Braithwaite, T

Ferrat, L

Green, H

Loginovic, P

Oram, R

Petzold, A

Tyrrell, J

Weedon, M

English

UCL Discovery

  Word count: 2495 characters, aim <2500 Prediction of conversion from optic neuritis to multiple sclerosis: novel application of a genetic risk score   Pavel Loginovic1 Lauric Ferrat2 Harry Green2 Jessica Tyrell2 Michael Weedon2 Richard Oram2,3 Tasanee Braithwaite4,5 Axel Petzold 6,7 *  On behalf of UK Biobank Eye and Vision Consortium   1. University of Exeter Medical School, Exeter, UK 2. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK 3. Royal Devon & Exeter, NHS Foundation Trust, Exeter, UK 4. School of Life Course and Population Science, King’s College London, London, UK 5. The Medical Eye Unit, Guys’ and St Thomas’ Hospital, NHS Foundation Trust, Westminster Bridge Road, London, UK 6. UCL Institute of Neurology, Department of Molecular Neurosciences, Moorfields Eye Hospital and The National Hospital for Neurology and Neurosurgery, London, UK 7.  MS Centre Amsterdam UMC, Locatie VUmc, NL.  Optic Neuritis (ON) is a frequent first feature of multiple sclerosis (MS), but a formal diagnosis of MS may be delayed by years. The challenge is to distinguish MS-ON from other forms of ON at time of presentation. MS is heritable with numerous common genetic variants associated with disease risk. We aimed to investigate if a multiple sclerosis genetic risk score (MS-GRS) aids prediction of MS at time of diagnosis of ON as a clinically isolated syndrome (CIS).  Methods:   We studied individuals in the United Kingdom Biobank, a large longitudinal database containing phenotypic and genetic data on 500,000 individuals. We retrieved diagnoses of MS and ON from retrospective (before baseline visit) and prospective (after baseline visit) self-report, hospital, and GP records, and analysed the co-occurrence of MS and ON.  We developed the MS-GRS based on 310 single nucleotide polymorphisms (SNPs) and eight HLA alleles associated with MS risk in previous studies. We assessed the power of MS-GRS to discriminate between MS and healthy controls using receiver-operator characteristics-area under the curve (ROC-AUC). We analysed whether, in those with a diagnosis of ON (which includes ON as CIS), MS-GRS improved prediction of conversion to MS using a Cox model adjusting for known MS risk factors (age of ON diagnosis, sex).   Word count: 2495 characters, aim <2500  Results:  We identified 2103 individuals with MS, 266 with MS-ON and 421 with non-MS ON by end of cumulative follow-up. The MS-GRS was discriminative of MS (ROC-AUC=0.753). People with non-MS-ON had lower MS-GRS than those with MS-ON (mean 3.02 (SD 1.29) vs 3.71 (1.17), p<0.0001), whereas individuals with MS-ON had similar MS-GRS to MS cases without ON (3.62 (1.22) vs 3.71 (1.17), p=0.32). In those with an initial presentation ON (n=529, n=121/529 progressing to MS after median (IQR) 21 (12-35) years follow-up), MS-GRS improved prediction of future MS compared to a model using diagnosis age and sex alone, with hazard ratio of 1.31 (95% CI 1.09-1.59, p<0.005) per SD increase in MS-GRS. We were able to stratify individuals into groups of low (4%), medium (23%), or high (43%) future MS risk.  Conclusion:   People with MS-ON have the same MS genetic risk as other MS cases. This novel application of MS-GRS improved risk stratification for future MS diagnosis of ON, including ON as CIS. An MS-GRS integrated into a risk model combined with other demographic characteristics may be found useful for personalising investigation and treatment in individuals with CIS.    Word count: 2495 characters, aim <2500 Disclosure of potential conflict of interest  -A. Petzold reports personal fees from Novartis, Heidelberg Engineering, Zeiss, grants from Novartis, outside the submitted work; and is part of the steering committee of the OCTiMS study which is sponsored by Novartis and the Angio-OCT steering committee which is sponsored by Zeiss. He does not receive compensation for these activities  R. Oram holds a UK Medical Research Council Institutional Confidence in Concept Grant to develop a 10 SNP biochip T1D genetic test in collaboration with Randox.  Other authors declare no conflicts of interest  Sources of funding  This study was funded by  

Prediction of conversion from optic neuritis to multiple sclerosis: novel application of a genetic risk score

https://discovery.ucl.ac.uk/10161969/1/Petzold_ECTRIMS_abstract_v3.pdf

Prediction of conversion from optic neuritis to multiple sclerosis: novel application of a genetic risk score

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UCL Discovery