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    • This study is limited in that the metabolomic abnormalities

    2018-11-07

    This study is limited in that the metabolomic abnormalities described in children in Malawi may not be generalizable to other populations due to differences in diet, environment, socioeconomic factors, and other variables. The Metabolon HD4 platform provides wide coverage of many metabolic pathways, but the serum metabolite measurements are semi-quantitative. This discovery platform can foster the development of targeted LC-MS/MS assays that provide absolute quantification using deuterated or stable isotope-labeled standards. Such targeted assays could be used for absolute quantification of specific metabolites such as acylcarnitines and dicarboxylic acids in the future. Although the present study shows abnormalities in metabolites that are known to be associated with altered gut microflora, the gut microbiome was not assessed in the present study. However, a previous studies show that EED is associated with alterations in the gut microbiome (Yu et al., 2015; Ordiz et al., 2016). Another limitation is that EED remains a poorly defined disease state that is ideally assessed by biopsy of the small intestine and endoscopy. The dual sugar nicotinic receptor agonist test is commonly used for diagnosis but has potential for misclassification (Denno et al., 2014). Future studies are needed in children with EED to examine the relationship between serum metabolites and the gut microbiome and between serum metabolites and vaccine failure. Also, studies using a longitudinal design could examine the relationship between serum metabolites and growth faltering. The strengths of this study are the large sample size, the use of a highly advanced metabolomics platform, and a community-based study design in a setting where EED is a major cause of morbidity. The following are the supplementary data related to this article.
    Conflicts of Interest
    Author Contributions
    Acknowledgements This work was supported by the Children\'s Discovery Institute of Washington University and St. Louis Children\'s Hospital, the Hickey Family Foundation, the National Institutes of HealthR01 AG27012 and the Intramural Branch of the National Institute on Aging, Baltimore, Maryland. The funders had no role in the study design, data collection, data analysis, interpretation, or writing of the report.
    Introduction Modern humans have inhabited Africa for longer than any other geographic region (>200,000years; Tishkoff et al., 2009); the processes of random mutation, meiotic recombination, and genetic drift have therefore led to the accumulation of a relatively large pool of genetic variation in Africa compared with elsewhere. Approximately 100,000years ago, a limited number of African subgroups migrated from Africa to other continents; many genotypes are therefore found only in Africa (Tishkoff et al., 2009; Fujikara et al., 2015; Kozyra et al., 2016; Wright et al., 2016). Based on a study calculating worldwide disease burden for 21 regions, the African continent has 15.5% of the global population but carries approximately 25% of the global disease burden (Murray et al., 2012). Furthermore, the African population carries a high burden of adverse drug reactions owing partly to the use of old, poorly-optimized drugs for the treatment of parasitic infections (Prentis et al., 1988; Ampadu et al., 2016), and also possibly owing to high levels of genetic diversity resulting in a greater proportion of patients having adverse reactions to therapeutic drugs. Drug metabolism involves a complex interplay between multiple metabolic enzymes, often with overlapping substrate specificity. One significant class of enzymes involved in therapeutic drug metabolism is the cytochrome P450 (CYP) family. CYP1, CYP2, and CYP3 are the key sub-families involved in phase I drug metabolism. Single nucleotide polymorphisms (SNPs) in CYP genes have been extensively reported (Fujikara et al., 2015) with over 400 allelic variants recorded across the CYP1, CYP2, and CYP3 sub-families (The human cytochrome P450 allele nomenclature database http://cypalleles.ki.se/ accessed 28 October 2016). Variations in gene sequence and protein structure give rise to alleles conferring no enzyme function, decreased enzyme function, normal enzyme function or increased enzyme function. Individuals who carry allelic variants may demonstrate one of the following metabolic phenotypes: poor metabolizers (PM; individuals with a combination of no function or decreased function alleles, and little to no enzyme activity); intermediate metabolizers (IM; individuals with a combination of normal and decreased function alleles conferring decreased enzyme activity); normal metabolizers (NM; individuals with fully functional enzyme activity) or rapid and ultra-rapid metabolizers (UM; individuals with two increased function alleles or more than two normal function alleles) (Caudle et al., 2016; Gaedigk et al., 2016). Genotype information can be used to guide appropriate therapeutic drug doses to reduce the risk of drug-induced adverse reactions in PMs or drug resistance in UMs for drugs with inactive metabolites, or of drug-induced adverse reactions in UMs and drug resistance in PMs for pro-drugs that require metabolic activation (Ingeman-Sundberg et al., 2007).