deloukas, Panos;Mathew, Christopher G.;Parkes, Miles;Satsangi, Jack
通讯作者：
Satsangi, Jack
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D
影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
56.9
作者：
Duerr, Richard H.;Taylor, Kent D.;Cho, Judy H.
通讯作者：
Cho, Judy H.