“Omic” approaches may provide better insight into highly complex diseases, such as sepsis, trauma, and other illnesses with multiorgan dysfunction that could result in improved diagnostic tests and novel therapies.
Genomics is the study of the structure and function of DNA within cells. Genomics includes efforts to determine nucleotide sequences, to fine-scale map genes, and to analyze interactions between loci that occur within the genome.
Variants that alter protein levels or function are partially responsible for genetically determined variation in our physical characteristics, physiology, and personality traits. Genetic variability also explains some of the variability in disease susceptibility, disease severity, and response to treatment that is observed in patient populations.
Epigenetics is the study of heritable changes in gene activity and expression that are not dependent on changes in the gene sequence, and epigenomics is the study of the global epigenetic signature in a cell or tissue.
The transcriptome refers to all RNAs produced in the cell, including messenger RNA, ribosomal RNA, and transfer RNA in addition to noncoding RNAs, such as micro RNAs (miRNAs). The majority of research on the transcriptome has focused on examining gene expression profiles in different disease states or following various treatments. Specifically, these studies have examined gene expression or repression in various conditions, such as sepsis or acute respiratory distress syndrome.
Genome-wide expression profiling in children with septic shock has been instrumental in providing a better understanding of the molecular biology of sepsis.
In critical illnesses, miRNAs have been examined as potential biomarkers of diseases, such as sepsis, traumatic brain injury, and cardiac arrest, and may be useful in understanding mechanisms of disease.
Proteomic studies have been performed in several processes relevant to critical care, including sepsis, acute lung injury, trauma, burns, acute kidney injury, and traumatic brain injury.
Critical illnesses and injury are accompanied by severe metabolic changes. Another “omics” approach that has clinical applications in critical care is metabolomics, which commonly uses mass spectrometry or high-resolution nuclear magnetic resonance to characterize and quantify small molecules generated from cellular metabolic activity.
In conclusion, the recent development of new “omic” technologies has provided new tools for examining the “global” molecular response to critical illness and injury that occurs in children.global epigenetic changes in cells or tissues. High-throughput, high-dimensional study of the genome, transcriptome, proteome, metabolome, and epigenome has produced a massive amount of interconnecting data from many biological systems and processes. However, the sheer volume and complexity of these data make analyses and interpretation extremely challenging. Increasingly sophisticated bioinformatics tools and computational analyses are required to perform studies using
these technologies. These “omic” approaches may provide better insight into highly complex diseases, such as sepsis, trauma, and other illnesses with multiorgan dysfunction that could result in improved diagnostic tests and novel therapies. In the following sections, these various “omics” disciplines will be discussed in relation to critical illness and injury.
Genomics is the study of the structure and function of DNA within cells. Genomics includes efforts to determine nucleotide sequences, to conduct fine-scale genetic mapping, and to analyze interactions between loci that occur within the genome. The key technology driving genomics is high-throughput DNA sequencing combined with bioinformatics to analyze the large volumes of data. High-throughput DNA sequencing technology facilitated the sequencing of the entire human genome, in addition to the genomes of many other organisms. These data revealed that many sites in the human genome are variable and there are numerous differences in DNA sequences between individuals.
for genetically determined variation in our physical characteristics, physiology, and personality traits. Genetic variability also explains some of the variability in disease susceptibility, disease severity, and response to treatment that is observed in patient populations.site affect exon 9 skipping owing to differences in the binding affinity of splicing regulatory proteins (24,25). Exon 9 is essential for CFTR function given that, together with exons 10-12, it encodes the first nucleotide-binding domain, and mRNA transcripts without exon 9 do not produce functional CFTR (26,27,28). In healthy individuals, 5%-90% of CFTR transcripts are missing exon 9 (29), suggesting that CFTR activity in healthy individuals varies greatly. Although CFTR activity may be reduced to <5% of normal in CF, other variants that have less profound effects on CFTR may still increase the risk of other lung diseases (11). We examined the (TG)mTn alleles in a cohort of children with community-acquired pneumonia (CAP). African American children with CAP who have (TG)mTn alleles associated with increased exon 9 skipping are more likely to require mechanical ventilation and to develop ARDS (30). These data suggest that less functional CFTR may contribute to more severe lung injury and that the genetic makeup of the host may contribute to an increased risk for ARDS.
TABLE 18.1 GENETIC POLYMORPHISMS ASSOCIATED WITH SEPSIS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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