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 IFNα2 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. Author summary Individuals of European and African ancestry have different susceptibility for developing specific infections and diseases. Part of this difference in immune response is thought to arise from genetic differences accumulated over the millennia that conferred advantages in fighting different infectious pathogens endemic to different parts of the world. The impact of these immune differences and how they are influenced by modern lifestyles and living environments remains to be understood. Findings from this study revealed population differences in the levels of circulating cytokines, i.e. chemical messengers of the immune system, which were due in part to different demographic and lifestyle factors. Further, a change in the gene encoding for the Duffy antigen receptor protein, identified as rs2814778 and known as the Duffy-null allele, was the most important factor explaining low circulating levels of CCL2 and CCL11, key chemokines regulating the migration of white blood cells, specifically monocytes and eosinophils, which play a role in inflammation. This genetic variant occurs almost exclusively among Africans, likely because of its role in protecting against malaria infection, and results in loss of Duffy antigen protein on red blood cells. The substantial immune differences by ancestry may have broad implications for health disparities.
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