Martinez-Chamorro Alba, Moreno Antonia, Gómez-García María, Cabello María José, Martin Javier, Lopez-Nevot Miguel Ángel
Section of Immunology, Hospital Virgen de las Nieves, Granada, Spain; University of Granada, Spain.
Section of Immunology, Hospital Virgen de las Nieves, Granada, Spain.
Immunobiology. 2016 Sep;221(9):927-33. doi: 10.1016/j.imbio.2016.05.015. Epub 2016 May 28.
Crohn's Disease is one of the two major forms of the Inflammatory Bowel Diseases and, although the etiology is not completely understood, the confluence of environmental and genetic factors has been demonstrated. The aim of this study was to determine the distribution of TLR4 variants in a Spanish cohort of Crohn's Disease patients and their relation with phenotype and common NOD2 variants. A total of 371 Crohn's Disease (CD) patients and 636 healthy controls (HC) were included. Single Nucleotide Polimorphisms (SNPs) in TLR4 (D299G and T399I) and NOD2 (R702W and G908R) detection was performed by a Taqman(®) Allelic Discrimination Assay. 1007insC NOD2 variant was analyzed using a PCR combined with fluorescent technology and the different alleles were determined depending on the PCR products size. D299G and T399I were related to CD only in patients carrying NOD2 variants (NOD2+/TLR4+ haplotype) (p=0.036; OR=1.924), increasing the risk to develop CD when 1007insC and TLR4 variants were both present (OR=4.886). We also described a strong association between mutant NOD2 and CD risk (p<0.001, OR=3.214). R702W, G908R and 1007insC were associated when they were considered separately (p<0.001; p=0.002; p<0.001, respectively). Moreover, the patients carrying any mutant D299G or T399I polymorphisms were predisposed to develop a stricturing disease (p=0.013; OR=2.391), especially in the presence of NOD2 mutation (p=0.002; OR=4.989). In this study, ileal disease was also associated with the presence of at least one NOD2 susceptibility allele (p=0.001; OR=3.838) and, the risk of ileal CD was increased if TLR4 variants were presents (p<0.050; OR=4.160). TLR4 variants were related to bowel perforation, independently of NOD2.
克罗恩病是炎症性肠病的两种主要形式之一，尽管其病因尚未完全明确，但环境因素和遗传因素的共同作用已得到证实。本研究旨在确定西班牙克罗恩病患者队列中TLR4变体的分布及其与表型和常见NOD2变体的关系。共纳入371例克罗恩病（CD）患者和636例健康对照（HC）。采用Taqman（®）等位基因鉴别分析法对TLR4（D299G和T399I）和NOD2（R702W和G908R）中的单核苷酸多态性（SNP）进行检测。使用PCR结合荧光技术分析1007insC NOD2变体，并根据PCR产物大小确定不同等位基因。D299G和T399I仅在携带NOD2变体（NOD2+/TLR4+单倍型）的患者中与CD相关（p=0.036；OR=1.924），当1007insC和TLR4变体同时存在时，患CD的风险增加（OR=4.886）。我们还描述了突变型NOD2与CD风险之间的强关联（p<0.001，OR=3.214）。R702W、G908R和1007insC单独考虑时具有相关性（分别为p<0.001；p=0.002；p<0.001）。此外，携带任何突变型D299G或T399I多态性的患者易患狭窄性疾病（p=0.013；OR=2.391），尤其是在存在NOD2突变的情况下（p=0.002；OR=4.989）。在本研究中，回肠疾病也与至少一个NOD2易感等位基因的存在相关（p=0.001；OR=3.838），如果存在TLR4变体，回肠CD的风险会增加（p<0.050；OR=4.160）。TLR4变体与肠穿孔相关，与NOD2无关。
