Author Of 2 Presentations
P0164 - Smoking is associated with increased plasma neurofilament light levels in multiple sclerosis (ID 1834)
Elevated levels of plasma neurofilament light chain (pNfL) is associated with increased disease activity, physical disability and reduced treatment response in persons with multiple sclerosis (MS). However, the association between environmental exposures such as cigarette smoking and pNfL levels is not clear.
To investigate the association between cigarette smoking, as one of the most prominent environmental factor associated with MS disease activity, and pNfL-levels in MS.
This is a retrospective population-based cohort study. Blood samples from incident MS cases were collected at time of diagnosis (from 2001). Concentrations of pNfL were determined using antibodies from UmanDiagnostics and the high-sensitive Single Molecule Array (SimoaTM) NF-light® Advantage kit. We assessed the impact of self-reported cigarette smoking habits at time of sampling on age-stratified pNfL levels above 80th, 95th, and 99th of non-MS controls' percentiles (>C80, >C95, and >C99).
pNfL levels were measured in 2881 MS cases with smoking history of which 320 (11.1%) were current regular smokers and 828 (28.7%) were past regular smokers (median years since quitting 6; IQR 1 to 14). Current smoking was associated with significantly increased odds ratios (OR) of having pNfL-levels >C80, >C95 and >C99 with OR ranging from 1.27 (95% CI: 0.96-1.68) to 1.70 (95% CI: 1.24-2.33) comparing current smokers to never smokers and 1.44 (95% CI: 1.06-1.94) to 1.6 (95% CI: 1.12-2.27) comparing current smokers to past smokers. The OR of having pNfL-levels >C80, >C95 and >C99 in past smokers who quitted 6 to 10 years ago, compared to current smokers, ranged from 0.6 (95% CI: 0.39-0.92) to 0.55 (95% CI: 0.30-0.95), and from 0.62 (95% CI: 0.43-0.89) to 0.53 (95% CI: 0.31-0.87) in those with >10 years since quitting smoking. Although decreased, the ORs were not significant among those quitting smoking 1 to 5 years before sampling (P>0.05).
Current regular smoking is associated with significantly increased risk of displaying high pNfL levels in MS patients, which argue for a negative effect on disease activity. In contrast, there was a beneficial effect of quitting smoking that increased with time since stopping. Our findings support the rational for life style counselling in MS.
P0526 - Methylome and transcriptome analysis implicates NBPF locus in PPMS etiopathology (ID 880)
Multiple Sclerosis is characterized by autoimmune destruction of myelin and neurons in the CNS leading to a variety of neurological symptoms. Primary progressive multiple sclerosis (PPMS) is characterized by accumulation of clinical disability from the onset, without relapses or remissions. The mechanisms underpinning MS progression are still largely unknown and specific clinical translations are lacking.
To identify DNA methylation and gene expression changes that associate with progressive MS states using genetic, epigenetic and network analysis approaches.
Our methylome analysis in blood showed a striking increase in methylation at the NBPF locus specifically in PPMS (n=279, p=5x10-6), which was validated in independent samples. We then discovered that genetic variants determine methylation levels at this locus (p-val. range 10-21-10-13) and that the strongest variant potentially associates with the risk of developing PPMS (nPPMS=482, ncontrols=11718, p<0.03, OR=1.2). The same variant associated with reduced expression of FMO5, PRKAB2 and CHD1L in blood (n=156, p-val. range 10-7-10-2).
Notably, a large body of evidence strongly implicate the identified locus in nervous processes involved in brain size and neuropsychiatric disorders. Thus, we hypothesize that it harbors the gene(s) that predispose for progressive disability in PPMS. To functionally confirm the identified differentially methylated region (DMR) can potentially regulate gene expression in a DNA methylation-dependent manner, we have used an in-vitro epigenetic reporter system and our data showed that the DMR region has properties of a gene-regulatory region. Moreover, we investigated the putative relevance of the genes included in the NBPF locus in PPMS brain pathology by constructing an unbiased correlation network analysis using RNA-sequencing data from brain tissue samples of MS patients (nPPMS=5 and nSPMS=7) and controls (n=10). Strikingly, identified gene modules were found centered on genes from the NBPF locus in PPMS. Indeed, exploration of the biggest module, revealed CHD1L as a major central node within this network. Gene ontology analysis of each module underscored implication in nervous processes. Thus, this unbiased in-silico approach further supports the potential implication of genes of NBPF locus in nervous processes in PPMS patients.
Our DNA methylation studies along with the unbiased network analysis approach using the transcriptome data independently suggest that the locus on chromosome 1 predisposes for PPMS.