Genetic ancestry and population differences in levels of inflammatory cytokines in women: Role for evolutionary selection and environmental factors
Genetic ancestry and population differences in levels of inflammatory cytokines in women: Role for evolutionary selection and environmental factors
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DOI：
10.1371/journal.pgen.1007368
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发表时间：
2018-06-01
期刊：
影响因子：
4.5
通讯作者：
Ambrosone, Christine B.
中科院分区：
文献类型：
--
作者：
Yao, Song;Hong, Chi-Chen;Ambrosone, Christine B.
由于暴露于非洲特有的传染性病原体的选择压力可以解释免疫反应基因的独特遗传变异。然而，这些遗传变异对人类免疫力的影响仍然没有得到充分研究，特别是在现代生活方式和生活环境的背景下，这些生活方式和环境与撒哈拉以南非洲的早期人类截然不同。关于体质免疫环境中的人群差异的数据很少，遗传祖先和环境可能是变异的两个主要来源。在一项整合遗传、分子和流行病学数据的研究中，我们在914名AA和855名EA妇女中研究了参与先天性和适应性免疫的14种细胞因子血浆水平的人群差异，包括与慢性炎症有关的细胞因子，以及可能导致这种差异的因素。我们观察到7种细胞因子的显著差异，包括EA中较高的血浆CCL 2、CCL 11、IL 4和IL 10水平以及AA中较高的IL 1 RA和IFN α 2水平。对广泛的人口统计学和生活方式因素的分析显示出显著的影响，年龄，教育水平，肥胖，吸烟和饮酒，解释了一些，但不是全部，观察到的细胞因子的人群差异。两种促炎趋化因子CCL 2和CCL 11的水平与AA中非洲血统的百分比密切相关。通过混合定位，该信号被精确定位到1 q23的当地祖先，精细定位分析细化到rs 2814778的Duffy无效等位基因。在AA女性中，这种变异是CCL 2（p = 1.1e-58）和CCL 11（p = 2.2e-110）系统水平的主要决定因素，分别占表型变异的19%和40%。我们的数据揭示了炎症趋化因子调节中强大的祖先足迹。Duffy无效等位基因可能表明趋化因子水平的缓冲功能丧失。祖先的免疫差异可能对AA和EA人群之间的健康差异产生广泛的影响。
Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFN alpha 2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.