Department of Laboratory Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Thromb Haemost. 2021 May;121(5):573-583. doi: 10.1055/s-0040-1720980. Epub 2020 Nov 17.
DNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood-liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤ < 0.75) were detected for 6% and strong correlations ( ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood-liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.
DNA 甲基化在包括血栓性疾病在内的复杂疾病的发病机制中越来越受到重视。在流行病学研究中，通常采集血液进行基因分型，最近也用于在全基因组范围内进行 DNA 甲基化的表观基因组关联研究。DNA 甲基化模式通常具有组织特异性，因此，外周血可能无法准确反映相关组织中的甲基化模式。在这里，我们从 27 名接受肝脏手术的个体中同时收集了配对的肝和血样。我们对主要在肝脏中表达的 35 个止血基因进行了靶向亚硫酸氢盐测序，以分析超过 10,000 个胞嘧啶-磷酸-鸟嘌呤（CpG）二核苷酸的 DNA 甲基化水平。我们评估了血液中的 DNA 甲基化是否可以作为个体 CpG 中肝脏 DNA 甲基化的替代物。大约 30%的 CpG 是非可变的，在两种组织中均主要呈低甲基化（<25%）或高甲基化（>70%）。虽然在这些 CpG 中，血液可以作为肝脏的替代物，但由于低变异性，这些 CpG 不太可能解释表型差异。因此，我们将重点放在肝脏中甲基化水平可变的 CpG 上。这些可变 CpG 中血液-肝脏组织相关性的水平差异很大；中度相关性（0.5≤ < 0.75）检测到 6%，强相关性（ ≥ 0.75）进一步检测到 4%。我们的研究结果表明，研究个体 CpG 中血液和肝脏之间的 DNA 甲基化一致性至关重要。该配对的血液-肝脏数据集旨在作为辅助解释基于血液的 DNA 甲基化结果的资源。
