The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Denmark.
PLoS Genet. 2020 Nov 23;16(11):e1009163. doi: 10.1371/journal.pgen.1009163. eCollection 2020 Nov.
Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.
循环炎症标志物对人类健康和疾病至关重要，它们在癌症以及心血管、代谢、免疫和神经精神疾病中经常失调或出现功能障碍。然而，遗传因素对循环炎症标志物水平的生理变化的贡献在很大程度上是未知的。在这里，我们报告了一项针对十种细胞因子（包括迄今尚未研究的钙结合蛋白（S100B））血液浓度的全基因组遗传研究结果。该研究利用了来自 iPSYCH 计划的 9459 名丹麦新生儿血斑的独特样本。我们估计标记物水平的 SNP 遗传率从 EPO 的基本为零到 S100B 的 73%。我们确定并复制了 16 个相关的基因组区域（p < 5 x 10-9），其中 4 个是新的。我们表明，相关的变异映射到增强子元件，这表明基因组变异对细胞因子水平可能具有转录效应。鉴定细胞因子基本水平的遗传结构很可能会促使研究细胞因子与复杂疾病之间的关系。我们的研究结果还表明，细胞因子的遗传结构在新生儿到成年期是稳定的。
