Mandaviya Pooja R, Joehanes Roby, Aïssi Dylan, Kühnel Brigitte, Marioni Riccardo E, Truong Vinh, Stolk Lisette, Beekman Marian, Bonder Marc Jan, Franke Lude, Gieger Christian, Huan Tianxiao, Ikram M Arfan, Kunze Sonja, Liang Liming, Lindemans Jan, Liu Chunyu, McRae Allan F, Mendelson Michael M, Müller-Nurasyid Martina, Peters Annette, Slagboom P Eline, Starr John M, Trégouët David-Alexandre, Uitterlinden André G, van Greevenbroek Marleen M J, van Heemst Diana, van Iterson Maarten, Wells Philip S, Yao Chen, Deary Ian J, Gagnon France, Heijmans Bastiaan T, Levy Daniel, Morange Pierre-Emmanuel, Waldenberger Melanie, Heil Sandra G, van Meurs Joyce B J
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
PLoS One. 2017 Oct 30;12(10):e0182472. doi: 10.1371/journal.pone.0182472. eCollection 2017.
DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.
Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation.
Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5.
Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.
DNA甲基化受一碳代谢途径关键酶和中间代谢产物活性的影响，其中一种涉及同型半胱氨酸。我们研究了与轻度升高的同型半胱氨酸相关的著名基因变异：MTHFR 677C>T单独以及与其他同型半胱氨酸相关变异联合，对全基因组白细胞DNA甲基化的影响。
使用Illumina 450k芯片对来自12项队列研究的9894名欧洲血统个体的甲基化水平进行评估。采用线性混合模型研究MTHFR 677C>T的加性效应以及基于18个同型半胱氨酸相关单核苷酸多态性（SNP）的遗传风险评分（GRS）与全基因组甲基化的关联。
荟萃分析显示，MTHFR 677C>T变异与35个顺式CpG位点相关，GRS与同型半胱氨酸相关变异附近的113个CpG位点相关。全基因组分析显示，MTHFR 677C>T变异与1个反式CpG（最近基因ZNF184）相关，而GRS模型与注释到最近基因PTF1A、MRPL55、CTDSP2、CRYM和FKBP5的5个显著反式CpG相关。
我们的结果未显示全基因组DNA甲基化的广泛变化，因此不支持轻度升高的同型半胱氨酸与白细胞广泛甲基化变化相关的假设。
