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Periodic Report Summary 3 - PAIN-OMICS (Multi-dimensional omics approach to stratification of patients with low back pain)

Project Context and Objectives:
The PainOMICS project aims to find biomarkers of the transition of low back pain from acute to chronic status. It examines the variation in genetic, protein, epigenetic and glycan omics underlying low back in order to understand better the mechanisms involved. This will allow the identification of new pathological processes and hopefully reveal potential therapeutic targets. Further, the identification of biomarkers associated with the transition from acute to chronic low back pain will allow low back pain patients at high risk of transition to be identified and targeted for intervention. This is critical because the extraordinarily high costs of low back pain – to the individual in terms of disability and to society – are wrought by the minority of patients who have chronic pain and disability.

The main objectives were to collect blood samples from patients with acute and chronic low back and to follow the former to see if the pain resolves or becomes chronic. The samples were used for a broad range of omics analyses, to see if we can determine a biomarker of transition to chronic pain. To date we have analysed the samples for glycans, the sugar residues found on all proteins. We have focussed on those attached to immunoglobulin-G and total plasma glycans. We found associations between several glycan traits and low back pain, the pattern of which point at inflammation as a possible cause of low back pain. We identified high heritability of glycans suggesting the role of genetic factors in their variation. Based on this data, a genomewide association study for glycans is ongoing to discover genes associated with glycans important for low back pain. We have also performed the world’s largest genomewide association study for low back pain. Outstanding objectives include the analysis of Activomics (describes the sum of enzymatic activity of some proteins in a specimen) in the samples from the acute and chronic low back pain patients. Preliminary results are suggestive of a distinct pattern of enzyme activation in low back pain as well as unique genetic associations detectable in Activomics. We are now planning a larger study to determine if we can prove a genetic influence on the Activomics seen in low back pain. This is the first study of its kind. Preliminary data have also been obtained on epigenetic factors associated with the risk of transition from acute to chronic low back pain: several microRNAs have been identified to be changing during the transition and we are following these results up.

Project Results:
The work performed thus far includes
1. Recruitment of 1632 patients with acute low back pain, and following them longitudinally to see if the pain resolves (prospective study), with questionnaire information on the nature of their pain, general demographics, the outcome of any interventions; and sample collection for omic analysis
2. Recruitment of 3536 patients with chronic low back pain with collection of samples for omic analysis
3. The shipment of samples to different labs around Europe who specialise in omic analysis and the analysis and intergration of results with the help of a bespoke RedCap database.

The main results of the project are several omics associated with low back pain. First, the pattern of glycans attached to IgG is different in individuals with low back pain, implying that for a condition usually associated with degenerative change, the glycans reflect inflammation(1). The glycans point to biological pathways which include antibody mediated cellular cytotoxiticy, which is not what is expected for a degenerative condition. We have shown previously in novel work that glycans are heritable (2) – that is, despite sugar residues not be encoded by DNA as proteins are, we can detect a genetic influence on their expression. Clearly, the enzymes which attach the sugar residues are encoded in DNA, but the loci of control for this important pathological mechanism (thought to transcend multiple disease areas) remains unknown. To obtain insight into this, a multivariate genome-wide association study was carried out for IgG-glycome and 23 genomic loci influencing the IgG glycome have been revealed (3).

In a small sub-project, potential mechanisms of transition to chronic pain have been explored using epigenetic and miRNA. These novel techniques address the question of whether non-genetic mechanisms are important in transition. There is a suggestion from our preliminary data that certain miRNA are increased in chronic low back pain. Further studies are planned to determine the implications of our findings. Preliminary results on Activomics, in a subset of recruited patients, have been obtained that revealed two traits associated with low back pain. We also carried out a pilot genome-wide association study that identified loci associated with these traits.

Preliminary work on the genetic association study of low back pain in TwinsUK and Generation Scotland (n=10,000) demonstrated no significant findings despite a good sample size (4). This highlighted how very genetically complex the low back pain trait is, however it is defined (acute or chronic). These findings led to our collaboration with the CHARGE consortium which has enabled a very much larger sample to be studied. Because it became apparent that even with full recruitment (which seemed unlikely) within PainOmics we would not have a sufficiently large sample to produce meaningful results in a GWAS of back pain. So we changed strategry and directed our efforts at publically available databases having information about low back pain. This meant we could perform adequately powered studies, and have as a consequence idenfied several new loci associated with low back pain. In our first manuscript (under review at Plos Genetics and deposited here we have studied approximately 160,000 individuals across Europe and the USA. We revealed 3 loci reaching genome wide significance which we replicated within our study. In our second piece of work on almost 510,000 people we have (unsurprisingly) identified two of the same variants plus one novel variant (lying between SPOCK2 and CHST3 genes). Of interest, this latter locus has been reported in a large study from Asia of the related trait, such as intervertebral disc degeneration. As disc degeneration is one of the single identifiable biological risk factors for low back pain, this is of great interest. In addition we have shown interesting genetic correlations with many of the known risk factors for low back pain. Such risk factors are drawn from a wide area – they include medical risk factors such as obesity and smoking, but also the important psychological and social risk factors which are well recognised in epidemiology (manuscript in preparation). We have shown considerable genetic overlap with genes for depression and anxiety and also social factors. We see three clusters of genetic overlap which largely reflect the standard categorisation – body mass index and metabolic, psychological, smoking and parental death, cognitive and reproductive. This work highlights the extreme complexity of low back pain, both at the environment level but also deeply enmeshed in the genetic level, with overlaps between the two. Risk factors traditionally considered environmental, therefore, may actually have genetic predisposition, such as smoking. Examining shared genetic predisposition may reveal pathways of biological mechanisms not hitherto considered. For example, pathways shared with anxiety and depression may point to pain processing abnormalities, rather than primary spine pathology. Work continues to understand the genetic overlap with other chronic pain syndromes.

Potential Impact:
Our final pieces of work include:
1. Further work on Activomics to determine associations with low back pain and the genetic factors underlying Activomics
2. Integration of omics in combined analysis and further pathway analysis to identify potential drug targets
3. Determining a panel of omics markers which will predict which acute low back pain patients are at high risk of becoming chronic. These markers are likely to be most effective when combined with existing back pain stratification criteria such as the StartBack tool, devised by Keele University and in widespread clinical use. Our hope is that our panel will be able to complement such a tool, or at least be validated against it.

We aim to produce a panel of biomarkers of adequate sensitivity and specificity to predict progression to chronic pain. This raises the possibility of a comprehensive screening test for chronic pain risk without the patient having to fill out lengthy questionnaires (with some degree of subjectivity involved) and would hint at a possible primary care blood test to enable GPs to stratify those at high risk of chronic pain into a group for intervention. Clinical trials would be required but being able to target the most vulnerable patients would make such trials very much more cost effective and therefore more likely to be performed.

With further dissemination of our key results, we will continue to raise awareness of the many biological mechanisms implicated in low back pain. Our publicity will seek to put back pain firmly on the public agenda, raise awareness of the huge costs of back pain to society, and promote the use of existing tools to stratify patients into low and high risk. We continue to disseminate our findings at international scientific meetings, at national charity level and to the lay public, by engaging both face to face and using social media. The wider societal implications of the project will be realised by continuing to disseminate our findings. Importantly, any scientific findings given a platform in dissemination can be used as a way to remind the public the best way known to manage episodes of acute low back pain. This is a symptom that almost everyone has at some time in their life and normalising it, and helping people manage it without recourse to the many unvalidated interventions available, is an important part of the PainOmics message.


1. Freidin MB, Keser T, Gudelj I, Stambuk J, Vucenovic D, Allegri M, et al. The Association Between Low Back Pain and Composition of IgG Glycome. Sci Rep. 2016;6:26815.
2. Menni C, Keser T, Mangino M, Bell JT, Erte I, Akmacic I, et al. Glycosylation of immunoglobulin g: role of genetic and epigenetic influences. PLoS One. 2013;8(12):e82558.
3. Shen X, Klaric L, Sharapov S, Mangino M, Ning Z, Wu D, et al. Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation. Nat Commun. 2017;8(1):447.
4. Freidin MB, Karssen L, Hayward C, Wells H, Aulchenko YS, Williams FMK. Genome-wide association study of chronic low back pain in Northern European populations. The Challenge of Chronic Pain, Wellcome Trust Conference, Hinxton, 1-3 March 2017. 2017.

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Life Sciences
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