通过遗传学和单细胞表观学解释1型糖尿病风险
Joshua Chiou1,2, Ryan J Geusz3, Mei-Lin Okino4
1Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA. joshua.chiou@pfizer.com.
Nature
|May 20, 2021
概括
与1型糖尿病 (T1D) 相关的遗传变异在胰腺细胞中的活性调节元件中发现. 这项研究揭示了外分胰腺
科学领域:
- 基因组学和表观基因组学
- 免疫学和内分泌学
背景情况:
- 全基因组关联研究 (GWAS) 确定了诸如1型糖尿病 (T1D) 等复杂疾病的众多非编码遗传风险变体.
- 了解这些变异的功能影响需要详细地图的基因调节疾病相关的细胞类型.
研究的目的:
- 将T1D的大规模GWAS数据与单细胞表观基因分析结合起来.
- 确定在胰腺和免疫细胞中活跃的候选cis调节元件 (cCREs).
- 研究胰腺外分在T1D病变中的作用.
主要方法:
- 在520,580个样本中进行了T1D的GWAS.
- 在131,554个胰腺和外周血液单核细胞中进行了转化酶可访问的染色体测定 (snATAC-seq).
- 集成GWAS结果与snATAC-seq数据以识别丰富的cCREs.
主要成果:
- 在T细胞和外分胰腺细胞 (状和管状细胞) 中活跃的cCREs丰富了T1D风险变体.
- 一些T1D风险变体与外分特异性cCREs重叠,与外分特异性基因表达相关.
- 在CFTR位点,一种T1D风险变体 (rs7795896) 调节了管道细胞中的CFTR表达,风险基因降低了增强剂活性和CFTR表达.
结论:
- 外分胰腺在T1D的发病过程中起着重要作用.
- 单细胞表观基因组与大规模GWAS结合是发现复杂疾病细胞起源的强大方法.
- 管道细胞中的特定调节因素通过CFTR调节影响T1D风险.
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