ABSTRACT
Nonalcoholic fatty liver disease contributes to liver-related mortality and has a high prevalence among patients with human immunodeficiency virus (HIV). The early detection of steatosis could prevent disease progression through life-style changes. However, as the common serum markers are nonspecific and the gold standard for the detection of nonalcoholic fatty liver disease remains the invasive liver biopsy, its verification is limited. Therefore, the search for novel biomarkers is essential. Several studies have emphasized the role of microRNAs (miRNAs) as biomarkers for certain liver diseases. With our study, we aimed to investigate the potential of miR-200a as a biomarker for liver injury, fibrosis, and steatosis in HIV patients. The study cohort consisted of 89 HIV patients. Clinical and laboratory parameters were assessed twice, within a median follow-up period of 12 months. miR-200a serum levels were determined by real-time polymerase chain reaction and normalized to spiked-in RNA (SV40). miR-200a serum levels showed a significant correlation with the patients' controlled attenuation parameter scores and their body weight at baseline and with alanine aminotransferase serum levels at follow-up. At baseline, we observed a stage-dependent increase in miR-200a serum levels according to the degree of steatosis. More importantly, patients with higher baseline levels of miR-200a recorded a progression of steatosis at follow-up. Remarkably, miR-200a not only reveals a prognostic value for steatosis but possibly also for liver damage and metabolic adaptions as patients with an increase in alanine aminotransferase/aspartate aminotransferase serum levels over time also recorded higher baseline miR-200a levels. Conclusion : Our study reveals miR-200a not only to be a stage-dependent biomarker of steatosis but also to be a predictor of steatosis progression and probably liver cell injury in HIV patients. (Hepatology Communications 2017;1:36-45).
ABSTRACT
Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a â¼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10⻹5). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (pâ=â0.00003) and positive Tajima's D (pâ=â0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human-Neandertal divergence and is evolving under balancing selection, especially among European populations.
