DNA 甲基化分析用于鉴定与血液中循环纤维蛋白原水平相关的新的遗传位点。
DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood.
机构信息
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
出版信息
J Thromb Haemost. 2023 May;21(5):1135-1147. doi: 10.1016/j.jtha.2023.01.015. Epub 2023 Jan 28.
BACKGROUND
Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa.
OBJECTIVES
To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions.
METHODS
We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation.
RESULTS
We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10) and EPIC arrays (p < 5.78 × 10), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.
CONCLUSION
We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.
背景
纤维蛋白原在血液凝固和炎症中起着至关重要的作用。循环纤维蛋白原水平可能基于胞嘧啶-磷酸-鸟嘌呤 (CpG) 位点的 DNA 甲基化的个体间差异来确定，反之亦然。
目的
进行 EWAS 以检查血液 DNA 甲基化水平与循环纤维蛋白原水平之间的关联，以更好地了解其生物学和病理生理学作用。
方法
我们对来自基因组流行病学协作研究中心的 14 项研究的 18037 名白种人、黑种人、美洲印第安人和西班牙裔参与者的循环纤维蛋白原水平进行了全基因组关联研究。在 12904 名参与者中使用 Illumina 450K 阵列测量循环白细胞 DNA 甲基化，在 5133 名参与者中使用 EPIC 阵列测量循环白细胞 DNA 甲基化。在每项研究中，使用线性混合模型调整潜在混杂因素后，对纤维蛋白原进行全基因组关联研究。使用特定于阵列的荟萃分析合并研究特异性结果，然后对全基因组显著关联进行交叉复制。我们比较了有和没有 CRP 调整的模型，以检查炎症的作用。
结果
我们从 450K 阵列（p<1.03×10）和 EPIC 阵列（p<5.78×10）分别鉴定出与纤维蛋白原水平相关的 208 个和 87 个显著 CpG 位点。在 450K 阵列中有 78 个关联在 EPIC 阵列中复制，反之亦然。在考虑重叠位点后，有 83 个复制的 CpG 位点位于 61 个基因座中，其中只有 4 个先前报道与纤维蛋白原有关。位于这些 CpG 位点附近的基因的例子是 SOCS3 和 AIM2，它们参与炎症途径。在 CRP 调整后，所有 83 个复制的 CpG 位点的关联都减弱了，尽管许多仍具有统计学意义。
结论
我们确定了 83 个与循环纤维蛋白原水平相关的 CpG 位点。这些关联部分是由纤维蛋白原和 CRP 共享的炎症途径驱动的。
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