PMID- 37657941
OWN - NLM
STAT- MEDLINE
DCOM- 20231106
LR  - 20240214
IS  - 1526-632X (Electronic)
IS  - 0028-3878 (Print)
IS  - 0028-3878 (Linking)
VI  - 101
IP  - 17
DP  - 2023 Oct 24
TI  - Exploring the Role of Plasma Lipids and Statin Interventions on Multiple 
      Sclerosis Risk and Severity: A Mendelian Randomization Study.
PG  - e1729-e1740
LID - 10.1212/WNL.0000000000207777 [doi]
AB  - BACKGROUND AND OBJECTIVES: There has been considerable interest in statins 
      because of their pleiotropic effects beyond their lipid-lowering properties. Many 
      of these pleiotropic effects are predominantly ascribed to Rho small guanosine 
      triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the 
      role of lipids and statin interventions on multiple sclerosis (MS) risk and 
      severity. METHOD: We used two-sample Mendelian randomization (MR) to investigate 
      (1) the causal role of genetically mimic both cholesterol-dependent (through 
      low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) 
      and cholesterol-independent (through Rho GTPases) effects of statins on MS risk 
      and MS severity, (2) the causal link between lipids (high-density lipoprotein 
      cholesterol [HDL-C] and triglycerides [TG]) levels and MS risk and severity, and 
      (3) the reverse causation between lipid fractions and MS risk. We used summary 
      statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium, 
      and the International MS Genetics Consortium (IMSGC) for lipids, expression 
      quantitative trait loci, and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 
      31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n = 7,069). RESULTS: 
      The results of MR using the inverse-variance weighted method show that 
      genetically predicted RAC2, a member of cholesterol-independent pathway (OR 0.86 
      [95% CI 0.78-0.95], p-value 3.80E-03), is implicated causally in reducing MS 
      risk. We found no evidence for the causal role of LDL-C and the member of 
      cholesterol biosynthesis pathway on MS risk. The MR results also show that 
      lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], p-value 7.94E-03) increases MS 
      risk but TG was not. Furthermore, we found no evidence for the causal role of 
      lipids and genetically mimicked statins on MS severity. There is no evidence of 
      reverse causation between MS risk and lipids. DISCUSSION: Evidence from this 
      study suggests that RAC2 is a genetic modifier of MS risk. Because RAC2 has been 
      reported to mediate some of the pleiotropic effects of statins, we suggest that 
      statins may reduce MS risk through a cholesterol-independent pathway (that is, 
      RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on 
      MS risk.
CI  - Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on 
      behalf of the American Academy of Neurology.
FAU - Almramhi, Mona M
AU  - Almramhi MM
AUID- ORCID: 0000-0002-4370-373X
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Finan, Chris
AU  - Finan C
AUID- ORCID: 0000-0002-3319-1937
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Storm, Catherine S
AU  - Storm CS
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Schmidt, Amand F
AU  - Schmidt AF
AUID- ORCID: 0000-0003-1327-0424
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Kia, Demis A
AU  - Kia DA
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Coneys, Rachel
AU  - Coneys R
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Chopade, Sandesh
AU  - Chopade S
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Hingorani, Aroon D
AU  - Hingorani AD
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands.
FAU - Wood, Nick W
AU  - Wood NW
AD  - From the Department of Clinical and Movement Neurosciences (M.M.A., C.S.S., 
      D.A.K., R.R.C., N.W.W.), University College London Queen Square Institute of 
      Neurology, United Kingdom; Department of Medical Technology (M.M.A.), Faculty of 
      Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi 
      Arabia; Institute of Cardiovascular Science (C.F., A.F.S., S.C., A.D.H.), Faculty 
      of Population Health, and Health Data Research UK London (A.D.H.), University 
      College London; British Heart Foundation University College London Research 
      Accelerator (C.F., A.F.S., S.C., A.D.H.), United Kingdom; and Department of 
      Cardiology (C.F., A.F.S.), Division Heart and Lungs, University Medical Center 
      Utrecht, the Netherlands. n.wood@ucl.ac.uk.
LA  - eng
GR  - PG/18/50/33837/BHF_/British Heart Foundation/United Kingdom
GR  - PG/18/503383/BHF_/British Heart Foundation/United Kingdom
GR  - R01 LM010098/LM/NLM NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230901
PL  - United States
TA  - Neurology
JT  - Neurology
JID - 0401060
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Cholesterol, LDL)
RN  - 0 (Triglycerides)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - 0 (Cholesterol, HDL)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
CIN - Neurology. 101(17):733.
MH  - Humans
MH  - *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
MH  - Cholesterol, LDL
MH  - Triglycerides
MH  - Mendelian Randomization Analysis
MH  - *Multiple Sclerosis/epidemiology/genetics
MH  - Cholesterol
MH  - Cholesterol, HDL
MH  - rho GTP-Binding Proteins/genetics
MH  - Genome-Wide Association Study
MH  - Polymorphism, Single Nucleotide
PMC - PMC10624499
COIS- M. M. Almramhi is funded by the Faculty of Applied Medical Sciences, King 
      Abdulaziz University, Jeddah, Saudi Arabia. C. Finan received additional support 
      from the National Institute for Health Research University College London 
      Hospitals Biomedical Research Centre. C. S. Storm is funded by Rosetrees Trust, 
      John Black Charitable Foundation, and the University College London MBPhD 
      Programme. A. F. Schmidt is supported by BHF grant PG/18/503383 and acknowledges 
      support by grant R01 LM010098 from the NIH (United States). D. A. Kia is 
      supported by an MBPhD Award from the International Journal of Experimental 
      Pathology. R. Rachel Coneys is funded by Eisai, on the Wolfson-Eisai 
      Neurodegeneration University College London PhD programme. N. W. Wood is a 
      National Institute for Health Research senior investigator. N. W. Wood receives 
      support from the National Institute for Health Research University College London 
      Hospitals Biomedical Research Centre. All other authors report no disclosures 
      relevant to the manuscript. Go to Neurology.org/N for full disclosures.
EDAT- 2023/09/02 05:42
MHDA- 2023/11/06 06:42
PMCR- 2023/10/24
CRDT- 2023/09/01 21:38
PHST- 2022/10/12 00:00 [received]
PHST- 2023/06/29 00:00 [accepted]
PHST- 2023/11/06 06:42 [medline]
PHST- 2023/09/02 05:42 [pubmed]
PHST- 2023/09/01 21:38 [entrez]
PHST- 2023/10/24 00:00 [pmc-release]
AID - WNL.0000000000207777 [pii]
AID - WNL-2023-000524 [pii]
AID - 10.1212/WNL.0000000000207777 [doi]
PST - ppublish
SO  - Neurology. 2023 Oct 24;101(17):e1729-e1740. doi: 10.1212/WNL.0000000000207777. 
      Epub 2023 Sep 1.