TCR Alpha Variants in narcolepsy
Research type
Research Study
Full title
To investigate the presence or absence of polymorphisms in the T Cell Receptor Alpha locus associated with susceptibility of narcolepsy onset.
IRAS ID
257168
Contact name
Kay Poulton
Contact email
Sponsor organisation
Manchester University Foundation Trust
Clinicaltrials.gov Identifier
N/A, N/A
Duration of Study in the UK
1 years, 0 months, 1 days
Research summary
Research Summary
Narcolepsy is an autoimmune disorder of sleep, which causes an increased and intense need to sleep. It can occur in two forms - Type 1 (with an associated disorder called Cataplexy) or Type 2 (without Cataplexy). Patients with Narcolepsy have a rapid onset of REM (dreaming) sleep, and diagnosis is qualitative through the Multiple Sleep Latency Test. The disorder is strongly associated with the Human Leukocyte Antigen (tissue) type HLA-DQB1*06:02 and testing for the presence of this HLA type can help to confirm the diagnosis. However, because HLA-DQB1*06:02 is a common tissue type, present in approximately 20% of the UK population, this test is curretnly of more value to exclude the diagnosis. Advances in genomic analysis have identified additional genetic changes in the T Cell Receptor which may be critical for the development of narcolepsy. This study aims to look at the frequency of these genetic variants in a small number of patient samples which have been received for testing to support the diagnosis of narcolepsy, and to compare these with a larger number of non-affected controls from the same geographical area.Summary of Results
In our laboratory, we carry out a genetic test to support diagnosis of this disorder because there is a strong auto immune component evidenced by over 82% of people diagnosed with Narcolepsy carrying a specific tissue type – HLA-DQB1*06:02. Unfortunately, this is a very common type which is carried by around 15% of the UK population, so all people who have HLA-DQB1*06:02 will not go on to develop Narcolepsy. This limits the usefulness of our test, which must be interpreted along with clinical symptoms. Newer genetic studies have identified three additional genetic variants in the T cell Receptor Alpha locus which may be associated with Narcolepsy. Samples from 31 patients tissue typed to support a narcolepsy diagnosis were anonymised with paired clinical data and tested for the T Cell Receptor Alpha variants rs12587781, rs1263646 and rs1154155. Frequencies of alleles were compared against a control group of 96 unaffected individuals with the same tissue type. Of the three T cell receptor gene variants tested, two inherited copies of the rare allele of the variant rs12587781 was associated with narcolepsy onset, p=0.0001, Odds Ratio = 16.33. The other two variants tested showed no association. However, the presence of the variant rs12587781 as well as the tissue type HLA-DQB1*0602 was also seen in people who did not have narcolepsy. The data obtained from this brief initial investigation is promising but does not provide sufficient clarity to justify bringing it into clinical service as it stands. A second application is underway to extend this study by investigating additional polymorphisms in the same patients which may provide more direct correlation between having the gene, and the likelihood of developing narcolepsy, or even other sleep disorders.REC name
North West - Greater Manchester East Research Ethics Committee
REC reference
19/NW/0459
Date of REC Opinion
3 Sep 2019
REC opinion
Further Information Favourable Opinion