Background
Although multiple sclerosis is not strictly hereditary (directly transmitted from parent to child), the risk of developing MS is higher among siblings or children of a person with MS compared to the general population. This inheritance pattern suggests that genetic factors play a role in determining MS risk. In fact, over 100 genetic variations – many of which are associated with immune regulation – have been identified to be associated with MS risk using DNA analysis studies comparing people with the disease to similar, healthy people. However, these genetic variations only account for a portion of the inheritance pattern of MS, which remains largely unknown.
A study published by Drs. Anne Boullerne, Douglas Feinstein and colleagues in the journal American Society of Neurochemistry (ASN) Neuro has identified a new genetic risk factor for the development of MS. The study emerged serendipitously from the report of a family in which five siblings, but neither parent, were either diagnosed with or suspected of having MS, an occurrence that is exceptionally rare. The authors identified a genetic variation in these siblings called a single-nucleotide polymorphism (SNP) in a gene called STK11, which has traditionally been associated with tumour suppression, but has also been shown to play a role in the regulation of immune cells and the formation of myelin around nerves. The researchers then determined whether this genetic variation in the STK11 gene is linked to the risk of MS in a genetic population study.
The Study
Upon identifying the specific variation in the STK11 gene, the researchers screened DNA samples from over 1,400 individuals – 654 with relapsing-remitting MS, 100 with primary progressive MS, and 661 healthy controls – to determine if this genetic variation is more common in individuals with MS compared to those without the disease. Analysis of samples was segregated based on disease type as well as sex (male versus female).
Since the siblings also had a strong family history of certain cancers and cyst-related comorbidities (multiple co-existing conditions) linked to the STK11 gene, the researchers wanted to ensure that the genetic variation that was identified was in fact linked to MS, and not accounted for by an association with the presence of cancer and cyst-related comorbidities.
The researchers also tested the association between the STK11 genetic variation and another well-characterized genetic risk factor – dubbed HLA DRB1*1501 – in their DNA screen of people with MS and healthy controls.
Lastly, the researchers tested whether the STK11 genetic variation is a predictor of MS disease onset and severity based on each patient’s MS Severity Score (MSSS).
Results
Screening of DNA samples from individuals with MS and healthy controls revealed that the STK11 genetic variation was nearly twice as prevalent among women with relapsing remitting MS compared to women without the disease. Although the genetic variant also appeared to be more frequent in women with primary progressive MS than healthy controls, the difference was not statistically significant. There was no significant difference in the prevalence of the STK11 genetic variation between both male and female MS patients and healthy controls overall.
The researchers also found that the prevalence of the STK11 genetic variation in women was in fact associated with MS disease, and not linked to an increase in the presence of cancers or cyst-related comorbidities. However, there was no association between the STK11 genetic variation with HLA-DRB1*1501 in either sex or MS type.
Interestingly, the presence of the STK11 genetic variation on its own did not influence MS neurological severity, although women harboring both STK11 and HLA-DRB1*1501 genetic variants had reduced disease severity compared to women with MS overall.
Comment
The findings from this study have placed the STK11 genetic variation as one of the strongest reported genetic risk factors for the development of relapsing-remitting MS in women, while opening up the possibility of targeting cells harbouring this variation with drug therapies. Although this study helps to enrich the body of knowledge about genetic risk factors and MS risk, it does raise several new questions. Specifically, why was the association between STK11 and MS risk so modest in people with primary progressive MS, and why was there no link observed in men? Many lines of evidence suggest that primary progressive MS has a unique set of disease mechanisms compared to the relapsing-remitting type, which could potentially explain why the two disease types may not share the same genetic risk factors. Additionally, sex-dependent differences in the contribution of other risk factors to MS have been previously reported, although further study is required to determine why STK11 is not associated with MS risk in men.
These results support previous data in animal studies showing that switching off the protein produced by the STK11 gene leads to severe defects in myelination, neuronal damage and worsening of MS-like symptoms. One paradox that is difficult to reconcile is why the presence of both STK11 and HLA-DRB1*1501 genetic variations leads to increased risk of MS while resulting in lower MS severity. The authors plan to address these and other unresolved questions and examine the functions of the STK11 gene in future lab studies to help bring this new discovery from bench to bedside.
Source
Boullerne AI et al. (2015). A single-nucleotide polymorphism in serine-threonine kinase 11, the gene encoding liver kinase B1, is a risk factor for multiple sclerosis. ASN Neuro. 7(1)