The genetics behind MS are poorly understood, but a new discovery by Canadian researchers could shed light on the disease
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that destroys the myelin sheath that protects nerve cells, resulting in progressive neurodegeneration and disability, often presenting in young adulthood. The condition affects around one in every 600 people in the UK.
Environmental factors and MS
Whilst the processes that underlie MS are understood, the causes are not. Perhaps the most striking epidemiological feature of the disease is the geographical distribution; MS essentially only occurs in people who live in cooler parts of the world, becoming increasingly common the greater the distance from the equator, including in Northern Europe. This suggests that environmental factors such as sunlight exposure and vitamin D levels may be at play.
Other possible ‘triggers’ include certain viral infections, or hormonal changes. MS is around twice as common in women as men, which may be due to their lower testosterone levels; when testosterone levels are increased in pregnancy, female MS patients typically show slower disease progression.
Genetic factors and MS
Genetic factors clearly influence risk of MS too, rising to 2% and 5% if a parent or sibling has the disease, or 30% if an identical twin is affected. In fact, up to 15% of MS cases show some family history suggestive of an inherited disease, but genetic studies have not found any genetic variants that cause a significantly increased risk of the condition. Canadian researchers have found a genetic variant that they claim causes an inherited form of multiple sclerosis.
The variant, which was found in two families with multiple cases of a rapidly progressing form of MS, apparently gave a 70% chance of developing the disease. For comparison, the lifetime risk of breast cancer for carriers of a BRCA gene mutation is up to 85%. Possession of the familial mutation would not guarantee the disease would result; as senior author of the new research paper Professor Carles Vilarino-Guell put it: “This mutation puts these people at the edge of a cliff, but something still has to give them the push to set the disease process in motion”.
The research published in Neuron found the MS mutation in a gene called NR1H3, which makes the LXRA protein involved in control of inflammation. This fits with the theory that a combination of genetic and environmental triggers work together to activate a harmful inflammatory process in MS. However, other experts are dubious about the conclusion, not least because the NR1H3 gene variant is also found in individuals without MS. Dr. Nikolaos Patsopoulos of the Brigham and Women’s Hospital in Boston, US, an expert in MS genetics, told STAT news: “I would be very surprised if it turns out to be true”.
A new line of enquiry?
If these findings can be checked and proven in an independent study, their value to the estimated 999 out of every 1000 MS patients without the variant would be more limited, although it could mean that drugs targeting the LXRA signalling pathway might help suppress autoimmune inflammatory responses in common forms of MS. However, a full understanding of the genetics of MS clearly remains some way off.