Genetic and environmental influences on multiple sclerosis complications and aetiology

Multiple sclerosis (MS) is an immune mediated, neurological disease that results in a chronic accumulation of disability over time. Many advances in the understanding, diagnosis and treatment of MS have been made, yet questions surrounding causes and consequences still remain. The scope of this thesis was to examine aspects of MS aetiology and complications using individual level data from large, nationwide registers in Sweden. Register data was linked with genetic and lifestyle data and analyses used classic and genetic epidemiological methods. Using a multi-disciplinary approach in MS research is of importance given MS is believed to develop through a combination lifestyle and environmental factors coupled with underlying genetic susceptibility. This thesis includes a total of four studies with the overall goal of further understanding the timing of factors in MS risk and complications, while considering sex-specific differences.

Study I aimed to understand whether pneumonia, a common occurrence after MS diagnosis, is also involved in MS risk and if there are specific ages at which risk is elevated. The timing of risk factors is important to consider as there is evidence to support a critical risk period in adolescence for MS development. MS cases and matched general- population controls were included between 1968-2012. The National Patient Register and MS Register were the main exposure (hospital-diagnosed pneumonia) and outcome (MS) data sources. This study showed that pneumonia between ages 11-15 years was associated with increased risk of MS by 200% compared with no pneumonia between these ages. Examining sex differences was not possible due to small numbers. The association remained even after controlling for additional infectious risk factors. These were infectious mononucleosis, an infection that is usually a result of Epstein-Barr virus which is thought to be a cause of MS, and a control infection of urinary tract infections for prodromal or reverse causation effects.

Study II was a cohort study among people with MS that identified factors associated with first oral baclofen treatment. This study used various national registers including the Prescribed Drug Register and included MS patients between 2005-2014. Baclofen is a specific pharmacological treatment for spasticity, and its use among MS patients, particularly newly diagnosed patients, has not been well studied. This study included both people with incident and prevalent MS, to identify possible time-specific patterns of spasticity treatment. A larger proportion of new MS patients received baclofen than previously thought, as patients with incident and prevalent MS received baclofen most often 0.5 to 3 years after diagnosis, respectively. Males and females were similar in their spasticity treatment patterns after controlling for MS-specific factors. Age and disability specific patterns emerged with younger, more disabled patients receiving baclofen treatments at a rate three times that of older, similarly disabled patients. This is of importance as baclofen use previously has been reported more often among males and more disabled, older patients. Discontinuation of baclofen occurred rapidly, with over 75% of individuals discontinuing treatment within two years. This demonstrates the need for more effective, tolerable treatments for spasticity among people with MS.

The final two studies investigated associations with a human pigmentation gene, melanocortin-1 receptor gene (MC1R) for MS risk (Study III) and severity (Study IV). The MC1R codes for a receptor in the skin controlling skin sensitivity to ultraviolet radiation, which may be important in MS given low exposure to ultraviolet light and low levels of vitamin-D are risk factors. To investigate MS risk, a case-control study examined whether MC1R single nucleotide polymorphisms (SNPs) were associated with MS risk. This also included a possible overlapping, additional gene region with MC1R, tubulin beta class III (TUBB3). This identified rs885479-A, a SNP in the overlapping MC1R-TUBB3 region, as being inversely associated with MS only among females, with a 25% reduction in MS risk among female carriers. This SNP is known as a red hair colour variant in the MC1R, as it is also associated with red hair colour and high skin sensitivity to ultraviolet radiation. The association of this SNP with MS was further investigated and was shown to be independent of other known MS risk factors including genetic risk for low vitamin-D level, familial history of MS, body mass index and smoking. To investigate whether the MC1R- TUBB3 region was associated to MS severity, a cross-sectional analysis was used. Red hair colour MC1R variants were investigated for their association with the Age-Related Multiple Sclerosis Severity Score. There were possible sex-specific differences, but no association with MS severity withstood correction for multiple testing.

In conclusion, this thesis contributes to the understanding of the risk factors for MS aetiology and consequences. It adds to the growing evidence of a critical risk period in adolescence for MS risk and highlights the importance of assessing risk factors such as pneumonia prior to the potential prodromal period for MS. This thesis underlines the importance of using cohort studies to assess treatment timing for aspects such as spasticity to be able to identify age- and disability-specific trends. It further emphasizes the importance of long-term, effective management of MS symptoms given the high rates of spasticity treatment discontinuation. Ensuring that causes and consequences of MS are considered separately among males and females can help to better understand MS, and why females are diagnosed with MS more often. Using a combination of information types, including genetic data, can help to better understand how factors work together in MS. In this case, MC1R variants decreased MS risk among females only, but did not influence MS severity. Lastly, examining the same risk factors prior to and after MS diagnosis can help to better determine the causes and consequences of MS to inform future study directions, with the ultimate goal of helping people with MS.

List of scientific papers

I. Smith KA, Hiyoshi A, Burkill S, Bahmanyar S, Öckinger J, Alfredsson L, Olsson T, Montgomery S. Hospital diagnosed pneumonia before age 20 years and MS risk. BMJ Neurology Open. 2020; 2:e000044.
https://doi.org/10.1136/bmjno-2020-000044

II. Smith KA, Piehl F, Olsson T, Alfredsson A, Hillert J, Kockum I, Stridh P, Montgomery S. Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study. Journal of Neurology, Neurosurgery & Psychiatry. 2023 May;94(5):337-348.
https://doi.org/10.1136/jnnp-2022-329886

III. Smith KA, Shchetynsky K, Hedström AK, Huang J, Kockum I, Hillert J, Olsson T, Montgomery S, Stridh P. Sex differences in the association of the melanocortin-1 receptor gene with multiple sclerosis risk. [Manuscript]

IV. Smith KA, Shchetynsky K, Hedström AK, Huang J, Kockum I, Hillert J, Olsson T, Montgomery S, Stridh P. Melanocortin-1 receptor gene variants and multiple sclerosis severity. [Manuscript]