Polymorphisms in interleukin-10 gene according to mutations of NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn's disease

瞄准：检验 interleukin-10 (IL-10 ) 的贡献基因多型性到 Crohnos 疾病(CD ) 显型，和在 IL-10 基因多型性和 CARD15/NOD2 基因变化之间的可能的基因排泄制止。方法：有 Crohn 从一个单个中心招募的疾病的 205 个西班牙的无关的病人的一个队被学习。所有病人是严厉地 phenotyped 并且为至少 3 年跟随起来(吝啬的时间， 12.5 年) 。临床的显型在 genotyping 以前被建立。结果：遗传型的关联 -- 维也纳分类组证明回肠结肠地点显著地在 NOD2/CARD15 变化积极的病人与 -1082G 等位基因被联系(RR=1.52， 95%CI， 1.21 ～ 1.91， P=0.008 ) 。多，变量分析证明在 NOD2/CARD15 变化的 IL-10 G14 微卫星等位基因积极病人与二个风险因素被联系，阑尾切除术的历史(RR=2.15， 95%CI=1.1-4.30， P=0.001 ) 并且在诊断的吸烟习惯(RR=1.29， 95%CI=1.04-4.3， P=0.04 ) 。结论：在从马德里的西班牙的人口，在带至少一个 NOD2/CARD15 变化的 CD 病人， -1082G 等位基因与回肠结肠疾病被联系， IL-10G14 微卫星等位基因在诊断与阑尾切除术和吸烟习惯的以前的历史被联系。这些数据为 CD 的临床的异质的一个基因基础提供进一步分子的证据。

NOD2/CARD15 gene polymorphism in patients with inflammatory bowel disease: Is Hungary different?

AIM: To analyse the impact of NOD2/CARD15 mutations on the clinical course of Crohn's disease patients from an eastern European country (Hungary).METHODS: We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg,1007finsC) in 148 patients with Crohn's disease, 128patients with ulcerative colitis and 208 controls recruited from the University of Szeged, Hungary. In patients with Crohn's disease, the prevalence of NOD2/CARD15 mutations was correlated to the demographical and clinical parameters.RESULTS: In total, 32.4% of Crohn's disease patients carried at least one mutant allele within NOD2/CARD15compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P＜0.0001). In Crohn's disease patients, the allele frequencies for Arg702Trp,Gly908Arg and 1007finsC were 7.1%, 3.0% and 10.8%respectively. Interestingly, only the 1007finsC mutation was associated with a distinct clinical phenotype. The patients positive for the 1007finsC mutation suffered more frequently from stenotic disease behaviour (P = 0.008). Furthermore,51.9% of patients positive for the 1007finsC mutation underwent a surgical resection within the ileum compared to only 17.4% of patients without the 1007finsC mutation (P = 0.001). With respect to the other two mutations (Arg702Trp and Gly908Arg), no associations were found with all investigated clinical parameters.CONCLUSION: NOD2/CARD15 mutations are frequently found in Crohn's disease patients from Hungary. The 1007finsC mutation is associated with stenotic disease behaviour and frequent ileal resections.

OCTN and CARD15 gene polymorphism in Chinese patients with inflammatory bowel disease

AIM: To investigate the single nucleotide polymorphism (SNPs) distribution of NOD2/CARD15 (R702W, G908R), OCTN1 1672C/T and OCTN2-207G/C in Chinese patients with inflammatory bowel disease (IBD). METHODS: A total of 61 patients with Crohn’s disease (CD), 151 patients with ulcerative colitis (UC), and 200 unrelated healthy controls were genotyped. Genotyping was performed by sequence specif ic primer polymerase chain reaction (PCR-SSP) or by restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Among the subjects in our study groups, including patients with CD, UC and healthy controls, none had OCTN and CARD15 variants and very rare IBD family history was found in our patients with the percentage of 0 (0/61 with CD) and 1.3% (2/151 with UC). CONCLUSION: Our results indicate that although OCTN or CARD15 variation is associated with susceptibility to IBD in Western populations, these might be rare and may not be associated with susceptibility to IBD in Chinese patients.

Clinical significance of NOD2/CARD15 and Toll-like receptor 4 gene single nucleotide polymorphisms in inflammatory bowel disease

AIM: To evaluate the role of genetic factors in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), we investigated the single nucleotide poly- morphisms (SNPs) of NOD2/CARD15 (R702W, G908R and L1007fi nsC), and Toll-like receptor 4 (TLR4) genes (D299G and T399I) in a selected inflammatory bowel disease (IBD) population coming from Southern Italy. METHODS: Allele and genotype frequencies of NOD2/ CARD15 (R702W, G908R and L1007finsC) and TLR4 (D299G and T399I) SNPs were examined in 133 CD pa-tients, in 45 UC patients, and in 103 healthy controls. A genotype-phenotype correlation was performed. RESULTS: NOD2/CARD15 R702W mutation was sig-nificantly more frequent in CD (9.8%) than in controls (2.4%, P = 0.001) and in UC (2.3%, P = 0.03). No sig-nificant difference was found between UC patients and control group (P > 0.05). In CD and UC patients, no signifi cant association with G908R variant was found. L1007f insC SNP showed an association with CD (9.8%) compared with controls (2.9%, P = 0.002) and UC patients (2.3%, P = 0.01). Moreover, in CD patients, G908R and L1007finsC mutations were significantly associated with different phenotypes compared to CD wild-type patients. No association of IBD with the TLR4 SNPs was found in either cohort (allele frequencies: D299G-controls 3.9%, CD 3.7%, UC 3.4%, P > 0.05; T399I-controls 2.9%, CD 3.0%, UC 3.4%, P > 0.05). CONCLUSION: These findings confirm that, in our IBD patients selected from Southern Italy, the NOD2/ CARD15, but not TLR4 SNPs, are associated with in-creased risk of CD.

Role of CARD15,DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases

AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn’s disease (CD), 186 ulcerative colitis (UC) patients, 434 par- ents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more com- mon in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an in- creased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was morefrequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric on- set of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.

NOD2/CARD15基因突变与中国人克罗恩病相关性的研究

背景:近年多项研究证明NOD2/CARD15基因序列的单核苷酸多态性(SNP)与西方白种人克罗恩病(CD)明显相关,其中3个SNP(R702W、G908R和3020insC)与CD的相关性尤为显著。目的:探讨NOD2/CARD15基因SNP与中国人CD发病的相关性及其与CD临床特点的关系。方法:选取临床资料完整的CD患者48例、溃疡性结肠炎(UC)患者和健康对照者各50例,提取人血白细胞基因组DNA,经聚合酶链反应(PCR)扩增NOD2基因全部12对外显子,纯化后直接测序,根据结果分析其突变与CD病变特点的关系。结果:CD组、UC组和健康对照组均未检出3个西方人常见的NOD2/CARD15基因多态性位点。CD组的P268S突变率显著高于UC组和健康对照组(P<0.05)。5例P268S突变的CD患者病变均位于回肠(P<0.01),4例发病年龄≤20岁(P<0.01),且均并发肠腔狭窄(P<0.01)。结论:中国人CD患者中存在NOD2/CARD15基因P268S突变,且与患者的发病年龄、病变部位和并发症相关,有必要对其功能作进一步探讨。

NOD2/CARD15基因突变与中国人克罗恩病相关性研究

背景NOD2/CARD15基因是人类克罗恩病(Crohn′sdisease,CD)第一个易感基因,既往研究发现P268S可能与中国人CD发病及临床特征相关。目的本研究旨在证实P268S与中国人CD发病及其临床特征的相关性。方法血样来自临床确诊的50例CD患者,60例溃疡性结肠炎(ulcerativecolitis,UC)患者及100例健康体检者(healthycontrols,HC)。提取人血白细胞基因组DNA,PCR扩增目的片段,PCR-RFLP发现突变位点,DNA测序证实突变位点。结果共有8例CD患者发现有P268S改变,而在UC患者和HC中分别发现2例和3例P268S改变,CD组明显高于UC和HC组(χ2=10.829,P=0.004),而UC组和HC组无明显差异。8例有P268S改变的CD患者临床特征包括病变多位于回肠,发病年龄轻(6例<20岁),常并发肠腔狭窄而需手术治疗,中-重度患者比例高。结论P268S可能是NOD2/CARD15基因中与中国人CD相关的SNP。P268S与CD患者发病年龄、病变部位及并发症及病情严重程度可能相关。

P268S突变型NOD2/CARD15真核表达载体的构建及其体外表达

背景:NOD2/CARD15基因序列单核苷酸多态性(SNP)与欧美人群的克罗恩病(CD)明显相关,其中R702W、G908R和3020insC3个SNP位点与CD的相关性尤为显著。而日本、韩国以及我国香港和浙江地区的研究均未发现上述3个SNP的改变,但最近研究发现了可能与中国人CD相关的P268S突变。目的:构建P268S突变型NOD2/CARD15真核表达载体和体外转染体系,为研究突变型NOD2/CARD15的功能提供实验基础。方法:应用定点诱变技术构建P268S突变型NOD2/CARD15真核表达载体,以阳离子脂质体介导体外转染技术瞬时转染人胚肾细胞HEK293T,以蛋白质印迹法和逆转录聚合酶链反应(RT-PCR)检测HEK293T细胞NOD2/CARD15的表达。结果:经克隆、酶切、测序证实获得P268S突变型NOD2/CARD15基因,突变载体转入HEK293T细胞后,NOD2/CARD15有效表达。结论:成功构建了P268S突变型NOD2/CARD15真核表达载体,阳离子脂质体是人胚肾细胞有效的体外转染体系。

TLR2、TLR4和NOD2/CARD15基因多态性与溃疡性结肠炎相关性的meta分析

背景:近年我国溃疡性结肠炎(UC)的患病率明显增高,Toll样受体2(TLR2)、TLR4和NOD2/CARD15基因多态性与UC的发生、发展可能密切相关。目的:探讨TLR2、TLR4和NOD2/CARD15基因多态性对UC发生的影响。方法:计算机检索PubMed、中国生物医学文献、中国知网、万方数据库、重庆维普等数据库中所有TLR2、TLR4和NOD2/CARD15基因多态性与UC相关性的研究。按照纳入与排除标准筛选文献、评价质量并提取数据,采用RevMan 5.3软件进行meta分析。结果:共纳入15项研究。Meta分析结果显示,TLR2 Arg753Gln基因多态性与UC发生风险无关(P>0.05)。除隐性模型外,TLR4 Asp299Gly基因多态性可显著增加UC的发生风险(P<0.05),TLR4 Thr399Ile基因超显性模型可导致UC风险增加(P<0.05),但显性模型和隐性模型与UC无关(P>0.05)。NOD2/CARD15(Arg702Trp、Gly908Arg、Leu1007fsinsC)基因多态性均与UC无关(P>0.05)。结论:NOD2/CARD15(Arg702Trp、Gly908Arg、Leu1007fsinsC)、TLR2(Arg753Gln)与UC发生风险无关,TLR4(Asp299Gly、Thr399Ile)可增加UC的发生风险。

CARD15基因StyⅠ酶切多态性与奶牛结核病易感性的相关性分析

本试验旨在探讨CARD15基因StyⅠ酶切位点多态性与云南高原奶牛结核病易感性的关联。选择云南昆明、玉溪、大理等地结核病阳性奶牛103头,结核病阴性奶牛98头,共201头为研究对象,应用创造酶切位点原理设计引物,通过PCR-RFLP与PCR直接测序法相结合的检测方法,获得CARD15基因StyⅠ酶切位点的基因型及等位基因频率,分析该位点与云南高原奶牛结核病易感性的关系。结果显示,CARD15基因的StyⅠ酶切位点存在AA、AG、GG 3种基因型,在结核病例组中AA、AG、GG基因型频率为0.03、0.42和0.55,A、G等位基因频率为0.24和0.76;在结核对照组中AA、AG、GG基因型频率为0.01、0.05和0.94,A、G等位基因频率为0.04和0.96;对多态性位点的遗传模式进行分析,最佳遗传模式为显性遗传(dominant),在此遗传模式下基因型AG-AA在病例组的频率44.7%,明显高于对照组的频率6.1%,OR(95%CI)=0.08(OR<1),在病例组与对照组的分布之间有极显著差异(P<0.0001)。结果表明,云南高原奶牛CARD15基因StyⅠ酶切位点多态性与结核病的发生有显著关联性,且基因型AG-AA可能是结核易感型。

Risk factors and gene polymorphisms of inflammatory bowel disease in population of Zhejiang,China

AIM:To identify the risk factors and three single nucleotide polymorphisms(SNPs) of NOD2/CARD15 gene in inflammatory bowel disease(IBD) of the population in Zhejiang,China.METHODS:A case-control study was conducted using recall questionnaire to collect data on demographic,socioeconomic,lifestyle characteristics and dietary behaviors from 136 determined IBD patients and 136 paired healthy controls.COX regression method was used to screen the statistically significant risk factors for IBD.The polymorphisms of NOD2/CARD15 gene Arg702Trp,Gly908Arg and Leu1007fsinsC were genotyped and further compared between 60 patients with IBD and 60 healthy controls by polymerase chain reaction and restriction fragment length polymorphism.RESULTS:IBD occurred primarily in young and middle-aged people.The mean age for IBD patients was 42.6 years.The ratio of males to females was 1.23:1.COX regression indicated a higher statistical significance in milk,fried food and stress compared with the other postulated risk factors for IBD.None of the patients with IBD and healthy controls had heterozygous or homozygous SNPs variants.CONCLUSION:Milk,fried food and stress are associated with increased risk of IBD.The common variants in NOD2/CARD15 gene are not associated with IBD in China's Zhejiang population.

Association between polymorphisms in the Toll-like receptor 4,CD14,and CARD15/NOD2and inflammatory bowel disease in the Greek population

AIM: Crohn's disease(CD)and ulcerative colitis(UC)are multifactorial diseases with a significant genetic background.Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp,Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC.METHODS: DNA was obtained from 120 patients with CD,85 with UC and 100 healthy individuals. Genotyping was performed by allele specific PCR or by PCR-RFLP analysis.RESULTS: The 299Gly allele frequency of the TLR4 gene and the T allele and TT genotype frequendes of the CD14 promoter were significantly higher in CD patients only compared to healthy individuals (P = 0.026＜0.05; P = 0.0048＜0.01 and P= 0.047＜0.05 respectively). Concerning the NOD2/CARD15mutations the overall presence in CD patients was significantly higher than that in UC patients or in controls.Additionally, 51.67% of the CD patients were carriers of a TLR4 and/or CD14 polymorphic allele and at least one variant of the NOD2/CARD15, compared to 27% of the UC patients. It should be pointed out that both frequencies significantly increased as compared with the 10% frequency of multiple carriers found in healthy controls. A possible interaction of the NOD2/CARD15 with TLR4 and especially CD14, increased the risk of developing inflammatory bowel disease (IBD).CONCLUSION: Our results indicate that co-existence of a mutation in either the TLR4 or CD14 gene, and in NOD2/CARD15is associated with an increased susceptibility to developing CD compared to UC, and to developing either CD or UC compared to healthy individuals.

克罗恩病的发病机制和治疗进展

克罗恩病(Crohn's disease,CD)是一种以小肠为主,累及全层节段性全胃肠道的非特异性炎症性肠道疾病(inflam-matory bowel disease,IBD)。该病须与溃疡性结肠炎、急性感染性结肠炎等鉴别诊断。该病在亚洲的发病率远低于西方国家,近10年来在我国的发病率有明显上升趋势。CD的病因与发病机制尚不明确,临床表现也复杂多样,且容易误诊,复发率高。在过去的10多年里,遗传和肠道免疫领域取得的研究成果为我们在研究IBD病因以及治疗上提供了新的思路。本文就CD的发病机制和治疗进展作一综述。

早发型结节病临床及基因突变分析

目的:探讨伴随血压升高的1例早发型结节病患儿临床表现及CARDl5基因突变情况。方法:提取患儿、其父母及102例健康人对照组外周血DNA,PCR扩增CARDl5基因所有编码区外显子,测序结果与正常序列对比,寻找致病的突变位点。结果:患儿临床及皮损组织病理表现均符合结节病,并随疾病发展出现血压增高。基因检测发现其CARDl5/NOD2基因4号外显子发生c.1000C>T杂合突变(p.R334W),其父母及102例健康对照者的相应外显子测序均未发现该突变。结论:该例早发型结节病患儿存在CARDl5/NOD2基因p.R334W热点突变,因此基因诊断可能是辅助诊断早发型结节病的有效手段。

Nod2与克罗恩病相关性研究的进展

Nod2(Card15)及其相关的Nod1(Card4)都属于近年来研究较多的Nod分子家族。Nod蛋白最初被描述为细胞内Caspase和核因子-κB(NF-κB)信号转导通路的活化因子。随着分子生物学和遗传学研究的深入,NOD2(CARD15)基因与克罗恩病(CD)易患体质的关系逐渐明确。与此同时,生物化学研究证实Nod1及Nod2是细菌肽聚糖成分的细胞内识别分子。作者就Nod蛋白介导的细胞内细菌识别与CD的相关性研究作一综述。

NOD2/CARD15基因多态性与克罗恩病患者相关性研究

目的NOD2/CARD15基因是人类的第一个克罗恩病(CD)易感基因,其间的3个单核苷酸多态性(SNPs)与白种人CD有显著性相关,但与日本人无关。本研究旨在证实这3个SNPs是否与浙江地区人群的CD易感性有关。方法血样来自浙江地区32例CD患者,110例溃疡性结肠炎患者及292例健康对照者。通过PCRSSP方法直接检测野生型及NOD2/CARD15基因的3个多态性(Arg702Trp,Gly908Arg,Leu1007fsinsC)。结果没有发现1例CD患者纯合子或杂合子的SNPs突变,同样在溃疡性结肠炎患者和健康人中也未能检测到。结论本研究表明一些存在于特定人群的CD易感基因可能在其他人群中不存在,白种人CD患者相关的易感基因NOD2/CARD15常见的3个SNPs与浙江地区CD人群无关。

克罗恩病CARD15/NOD2基因突变的研究

目的 发现与中国人克罗恩病（CD）发病相关的单核苷酸多态性（SNP）及其与临床特点的关系.方法 临床资料完整的CD、溃疡性结肠炎（UC）患者及健康体检者各30例.提取人血白细胞基因组DNA,PCR扩增NOD2基因第4、8、11外显子,纯化后直接测序.结果 5例CD患者有SNP改变,其中2例为P268S,1例为R459R,2例为P268S和R459R,而在UC患者和健康人中各检测到1例R459R.所有研究对象未发现R702W、G908R及3020insC改变.CD有4例P268S,与UC和健康体检者比较差异有统计学意义（χ^2=8.037,P＜0.05）.4例P268S CD患者病变均在回肠（χ^2=9.231,P=0.01）,发病年龄小于20岁（χ^2=10.769,P＜0.01）,并发肠腔狭窄而需手术（χ^2=7.972,P＜0.01）,2例有P268S和R459R的患者病情较重,多次复发.结论 P268S可能是CARD15/NOD2基因中与中国人CD相关的SNP,与患者发病年龄、病变部位及肠腔狭窄明显相关,与患者性别及病变严重程度无关.

一例早发型结节病患者CARD15／NOD2基因的突变

目的探讨1例结节病和肺结核的患者CARD15基因突变情况。方法收集患者的临床资料，提取患者外周血DNA，PCR扩增CARD15基因所有编码区外显子及侧翼序列并测序，测序结果与正常序列比对，寻找致病性突变位点。结果患者皮疹及组织病理表现均符合结节病，但伴有明确的指问关节屈曲挛缩和虹膜睫状体炎。基因检测发现其CARD15／NOD2基因4号外显子发生c．1000C〉T杂合突变（p．R334W），父母及102例健康对照的相应外显子测序均未发现该突变。该突变位点在既往研究中的其他早发型结节病及Blau综合征患者中曾被报道过。结论患者为CARD15／NOD2基因p．R334W突变所致的早发型结节病，基因诊断是明确早发结节病病因的有效手段。

Blau综合征NOD2/CARD15基因突变及临床特征分析

目的回顾总结4个Blau综合征家系先证者患儿及其父母NOD2/CARD15基因突变及临床特征。方法采用PCR扩增4个家系所有成员的NOD2/CARD15基因所有外显子。Sanger法测序NOD2基因所有外显子序列,Ensembl和NCBI dbSNP基因数据库比对确定致病位点,根据ACMG指南判定基因变异的致病性。对先证者患儿及其父母行查体及病史问诊。结果所有先证者患儿均检测到NOD2基因突变,家系1和3检测到NOD2基因突变c.1000C>T p.R334W,突变分别来源于父亲和母亲;家系2检测到NOD2基因突变c.956G>A p.G319E,突变为自发性;家系4检测到NOD2基因突变c.1469G>T p.W490L,突变来源于其母亲。所有先证者患儿均有不同程度皮肤、眼及关节损害,其中3/4患儿伴有智力及体格发育迟缓,2/4患儿伴有频繁发热,1/4患儿伴有肝肿大。家系1先证者父亲、家系3和4先证者母亲均有不同程度眼睛和关节损害。结论Blau综合征均由NOD2/CARD15基因突变,突变位于第四外显子,发病符合显性遗传;患儿除了具有Blau综合征的临床三联征,还具有其他临床特征。

浙江地区炎症性肠病136例危险因素及其基因多态性分析

目的研究浙江地区住院治疗的炎症性肠病(IBD)患者的可能危险因素及NOD2/CARD15基因3个单核苷酸多态性(SNPs)与IBD的相关性。方法通过问卷调查对2005年1月至2008年12月浙江大学医学院附属第一医院、浙江省金华市中心医院、宁波李惠利医院及台州地区医院136例IBD患者和等量健康对照者进行病例对照研究,对结果进行COX回归分析;采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)法对60例无血缘关系的IBD患者及60例健康对照者NOD2/CARD15基因Arg702Trp、Gly908Arg和Leu1007fsinsC多态性进行分析。结果 IBD平均发病年龄42.6岁,男性稍多于女性。牛奶、油炸食品和精神因素在IBD致病因素中具有统计学意义。IBD患者和健康对照者均未检测出纯合子和杂合子的单核苷酸多态性(SNPs)突变。结论牛奶、油炸食品和精神紧张可能是浙江地区IBD潜在的危险因素,白种人克罗恩病(CD)患者相关易感基因NOD2/CARD15常见的3个SNPs与浙江地区IBD患者无关。