Epigenetics Group, International Agency for Research on Cancer (IARC), 69372 Lyon CEDEX 08, Lyon, France.
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Biocruces-Bizkaia Health Research Institute, Leioa, Basque Country, 48940, Spain.
Sci Rep. 2019 Feb 4;9(1):1298. doi: 10.1038/s41598-018-37746-6.
The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately. We found a cell type-specific methylation signature that includes genes mapping to the HLA region, namely TAP1 and HLA-B. We also performed Immunochip SNP genotyping of the same samples and interrogated the expression of some of the affected genes. Our analysis revealed that the epithelial methylome is characterized by the loss of CpG island (CGI) boundaries, often associated to altered gene expression, and by the increased variability of the methylation across the samples. The overlap between differentially methylated positions (DMPs) and CD-associated SNPs or variants contributing to methylation quantitative trait loci (mQTLs) is minimal. In contrast, there is a notable enrichment of mQTLs among the most significant CD-associated SNPs. Our results support the notion that DNA methylation alterations constitute a genotype-independent event and confirm its role in the HLA region (apart from the well-known, DQ allele-specific effect). Finally, we find that a fraction of the CD-associated variants could exert its phenotypic effect through DNA methylation.
人类白细胞抗原（HLA）基因座和其他全基因组关联（GWA）研究中鉴定的 DNA 序列变异解释了约 50%的乳糜泻（CD）的遗传率。然而，CD 的发病机制可能由与序列变异无关的其他基因组信息层驱动，例如 DNA 甲基化，并且等位基因特异性甲基化可能解释了部分 SNP 关联的部分原因。由于 DNA 甲基化景观预计在不同的细胞类型中存在差异，我们分别分析了 CD 患者和对照者十二指肠活检的上皮细胞和免疫细胞群体的甲基组。我们发现了一个具有细胞类型特异性的甲基化特征，其中包括映射到 HLA 区域的基因，即 TAP1 和 HLA-B。我们还对相同样本进行了 Immunochip SNP 基因分型，并检测了一些受影响基因的表达。我们的分析表明，上皮细胞甲基组的特征是 CpG 岛（CGI）边界的丧失，通常与基因表达改变有关，并且样本之间的甲基化变化具有更大的可变性。差异甲基化位置（DMP）与 CD 相关 SNP 或导致甲基化数量性状基因座（mQTL）的变异之间的重叠很小。相比之下，在最显著的 CD 相关 SNP 中，mQTL 显著富集。我们的研究结果支持 DNA 甲基化改变构成基因型独立事件的观点，并证实了其在 HLA 区域的作用（除了众所周知的 DQ 等位基因特异性效应）。最后，我们发现一部分 CD 相关变异可能通过 DNA 甲基化发挥其表型效应。
