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结肠炎相关基因座位于染色体 2 上，影响谷胱甘肽过氧化物酶 1（GPX1）和谷胱甘肽过氧化物酶 2（GPX2）基因敲除小鼠早发型疾病的严重程度。

Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2.

机构信息

Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, California, USA.

出版信息

Inflamm Bowel Dis. 2011 Jun;17(6):1373-86. doi: 10.1002/ibd.21479. Epub 2010 Sep 24.

DOI:10.1002/ibd.21479
PMID:20872835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3526817/
Abstract

BACKGROUND

Genetic background has a profound effect on inflammatory bowel disease. The Gpx1 and Gpx2 double knockout (GPX1/2-DKO) mice on a mixed C57BL/6 (B6) and 129S1/SvimJ (129) background exhibit spontaneous ileocolitis. The DKO mice on a B6 background have mild ileocolitis. We characterized the 129 DKO mice to identify a genetic locus affecting disease severity.

METHODS

We backcrossed B6;129 DKO mice to 129 and analyzed for ileocolitis penetrance and severity at N5, N7, and N10. By correlating disease severity with single-nucleotide polymorphism (SNP) markers, we identified a colitis locus.

RESULTS

As early as 9 days of age, 129 DKO N5 and N10 mice showed disease signs and morbidity. The N10 DKO mice had the severest colitis with nearly complete penetrance and high morbidity compared with other generations or backgrounds. 129 DKO mice had elevated colonic KC and SAA3 expression, shorter colon length, and cecal E. coli overgrowth compared to B6 DKO mice. Analysis of the B6 loci in 129 N5, N7, and N10 cohorts pointed to a region of chromosome 2: 119 Mbp contributing to mild symptoms.

CONCLUSIONS

GPX1/2-DKO mice on 129 genetic background have the most aggressive colitis compared to B6;129 and B6 colonies. A B6 locus significantly contributing the resistance resides on chromosome 2: 119 Mbp. This region coincides with cytokine-deficiency-induced colitis susceptibility, Cdcs3, identified in the resistant B6 and sensitive C3H/HeJBir (C3Bir) with IL-10 deficiency. A three-way SNP analysis between 129, B6, and C3Bir locus points the major candidate genes to B2m, Dnajc17, Duox2, Pla2g4b, Pla2g4e, Pla2g4f and Slc30a4.

摘要

背景

遗传背景对炎症性肠病有深远影响。Gpx1 和 Gpx2 双敲除 (GPX1/2-DKO) 小鼠在混合 C57BL/6 (B6) 和 129S1/SvimJ (129) 背景下自发出现回肠炎。B6 背景下的 DKO 小鼠表现为轻度回肠炎。我们对 129 背景的 DKO 小鼠进行了特征描述，以确定影响疾病严重程度的遗传位点。

方法

我们将 B6;129 DKO 小鼠回交至 129，并在 N5、N7 和 N10 时分析回肠炎的穿透性和严重程度。通过将疾病严重程度与单核苷酸多态性 (SNP) 标记物相关联，我们确定了一个结肠炎位点。

结果

早在 9 天时，129 DKO N5 和 N10 小鼠就出现了疾病症状和发病。与其他世代或背景相比，N10 DKO 小鼠的结肠炎最严重，几乎完全穿透，发病率高。与 B6 DKO 小鼠相比，129 DKO 小鼠的结肠 KC 和 SAA3 表达升高，结肠长度缩短，盲肠 E. coli 过度生长。对 129 N5、N7 和 N10 队列中的 B6 基因座进行分析表明，2 号染色体上的 119 Mbp 区域有助于症状较轻。

结论

与 B6;129 和 B6 群体相比，129 遗传背景的 GPX1/2-DKO 小鼠的结肠炎最为严重。一个显著影响抗性的 B6 基因座位于 2 号染色体上的 119 Mbp。该区域与细胞因子缺陷诱导的结肠炎易感性 Cdcs3 重叠，该易感性在具有 IL-10 缺陷的抗性 B6 和敏感 C3H/HeJBir (C3Bir) 中被鉴定。129、B6 和 C3Bir 基因座之间的三向 SNP 分析将主要候选基因指向 B2m、Dnajc17、Duox2、Pla2g4b、Pla2g4e、Pla2g4f 和 Slc30a4。

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