TY - JOUR
T1 - Early complement genes are associated with visual system degeneration in multiple sclerosis
AU - Fitzgerald, Kathryn C.
AU - Kim, Kicheol
AU - Smith, Matthew D.
AU - Aston, Sean A.
AU - Fioravante, Nicholas
AU - Rothman, Alissa M.
AU - Krieger, Stephen
AU - Cofield, Stacey S.
AU - Kimbrough, Dorlan J.
AU - Bhargava, Pavan
AU - Saidha, Shiv
AU - Whartenby, Katharine A.
AU - Green, Ari J.
AU - Mowry, Ellen M.
AU - Cutter, Gary R.
AU - Lublin, Fred D.
AU - Baranzini, Sergio E.
AU - de Jager, Philip L.
AU - Calabresi, Peter A.
N1 - Funding Information:
This study was supported by National Institutes of Health (NIH) grants R01NS082347 to P.A.C. and R01NS088155 to S.E.B. and by support from the Race to Erase. K.C.F. is supported by a postdoctoral fellowship from the National Multiple Sclerosis Society. Parts of this study were enabled by the collaboration with CombiRx Trial Investigators. The CombiRx study was funded by the NIH National Institute of Neurological Disorders and Stroke (phase III study grant UO1NS045719, planning grant R21NS41986) and is listed on www.clinicaltrials.gov as NCT00211887.
Funding Information:
K.C.F., K.K., M.D.S., S.A.A., N.F., A.M.R., D.K., P.B., K.A.W. report no competing interests. S.K. has served on consulting or advisory boards for Acorda, Bayer, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novartis, and Teva. S.S.C. has received personal compensation for activities with Orthotech Biotech, the American Academy for Orthopedic Surgery, Oxford University Press, Department of Defense, and Medimmune. S.S. has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen-Idec, Genzyme, Genentech Corporation, EMD Serono and Novartis. He is the PI of investigator-initiated studies funded by Genentech Corporation and Biogen Idec, and received support from the Race to Erase multiple sclerosis foundation. He has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer. He is also the site investigator of a trial sponsored by MedDay Pharmaceuticals. A.J.G. reports receiving research grants from the National Multiple Sclerosis Society, NIH, Novartis and Inception 5 Sciences. He has served on an end point adjudication committee for MedImmune and a steering committee for OCTiMS and has provided expert witness for Mylan and Anneal. He has also served on then Scientific Advisory Board of Bionure and Inception Sciences. E.M.M. reports receiving free glatiramer acetate for the investigator-initiated vitamin D trial, of which she is the PI from Teva Neuroscience provides. She is also the PI of investigator-initiated studies funded by Biogen, Sanofi-Genzyme. She is also a site investigator of trials sponsored by Sun Pharma, Biogen and royalties from Up-to-date. G.R.C. serves on Data and Safety Monitoring Boards: AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). He also serves on Consulting or Advisory Boards forAtara Biotherapeutics, Axon, Biogen, Biotherapeutics, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Incorporated, Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva pharmaceuticals, TG Therapeutics, UT Houston. G.R.C. is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. F.D.L. has received funding for research grants Novartis Pharmaceuticals Corp, Teva Neuroscience, Actelion, Transparency Life Sciences, and the National multiple sclerosis Society. He has received consulting fees, served on advisory boards, or data safety and monitoring boards for Bayer HealthCare Biogen, EMD Serono, Novartis, Teva, Actelion, Sanofi/Genzyme, Acorda, Roche/Genentech, MedImmune, Receptos/Celgene, Forward Pharma, TG Therapeutics, Abbvie, Regeneron, Medday, Atara Biotherapeutics, Polpharma, Mapi Pharma, Innate Immunotherapeutic, Apitope. S.E.B. has received consulting fees or participated in Scientific Advisory Boards from Novartis Pharma, Sanofi-Aventis, Teva, and Biogen-Idec. P.L.D. has received honoraria from Genzyme and Celgene. He is the principal investigator on grants from Biogen and Roche Pharmaceuticals. P.A.C. has received personal honorariums for consulting from Biogen and Disarm Therapeutics. He is PI on research grants to Johns Hopkins from MedImmune, Annexon, Biogen, and Genzyme.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - Early complement pathway genes
KW - Genome-wide association studies
KW - Multiple sclerosis
KW - Optical coherence tomography
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U2 - 10.1093/brain/awz188
DO - 10.1093/brain/awz188
M3 - Article
C2 - 31289819
AN - SCOPUS:85071899374
VL - 142
SP - 2722
EP - 2736
JO - Brain
JF - Brain
SN - 0006-8950
IS - 9
ER -