Genetic variants in the CPXM2, IGSF9B, and NLRP9 genes were found to potentially shape the disease course of multiple sclerosis (MS), and may be used as biomarkers to identify those with an aggressive or benign type of disease, a DNA sequencing study shows.
The study, “Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course,” was published in the Journal of Neuroinflammation.
However, little is known about genes that influence MS disease course. The way MS evolves varies considerably between patients, and over time. Some may experience episodes of relapse followed by periods of remission, while others experience a disease that progressively worsens. In addition, in more severe cases, the disease symptoms are markedly aggravated within a few years, while in MS cases considered benign, symptoms get worse at a slower pace.
The underlying cause of this variability is unknown, but there is scientific evidence suggesting that genetic variants may play a role.
To address this question, a team led by researchers at Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona in Spain conducted a DNA sequencing study to identify genes specifically associated with MS disease course.
First, they sequenced all the protein-coding genes (exome sequencing) of a group of 20 MS patients, 10 of whom had a disease course classified as aggressive and 10 characterized as having a benign disease course.
Benign MS was defined as having an Expanded Disability Status Scale (EDSS) score of three or lower over the course of 15 or more years from disease onset, and never having received MS therapies. An aggressive disease course was determined as having reached an EDSS score of six or higher within the first five years of disease onset, regardless of having received treatment.
From this first screen, researchers identified a list of 16 genetic variants — called single-nucleotide polymorphisms (SNPs) — potentially associated with either more aggressive or benign disease manifestations.
To validate the association of these genetic variants with disease course, they were assessed in two independent groups of MS patients: the first with 194 MS patients, 107 with benign and 87 with aggressive symptoms; the second with 257 patients, of whom 224 patients had benign symptoms and 33 aggressive disease courses.
From these studies, two genetic variants were validated as being associated with MS disease course, namely rs28469012 and rs10894768. The first is located in the gene CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with an aggressive disease course. The other, rs10894768, appeared in the gene IGSF9B (immunoglobulin superfamily member 9B) and was linked with a benign manifestation.
Additionally, another genetic variation called rs10423927 showed a trend, which was not statistically significant, toward association with a benign MS course. This variant is located in the gene NLRP9 (NLR family pyrin domain containing 9).
To explore whether these genetic variants could play specific roles in the formation of MS lesions at the central nervous system (CNS; spinal cord and brain), researchers investigated the expression of the proteins corresponding to the three genes in brain tissue from patients.
Specifically, they looked at the expression of IGSF9B, CPXM2, and NLRP9 proteins in chronic active lesions of brain samples from four MS patients.
IGSF9B proteins were present in astrocytes — star-shaped cells important for providing nutrients, support, and protection to the central nervous system — and macrophages/microglial cells — a type of immune cell present in the brain and spinal cord — whereas CPXM2 and NLRP9 proteins were restricted to brain macrophages/microglia.
IGSF9B and CPXM2 genes are known to play a role in the integrity of synapses, or the point of communication between nerve cells, which supports the need for additional studies “to explore at the CNS level the potential functional consequences of the reported polymorphisms associated with MS disease course,” the researchers wrote.
They concluded that “genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients.” In addition, the team believes that these genetic variants “may be used as disease activity biomarkers to identify patients with divergent disease courses.”