Genetics, Lipids, and Disability Progression in Multiple Sclerosis: Understanding a Gene–Environment Interaction
Multiple sclerosis (MS) is a chronic neurological disorder characterised by inflammation, demyelination, and progressive injury to the central nervous system. Although substantial progress has been made in identifying genetic and environmental factors that influence the risk of developing MS, considerably less is known about the biological mechanisms that determine how rapidly disability accumulates after disease onset. In a 2019 study published in the Journal of Neurology, Neurosurgery & Psychiatry, Zhang and colleagues investigated whether genetic variants associated with blood lipid levels and body mass index (BMI) could influence disability progression in people with MS. The study is particularly important because previous research had already suggested that an adverse lipid profile—including elevated total cholesterol and an increased total cholesterol-to-high-density lipoprotein ratio—may be associated with greater disability. The authors therefore examined whether inherited variation could help explain why the effects of lipids on MS progression appear to differ between individuals.
Investigating Genetic and Metabolic Risk Together
The researchers analysed 184 participants with diagnosed MS who were enrolled in the prospective Ausimmune Longitudinal, or AusLong, Study and followed for approximately five years. Disability was assessed using the Expanded Disability Status Scale (EDSS), a standard clinical measure ranging from minimal neurological impairment to severe disability, and progression was expressed as the annualised change in EDSS, termed ΔEDSS. At baseline, participants underwent measurements of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, non-HDL cholesterol, the total cholesterol-to-HDL ratio, BMI, and vitamin D status. Genotyping was performed using an Illumina exome array, and the investigators evaluated 162 lipid-related single-nucleotide polymorphisms (SNPs) previously identified through genome-wide association studies, together with 97 BMI-related SNPs. As reported in Table 1 on page 3, the cohort was predominantly female, with a mean age of approximately 38 years and a mean annual disability increase of 0.29 EDSS points.
Five Lipid-Related Variants Emerged as Potential Predictors
The analysis identified five lipid-associated genetic variants—rs2013208, rs9488822, rs17173637, rs10401969, and rs2277862—that were nominally associated with annualised disability progression. These SNPs are located near or within genes including RBM5, FRK, TMEM176A, CILP2, and ERGIC3, respectively. Several of the variants had previously been associated with HDL, LDL, total cholesterol, or triglyceride levels in genome-wide association studies. Table 2 on page 3 shows that some of these associations also demonstrated an apparent allele-dose relationship, meaning that disability progression tended to increase as the number of putative risk alleles increased. Importantly, however, none of the individual SNP associations survived strict correction for multiple statistical comparisons. This limitation means that the variants cannot be regarded as independently confirmed genetic determinants of MS progression on the basis of this study alone. Nevertheless, permutation testing and patterns of dose response provided additional support for investigating their combined influence.
Cumulative Genetic Risk Revealed a Stronger Signal
Rather than considering each genetic variant in isolation, the investigators combined the five lipid-related SNPs into a cumulative genetic risk score (CGRS). This approach produced one of the study's most striking observations. Participants carrying three or fewer risk alleles experienced an average annualised EDSS progression of approximately 0.21 points, whereas those carrying six or more risk alleles demonstrated an additional 0.38 EDSS points of progression per year relative to the lower-risk group. The relationship was strongly dose dependent, with a reported trend probability of 1.4 × 10⁻⁶. After adjustment for age, sex, study site, and relapse status at the five-year assessment, the genetic risk model explained approximately 16% of the variation in disability progression. A sensitivity analysis using only three variants whose effects on lipid levels and disability were biologically consistent still explained approximately 9% of disability variation, suggesting that the cumulative signal was not entirely dependent on the two variants showing directionally unexpected effects.
Gene–Lipid Interactions May Be More Important Than Either Factor Alone
Perhaps the most biologically informative result was the interaction between genetic risk and circulating lipid levels. The investigators observed significant interactions between the lipid CGRS and both HDL concentration and the total cholesterol-to-HDL ratio. Among participants with four or fewer risk alleles, variations in HDL or the total cholesterol-to-HDL ratio were not strongly associated with disability progression. In contrast, participants carrying more than four risk alleles showed substantially greater progression when HDL levels were lower or when the total cholesterol-to-HDL ratio was higher. Figure 1 on page 4 visually illustrates this divergence: predicted annualised EDSS progression changes relatively little across lipid levels in the lower-genetic-risk group, whereas a stronger relationship appears in participants with higher genetic risk. Adding the CGRS to models containing HDL increased the explained variance in disability progression from approximately 4% to 26%, while the corresponding model for the total cholesterol-to-HDL ratio increased from about 1% to 27%. These findings support the concept of gene–environment interaction, in which the clinical significance of a modifiable biological factor such as serum lipids may depend partly on inherited susceptibility.
Biological and Clinical Implications
The findings raise several important hypotheses about the mechanisms underlying MS progression. Lipids have structural and signalling roles in the nervous system, are essential components of myelin membranes, and are closely connected with vascular and inflammatory biology. An adverse lipid profile may therefore influence neurodegeneration, vascular comorbidity, inflammatory responses, or tissue repair processes in MS. The authors also discuss possible functional relevance of genes located near the identified variants. For example, RBM5 has been linked with RNA regulation, while TMEM176A has shown altered expression in blood samples from people with MS. The study further raises the possibility that genetic differences could contribute to inconsistent clinical responses to lipid-lowering interventions such as statins. However, these data do not demonstrate that statin therapy will reduce MS progression in genetically selected patients, nor do they establish that changing lipid concentrations will necessarily alter the biological effects of the identified variants. Such interpretations remain hypotheses that require validation through larger genetic studies, mechanistic experiments, and appropriately designed clinical trials.
A Promising Finding That Requires Replication
Overall, Zhang and colleagues provide evidence that the relationship between lipid metabolism and MS disability progression may be considerably more complex than a simple association between cholesterol levels and clinical outcome. Their longitudinal design, five-year follow-up period, prospective metabolic measurements, and use of cumulative genetic risk and interaction analyses are important strengths. At the same time, the relatively small sample of 184 participants represents a major limitation, particularly for genetic association research, and the failure of individual SNPs to remain significant after correction for multiple testing requires cautious interpretation. The authors appropriately conclude that replication in independent and larger cohorts is essential before these variants can be considered reliable prognostic biomarkers or therapeutic targets. Nevertheless, the study illustrates an important direction for precision medicine in MS: future risk prediction may depend not on genetics or lifestyle factors alone, but on understanding how inherited biological susceptibility interacts with modifiable metabolic exposures to shape the long-term course of neurological disability.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Zhang, Y., Zhou, Y., van der Mei, I. A. F., Simpson, S., Ponsonby, A. L., Lucas, R. M., Tettey, P., Charlesworth, J., Kostner, K., Taylor, B. V., & Ausimmune/AusLong Investigators Group (2019). Lipid-related genetic polymorphisms significantly modulate the association between lipids and disability progression in multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry, 90(6), 636–641. https://doi.org/10.1136/jnnp-2018-319870
