Genetics
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Researchers continue to unravel the genetic basis of MS, identifying genetic variants associated with increased risk for multiple sclerosis and exploring how complex interactions between genetics and environmental factors affect disease onset and course. The summarized studies to follow highlight representative findings from these investigations.
A team of Spanish investigators concluded that environmental factors play a larger role than genetic predisposition in development of MS. They reached this conclusion after examining the relative contributions of the two types of risk factors in a study that involved 150 people with MS and 150 healthy controls.
In terms of environmental factors, the researchers focused on latitude, smoking status, and Vitamin D deficiency. They included study subjects from three different latitudes within Spain and surveyed those participants on their smoking history. Interestingly, they used skin tone as a marker for Vitamin D status, employing a medical classification system that relates skin tone to levels of Vitamin D, which influences skin tone. In examining genetic factors, they focused on the HLA-DRB1*15:01 allele, a genetic variation linked to elevated risk for MS.
The researchers then used sophisticated statistical processes to identify the significance of various risk factors and combinations of risk factors. Looking at individual factors, they found that having light brown skin rather than clear skin and being a smoker versus a non-smoker were associated with greater risk for developing MS than was having the HLA-DRB1*15:01 allele versus not having that genetic variation.
However, the genetic factor had more influence on MS risk than whether a person was female or male (nonetheless, compared to men, women had roughly twice the risk for MS). In looking at combinations of risk factors, they found that smokers with light brown skin were 1.5 times more likely than those with light brown skin and the HLA-DRB1*15:01 allele to develop MS. However, both groups were at far greater risk for MS than people without any of the risk factors studied. The investigators concluded, “Our study suggests that the confluence of several environmental factors contributes to MS developments to a greater extent than the greatest genetic risk factor known today.”88
Why do relapses tend to peak in spring (at least in the northern hemisphere), and occur least often in autumn? Similarly, why are new focal lesions more frequently identified in the spring and summer than in autumn or winter? While those questions remain unanswered, researchers and clinicians have proposed causes including seasonal fluctuations in Vitamin D levels related to sun exposure and the waxing and waning of viral infections over the course of the year. More recently, a team of international investigators explored whether genetics play a role in these patterns.
The researchers analyzed data on 731 people with MS who participate in a long-term study at the Brigham and Women’s Hospital in Boston. They looked for the presence or absence of 9 single nucleotide polymorphisms (SNPs), or types of genetic variations. Seven of those SNPs previously have been linked to increased risk for MS and are positionally or functionally linked to so-called “seasonal genes,” meaning genes whose expression varies by season. The two other SNPs that were assessed are linked to Vitamin D metabolism or function.
The investigators then used a statistical method called a Wald test to see whether there were significant differences in when relapse peak occurred among patients with different genotypes for the various SNPs being studied. They found that participants who carried an MS-risk allele (an alternative form of a gene resulting from mutation) for the SNP known as rs2248137 had a significant shift in time of relapse peak compared to other patients who did not have that allele. Interestingly, this SNP affects an enzyme involved in Vitamin D metabolism, further focusing attention on that vitamin – and the genetic factors influencing Vitamin D levels – in seasonal patterns of disease activity.89
Certain genetic variations long have been associated with increased susceptibility to MS, but do specific genes or genetic mutations also influence disease severity? Researchers sought to answer that question by drawing on data from three large, randomized controlled trials sponsored by the biopharmaceutical company Biogen.
The investigators focused on two measures of disease severity – levels of serum neurofilament light (sNfL), a protein found in the blood that is elevated in people with MS and other neurologic diseases – and percent brain volume change (PBVC). For sNfL, they examined data on 500 patients with secondary- progressive MS and 474 study participants with relapsing MS. Their assessment of percent brain volume change (PBVC) involved data on 1,796 people with MS.
The researchers performed genome-wide association studies (GWAS) to identify loci, or areas, on different chromosomes associated with increased sNfL levels and decreasing brain volume over time. The investigators found loci on chromosomes 17 and 18 that were associated with elevated sNfL. The overall analysis found no genome-wide significant “hits” for brain atrophy, but
did identify three significant hits, on chromosomes 2 and 5, in the secondary-progressive MS group. “Thus far,” they wrote, “we have not found overlap in signal between MS susceptibility, sNfL, and brain atrophy.”
Having identified genetic regions potentially associated with those two measures of MS progression, the researchers now are working to validate their results by examining data on 1,056 patients, for sNfL, and 1,555 people with MS, for PBVC, who participated in large clinical trials sponsored by another biopharmaceutical company, Roche.90