Early complement genes are associated with visual system degeneration in multiple sclerosis.

Autor:	Fitzgerald KC; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Kim K; Department of Neurology, University of California San Francisco, San Francisco, CA, USA., Smith MD; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Aston SA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Fioravante N; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Rothman AM; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Krieger S; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Cofield SS; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA., Kimbrough DJ; Department of Neurology, Harvard Medical School, Boston, MA, USA., Bhargava P; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Saidha S; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Whartenby KA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Green AJ; Department of Neurology, University of California San Francisco, San Francisco, CA, USA.; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA., Mowry EM; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Cutter GR; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA., Lublin FD; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Baranzini SE; Department of Neurology, University of California San Francisco, San Francisco, CA, USA., De Jager PL; Center for Translational and Computational Neuroimmunology, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., Calabresi PA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2019 Sep 01; Vol. 142 (9), pp. 2722-2736.
DOI:	10.1093/brain/awz188
Abstrakt:	Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration. (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu