Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease.
Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease.
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DOI：
10.1097/mib.0b013e318281f275
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发表时间：
2013-07
影响因子：
4.9
通讯作者：
McGovern DP
中科院分区：
文献类型：
--
作者：
Dubinsky MC;Kugathasan S;Kwon S;Haritunians T;Wrobel I;Wahbeh G;Quiros A;Bahar R;Silber G;Farrior S;Stephens M;Teleten N;Panikkath D;Ippoliti A;Vasiliauskas E;Fleshner P;Williams C;Landers C;Rotter JI;Targan SR;Taylor KD;McGovern DP
识别手术风险最高的克罗恩病（CD）患者的能力在指导治疗方面将是非常宝贵的。全基因组关联（GWA）研究已经确定了多个IBD基因座与未知的表型后果。1)鉴定已知和新的CD基因座与早期切除性CD手术之间的关联2）使用表型、血清学和遗传变量的组合开发手术时间的最佳预测模型。使用基于Illumina的全基因组技术对1115名受试者进行基因分型。单变量和多变量分析测试了5年内需要手术的遗传相关性。通过检测已知CD基因座（n=71）和进行GWA研究进行分析。使用考克斯回归模型分析手术时间。临床和血清学变量包括沿着基因型，以建立手术时间的预测模型。239例受试者在5年内接受了手术，中位时间为12个月。3个CD易感基因位点（IL 12 B、IL 23 R、C11 orf 30）与5年内的手术独立相关。GWA确定了与早期手术相关的新的推定基因座; 7 q21（CACNA 2D 1）和9 q34（RXRA，COL 5A 1）。最具预测性的手术时间模型包括遗传和临床风险因素。在最低和最高风险组之间，进展到手术的频率差异超过20%。同时具有遗传和临床风险因素的CD患者进展到手术更快。IL 12 B与CD患者的早期手术需求和时间独立相关，并证明了对影响该途径的新疗法和现有疗法的研究是合理的。
The ability to identify patients with Crohn’s disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association (GWA) studies have identified multiple IBD loci with unknown phenotypic consequences. 1) to identify associations between known and novel CD loci with early resective CD surgery2) to develop the best predictive model for time to surgery using a combination of phenotypic, serologic and genetic variables. Genotyping was performed on 1115 subjects using Illumina-based Genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n=71) and by performing a GWA study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, C11orf30). GWA identified novel putative loci associated with early surgery; 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. Progression to surgery is faster in CD patients with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.