Written by Vered Smith, Science Writer
Researchers at the University of Michigan have published a study in PLOS ONE identifying genetic variants associated with sepsis. They identified 163 risk variants for sepsis through a GWAS, and used them to produce a polygenic risk score with good discrimination.
Sepsis is a syndrome that results in organ system dysfunction, due to systemic inflammation and infection. It is one of the leading causes of death, and even if patients survive it often has long-lasting impacts on their physical, psychological and cognitive health. It is currently treated with general treatments such as antibiotics, as drugs designed to target sepsis specifically have failed so far. This may be because it is a polygenic disease, and there are many pathways involved in its development and progression.
Sepsis has a higher heritability than cancer or heart disease, and past studies have associated many genes with it. Gene functions identified so far include involvement in immunity and coagulation, such as interleukins, receptors and fibrinogen. However, these studies have been limited by small patient populations.
In this study, the researchers performed a GWAS on 2261 patients with sepsis and 13,068 control patients without sepsis. They aimed to produce a polygenic risk score that would be clinically useful, and through doing so identify genetic variants associated with the disease.
The researchers found 95 variants on 72 genes associated with Sepsis-2, and 68 variants on 54 genes associated with Sepsis-3. Most of the variants had small effect sizes. 32 genes identified were present in both groups, and 25 variants of these genes were the same in both groups. They found 11 variants on 10 genes to be associated with mortality, and one of these variants (7:105901555:C:T variant of NAMPT) was associated with a 10-fold higher risk of death.
The genes were involved in a range of functions, including immune, metabolic, vascular, and signalling pathways. Some of these genes are involved in other diseases, and therefore already have drugs targeting them. For example, a PCKS9 variant was associated with almost double the risk of developing sepsis. There are already approved PCSK9 inhibitors, which are given to lower LDL cholesterol and decrease the incidence of strokes and myocardial infarction. Two of these are in clinical trials for treating sepsis.
The polygenic risk scores were able to identify patients with sepsis with good discrimination (c-statistic = 0.752 ± 0.005 for Sepsis-2 and 0.752 ± 0.007 for Sepsis-3).
Potential for Personalised Medicine
The researchers suggested that as genotyping patients becomes more common, it will be possible to use this polygenic risk score to select patients at high risk of developing sepsis. This would enable doctors to protect patients better, and give preventative treatment. This is especially important for patients if sepsis develops because of complications from other treatments, such as chemotherapy, immunotherapy, or surgery. They proposed as an example that a patient undergoing surgery would be screened for sepsis risk. If they receive a high score, they could be given prophylactic antibiotics for longer to lower the risk.
Furthermore, once we understand the roles specific variants play in sepsis, personalised medicine could be given to the patient based on the variants that make up their risk score. The next steps are therefore researching how to translate this information into the clinic, and how it can be used to improve patient treatment and reduce mortality.
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