NEW YORK – A research team from the UK has started untangling sepsis-related regulatory features linked to genetic variation in individuals suffering from the condition.
The findings, appearing in Cell Genomics on Tuesday, offered clues to potential sepsis treatment targets as well as apparent drivers behind particularly serious forms of the organ dysfunction syndrome, based on expression-based sepsis response signatures (SRS).
"We find evidence of genetic variation associated with widespread transcriptomic differences in the sepsis response and leverage this to identify putative key regulators of SRS," senior and co-corresponding author Emma Davenport, a researcher with the Wellcome Sanger Institute, and her colleagues wrote.
As part of the UK Genomic Advances in Sepsis study, Davenport and colleagues from Wellcome Sanger , the University of Oxford, and other centers in the UK considered array-based genotyping data for nearly 1,200 adult sepsis patients recruited at almost three dozen intensive care units over more than a decade, from late 2005 to the spring of 2018. They also considered RNA sequencing-, qPCR-, or array-based gene expression profiles for blood samples from 1,043 individuals with sepsis.
"We hypothesize that the host response to sepsis, as represented by the transcriptomic SRS subgroups, has a polygenic basis with additional environmental modulators," the authors explained, "and that the elucidation of these underlying regulatory networks will be key in understanding interindividual variation in disease responses and identifying treatable traits."
With a genome-wide association study aimed at uncovering genetic variants linked to a high-risk form of sepsis known as SRS1, for example, the team tracked down SNPs at 25 loci that coincided with sepsis cases classified as SRS1 at some point in the disease process — a set that included variants implicated in everything from lung function to immune cell counts or blood clotting factors.
With the help of whole blood data from version 8 of the Genotype-Tissue Expression (GTEx) portal and Phase I of the eQTLgen consortium study, meanwhile, the researchers highlighted quantitative trait loci linked to sepsis-related gene expression or co-expression modules (modQTLs) with ties to SRS in a subset of 638 sepsis cases with available blood RNA-seq and genotyping data.
"Our study is the next step towards being able to treat sepsis based on someone's genetics and their particular immune response, instead of their symptoms, which can vary greatly from person to person," first author Katie Burnham, a researcher with the Wellcome Sanger Institute, said in a statement, noting that the study highlighted two groups of sepsis patients with distinct regulatory features and related immune responses.
"Being able to molecularly categorize patients with sepsis allows clinicians to correctly identify who could benefit from the available treatments," she explained, "and gives new direction to those developing targeted therapies."
In particular, the investigators flagged nearly 1,600 SRS-genotype interactions and 32 modQTLs, offering clues to sepsis- and sepsis severity-related biology and related shifts in cell types in the blood. From there, they relied on a SNP2TFBS database and DoRothEA regulon predictions to focus in on transcription factor binding sites and regulons interacting with sepsis-associated variants, respectively.
"Research such as this, that dives deeper into the molecular basis of the disease, aids in the ongoing development of tests that could identify different subtypes of sepsis and allow medical professionals to treat this straightaway," co-corresponding author Julian Knight, a researcher affiliated with the University of Oxford's Centre for Human Genetics and its Chinese Academy of Medical Science Oxford Institute, said in a statement.
Knight added that the current research "can be directly translated into the clinic, and we hope that it allows us to start to develop an efficient, targeted approach to treating this life-threatening disease."