Relationship Between Smoking and Multiple Sclerosis Risk: Insights from a Mendelian Randomization Study

The association between lifestyle factors and the risk of developing multiple sclerosis (MS) has drawn increasing interest, particularly as these factors are potentially modifiable. In recent decades, rising MS rates, along with changes in smoking habits and obesity prevalence, suggest that certain environmental exposures might influence MS susceptibility. The study by Vandebergh and Goris (2020) harnesses Mendelian randomization (MR) to examine whether smoking could be causally linked to MS risk, overcoming common biases inherent in observational studies​.

Background
Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system, where both genetic predisposition and environmental factors play a role in its etiology. Observational studies have consistently reported associations between MS and factors like Epstein-Barr virus infection, low vitamin D levels, obesity, and smoking. However, observational data on smoking's role in MS risk often struggle with biases such as recall bias and reverse causation, where it is unclear if smoking increases MS risk or if people with early symptoms are more likely to smoke. MR, an advanced technique leveraging genetic variants associated with lifestyle factors, provides a way to circumvent these issues by estimating the causal effect of exposures like smoking on disease outcomes​.

Study Design and Methods
This study employed a two-sample MR approach, using genome-wide association study (GWAS) data on smoking behaviors and MS. By using genetic variants as proxies for smoking exposure, the researchers could evaluate whether genetically predicted smoking status (whether a person was a smoker) and the intensity of smoking (cigarettes per day) had a causal relationship with MS risk. This method allowed the researchers to bypass limitations like residual confounding (e.g., unmeasured factors influencing both smoking and MS) and to account for correlations between smoking and other risk factors like body mass index (BMI)​.

Key Findings
1. No Causal Link Found Between Smoking and MS Risk
Contrary to findings from observational studies, this MR study did not find evidence that smoking, either through initiation or intensity, causally increases MS risk. The analysis suggested that while observational studies indicate a link between smoking and MS, the MR approach did not support this as a direct causal effect. Smoking initiation, smoking heaviness, and lifetime smoking index were all tested, with none showing a statistically significant association with increased MS risk​.

2. BMI and MS Risk
The study confirmed previous findings that a higher BMI is associated with an increased risk of MS. Each standard deviation increase in BMI (around 5 kg/m²) was associated with a 30% increase in MS risk. This finding aligns with both MR and observational data, reinforcing that obesity may play a causal role in MS development​.

3. Complex Interplay Between BMI and Smoking
Notably, the study highlighted a genetic correlation between BMI and smoking, where individuals genetically predisposed to higher BMI were more likely to smoke. However, this correlation did not alter the main findings: even when accounting for this relationship, only BMI, not smoking, showed a significant association with MS risk. This insight emphasizes that while lifestyle factors often co-occur, they may exert independent effects on health outcomes​.

Discussion
The lack of a causal association between smoking and MS in this MR study challenges the previously accepted notion that smoking is a direct risk factor for MS. The discrepancy may stem from the differences between MR and observational studies: MR uses genetic predisposition as a proxy for behavior, which could reflect an individual's lifetime likelihood to engage in smoking rather than specific patterns of smoking that could influence MS development differently.

Another point of discussion is the complexity of environmental influences on MS. Smoking and BMI are intertwined with sociodemographic and behavioral factors, creating potential confounding influences in traditional studies. In contrast, MR offers a clearer view by isolating these factors, suggesting that BMI might play a more direct role in MS pathogenesis than smoking.

Implications for Future Research and Public Health
The study underscores the importance of distinguishing between correlation and causation in public health policy. While smoking cessation has undeniable health benefits, its direct impact on MS risk remains unclear based on these findings. Obesity, however, continues to emerge as a significant modifiable risk factor, supporting public health initiatives aimed at reducing obesity as part of MS prevention strategies.

In conclusion, this Mendelian randomization study by Vandebergh and Goris provides valuable insight, suggesting that while smoking does not directly cause MS, high BMI might be a causal factor. These findings encourage a continued focus on BMI management in MS prevention efforts and advocate for further investigation into the complex genetic and environmental interplay underlying MS risk​.

References:
Vandebergh, M., Goris, A. Smoking and multiple sclerosis risk: a Mendelian randomization study. J Neurol 267, 3083–3091 (2020).