Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
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DOI：
10.1016/j.jnim.2017.03.002
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发表时间：
2017-06-01
期刊：
影响因子：
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通讯作者：
Arnett, Donna K
中科院分区：
文献类型：
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作者：
Aslibekyan, Stella;Irvin, Marguerite R;Arnett, Donna K
背景：三甲胺- n -氧化物（TMAO）是一种致动脉粥样硬化代谢物，已成为心血管疾病可能的新危险因素。动物研究表明，循环中的氧化三甲胺水平受遗传和环境因素的调节。然而，大规模的人体研究未能复制所观察到的遗传关联，并且表观遗传因素如DNA甲基化从未被研究过与TMAO水平的关系。方法和结果：我们使用基于家族的降脂药物和饮食网络（GOLDN）的数据来研究人类血浆TMAO的遗传决定因素。氧化三甲胺与心血管疾病的其他血浆标志物（如脂质或炎症细胞因子）无关。我们首先估计TMAO遗传率为27%，表明遗传影响中等。我们使用1000个基因组输入的数据（n=626）来估计全基因组与TMAO水平的关联，调整了年龄、性别、家庭关系和研究地点。全基因组研究在全基因组水平上发现了一个重要的打击，位于4号染色体的基因间区域。随后，我们使用Illumina Infinium阵列在CD4+ t细胞上量化表观基因组范围的DNA甲基化。我们测试了甲基化位点与循环TMAO的关联（n=847），调整了年龄、性别、家庭关系和研究地点，作为全基因组研究加上捕获CD4+ t细胞纯度的主要成分。在调整多重测试后，没有任何表观遗传发现具有统计学意义。结论：我们的发现提供了越来越多的证据，表明遗传和表观遗传因素在建立人类循环TMAO水平中都不起关键作用。
BACKGROUND: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels.METHODS AND RESULTS: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n=626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n=847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant.CONCLUSIONS: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans.