Philip De Jager presented his conclusions about the relationship between genetic variants like human leukocyte antigen (HLA) class II allele DRB1*1501 and Multiple Sclerosis at DHMC last Monday.
Philip De Jager, a medical researcher from Boston’s Brigham and Women’s Hospital, presented findings about the genetic components of multiple sclerosis (MS) at Dartmouth Hitchcock Medical Center last Monday.
Collaborative efforts and previous research have led to De Jager to new conclusions about the relationship between genetic variants like human leukocyte antigen (HLA) class II allele DRB1*1501 and this demyelinating disease.
Although a strong link has arisen in previous studies between DRB1*1501 and MS, DRB1*1501-negative MS patients do exist. Thus, DRB1*1501 is clearly not the sole causal variant behind MS. “DRB1 could be acting in combination with other variants or merely highly correlated with the casual variant,” De Jager said. To help differentiate the specific roles of these variants and to overcome the common issue of confounding variables, De Jager and colleagues rely on studying healthy subjects as well as MS patients. De Jager mentioned the ongoing PhenoGenetic Project at Brigham and Women’s Hospital that will ultimately become a functional public genetic database created from the blood samples from these healthy subjects.
Comparing DRB1*1501-negative and DRB1*1501-positive subjects suggests the involvement of new variants from the major histocompatible complex (MHC), which is known for its involvement in autoimmunity. The MHC class II region contains the suspect DRB1; however, DRB1*1501-negative data points to the HLA-C gene in the class I region. This variant may play a larger than expected role in the development of MS.
To locate other possible alleles genetically responsible for MS, De Jager uses genome-wide association scans that identify loci with statistically significant differences in allele frequencies between MS patients and healthy ones. Furthermore, RNA profiling in lymphoblastic cells lines (LCL) allows for functional analysis of the identified variants. De Jager’s presentation highlighted evidence of three new loci with genome-wide evidence of contributions to MS, TNFRSF1A, ICSBP1, and CD6, as well as seven others with suggestive evidence. Interestingly, some of the seven loci with suggestive evidence have ties to other inflammatory diseases like Celiac and Crohn’s disease. Although these findings give rise to new possibilities on the genetic front, De Jager said, “We are still seeking formal validation of these results.”
Finally, De Jager touched upon using genes to prognosticate how a patient’s disease will develop. Since most of the data he presented comes from patients within the pre-clinical stages of MS, making predictions is inherently difficult. Choosing to focus on brain atrophy in MS patients yielded “encouraging but by no means definitive results,” said De Jager. A genome-wide random effects model attempting to measure brain volume has been completed, and replication is ongoing. SNPs from MGST1 locus illustrate slower atrophy in patients with higher mRNA expression of MGST1. Although the exact mechanism remains unknown, these neurons have a pronounced ability to survive.
Overall, the work of De Jager and colleagues is leading to a better understanding of the relationship between genetics and multiple sclerosis. In addition to MS patients, healthy subjects will contribute to the understanding of function of alleles. As more studies are completed, the statistical evidence may lead researchers like De Jager in different directions or verify some of the aforementioned possibilities.