Identifying the Effect of Genetic Variants on Specialized Pro-resolving Mediators and Their Association With Chronic Inflammatory Conditions

This study aims to identify polymorphisms in SPM-related genes in a South Asian population and assess whether these lead to alterations in the functions of enzymes and proteins encoded by these genes. This information will then be used to identify those SNP (Single nucleotide polymorphism) that lead to loss of function. We will then evaluate whether these SNP are linked with altered white blood cell function and increased incidence of chronic inflammatory disorders by assessing data from the Gene & Health program and other databases such as UK Biobank. We expect that this approach will provide new insights into molecular mechanisms and the identification of new mediators/enzyme/receptors families that are dysregulated in inflammatory conditions.

To achieve this aim, we will identify volunteers from the Gene & Health program. The Gene & Health program has sequenced around 40,000 volunteers and identified around 500 gene variants that are predicted to lead to complete loss of gene function; among these SNP, 68 are presented in enzymes and receptors related with SPM including ALOX15, GPR18 and FPR2/ALX. As part of their recruitment to Gene & Health program, participants have consented to be contacted about future research studies such as this.

In order to study the differences in the lipid mediator profiles between the groups, we will use peripheral blood obtained from consented Gene & Health individuals that present the SNP of interest (cases) and individuals without the mutation (controls). For the lipid mediator profiling a liquid chromatography in tandem mass spectrometry strategy (LC-MS/MS) will be used. Cell biology assays (phagocytosis, platelet activation, etc.) will be conducted using peripheral blood phagocytes cells. In addition, volunteers will be consented for access to their centralised health records so we can identify associations between different polymorphisms and the development of inflammatory conditions through a candidate-gene association study.

The risks of this study to participants are low and relate to the sharing of confidential data and blood sample donation. Access to confidential clinical information with person-identifiable data will be restricted to the Chief Investigator and Principal Investigator, who are aware of their responsibilities under the Data Protection Act 2018 and all the obligations related to data management enforced by Gene & Health program. As for the blood donation, we believe that there is minimal risk to participants as they will only be asked to donate up to 60 ml of blood per sitting and donors will not be recalled more than 3 separate occasions.