Objective To investigate whether lipid-related or body mass index (BMI)–related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS).
Methods The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, ΔEDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting ΔEDSS. All analyses were conducted using linear regression.
Results Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with ΔEDSS. The constructed lipid CGRS showed a significant, dose-dependent association with ΔEDSS (ptrend=1.4×10−6), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in ΔEDSS. We also found significant interactions between the CGRS and lipid levels in modulating ΔEDSS, including high-density lipoprotein (HDL; pinteraction=0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; pinteraction=0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL.
Interpretation In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression.
- multiple sclerosis
- genetic polymorphism
- lipid profile
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Collaborators These authors belong to the Ausimmune/AusLong Investigators Group, and their individual names are not included in the author list:
Keith Dear (University of Adelaide, Australia); Terry Dwyer (Oxford Martin School, University of Oxford, England); Leigh Blizzard (Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia); Simon Broadley (School of Medicine, GriffithUniversity, Gold Coast Campus, Australia); Trevor Kilpatrick (Centre for Neurosciences,Department of Anatomy and Neuroscience, University of Melbourne, Melbourne,Australia); David Williamsand Jeanette Lechner-Scott (University of Newcastle, Newcastle,Australia); Cameron Shawand Caron Chapman (Barwon Health, Geelong, Australia); Alan Coulthard(University of Queensland, Brisbane, Australia); Michael P Pender (The University of Queensland,Brisbane, Australia) and PatriciaValery (QIMR Berghofer Medical Research Institute, Brisbane, Australia).
Contributors BVT, YaZ, YuZ, JC and IAFvdM were involved in the study concept and design. BVT, RML, IAFvdM, A-LP and KK were involved in data acquisition. YaZ, YuZ, SS and PT were involved in data analysis. SS, YaZ, BVT and YuZ were involved in drafting the manuscript. All authors participated in critical revision of the manuscript.
Funding The AusLong Study was funded by the Australian National Health and Medical Research Council (NHMRC APP544922).
Competing interests A-LP received personal fees from Biogen Pty Ltd and the fees were used for travel and conference presentation. BVT has received travel grants and honoraria for presentations and Advisory Board membership from Biogen Pty Ltd, Merck Serona Ltd, Roche Pty Ltd Novartis Pty Ltd and Sanofi Pty Ltd.
Patient consent for publication Obtained.
Ethics approval Nine regional human research ethics committees approved the studies.
Provenance and peer review Not commissioned; externally peer reviewed.