Does Genetic Susceptibility for Bleeding Affect Quantitative Faecal Immunochemical Test (qFIT) Results?

Quantitative faecal immunochemical testing (qFIT) is used to test for blood within faeces that cannot always be visible. The presence of blood in the stool has been shown to be a finding where there may be a problem within the large bowel. The test is able to give a numeric value to the blood in the stool and based on this result, further investigations can be planned, or if normal reassurance given.

The test is not perfect and minor bowel problems such as haemorrhoids (piles) can give a raised result. However, we have also seen raised results in people who when investigated have a completely normal large bowel. A small degree of 'physiological' non-visible bleeding is likely a normal part of life and for the majority this does not lead to a raised qFIT result.

It may be the case in people who have a raised qFIT but then go on to have a completely normal colonoscopy (telescope investigation of the large bowel) that there is a genetic predisposition that increases the amount of normal 'physiological blood' that they produce. This leads to the test being falsely positive and the person undergoing an unnecessary investigation.

This study aims to use saliva to test for known genetic markers that effect blood clotting and can increase how much someone bleeds. By comparing the occurrence of these genetic markers in people with a raised qFIT and normal colonoscopy to those with a normal qFIT and normal colonoscopy, we can test this theory. Should this be the case it will help explain why the test can be raised in normal large bowel and could lead to different levels of positivity being used for different people.

Quantitative faecal immunochemical testing (qFIT) measures the presence of haemoglobin within faeces. It is an immunoassay based method, measuring the globin portion of human haemoglobin or its early degradation products. Diet does not impact the result and because globin is broken down by gastric enzymes, it is more specific to lower gastrointestinal (GI) bleeding than previously used guaiac based occult blood tests. qFIT is the test currently used by the Scottish and English National Bowel Screening Programmes and more recently has been included in NICE guideline DG30, for the investigation of patients with lower gastrointestinal (GI) symptoms who are in a low-risk population.

qFIT is being increasingly used in a manner, unsupported by evidence in some cases, in the investigation of all symptomatic patients to aid decision-making in referral to secondary care and for allocation of endoscopy resources in secondary care. qFIT is not a perfect test to rule out colorectal cancer, a meta-analysis within a symptomatic population estimated the sensitivity for detecting colorectal cancer to be 90% with a specificity of 87%. From our own studies of repeated qFIT (n=3000, unpublished), a large variance is seen between the results. Therefore to improve the utility of qFIT within this group it is likely additional factors will also need to be considered, such as an individual's genetic susceptibility for bleeding.

There are well known genetic variants resulting in coagulopathy conditions such as haemophilia and von Willebrand disease. However, it has been shown that the levels of coagulation associated proteins vary within the population and this variation is linked with genetics. Multiple genes have been implicated in coagulation, and within them hundreds of singe nucleotide polymorphisms (SNPs). Reduced levels of circulating coagulation proteins may explain false positive cases seen with qFIT.

This study aims to add further knowledge to the utility of qFIT when investigating patients with lower gastrointestinal symptoms. There are a significant proportion of people who have a raised qFIT and normal colonoscopy (gold standard investigation). In our data approximately 10% of those with a completely normal colonoscopy had a raised qFIT defined as \>10 µg Hb/g. It is possible that these patients have a genetic susceptibility to bleeding and therefore have higher levels of faecal haemoglobin without any pathology. There are known genetic markers for bleeding tendency. By comparing these genetic traits in patients with a normal colonoscopy but a qFIT \>10 µg Hb/g against \<10 µg Hb/g the potential effects of these genes on qFIT results may be evaluated.

Eligibility Criteria:
Inclusion Criteria:

* Patients who were symptomatic at the time of referral
* Returned at least one qFIT sample
* Underwent a complete colonoscopy, which did not identify any pathology
* Willing to provide a saliva sample for genetic analysis
* Are able to consent to the study

Exclusion Criteria:

* Age \< 18
* Previous colorectal cancer
* Ongoing colonic polyp surveillance
* Known inflammatory bowel disease
* Taking anticoagulant medication (Aspirin, clopidogrel, warfarin or NOAC)
* History of liver disease or known bleeding disorder
* Incomplete colonoscopy
* Unable to consent to the study