New Genetic Variants Found in African Americans of European Ancestry at Higher MS Risk

Two genetic variants have been identified by researchers within a genome region previously reported to drive a 1.44-times increased risk of multiple sclerosis (MS) in a group of African Americans with European ancestry.

Located in genes involved in immune responses, the variants fully explain the reported European ancestry-associated increased risk of MS in that particular group of African Americans.

However, they cannot fully account for the general and unclear differences in MS rates between people of European and African ancestry, the researchers noted, adding that additional genetic and environmental factors must determine MS frequency across populations and in changing environments.

The findings were reported in the study, “Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans,” published in Nature Scientific Reports.

Previous research suggested that people of European ancestry are affected by MS some 1.49 to 2.27 times more than African Americans, “motivating genetic scans to identify variants that could contribute to such patterns,” the researchers wrote.

However, more recent studies have disputed that observation, with some suggesting an opposite association, and others pointing to a gender-specific increased risk between these populations.

Still, a 2005 study analyzing the genetic data of more than 1,500 African Americans (605 with MS and 1,043 without MS) found that a higher proportion of European ancestry patients had a genetic risk factor for MS compared with those with African ancestry. That genetic risk factor was near the centromere of chromosome 1 and was shown to increase the risk of MS by about 1.44 times. Of note, the centromere is the constricted region of a chromosome that separates it into a short arm and a long arm.

Despite the increasing number of MS genetic risk factors identified since that study, the specific variants responsible for the reported European ancestry-associated increased MS risk remain unresolved.

Now, researchers at Harvard Medical School, along with colleagues from other universities and institutes in the U.S., have identified the genetic variants near the chromosome 1 centromere region contributing to differences in MS risk between Africans and Europeans.

The team first assessed whether they could find a similar association between European ancestry in chromosome 1 and a higher risk of MS by analyzing the genetic data of an expanded group of African Americans. That group was comprised of 1,305 African Americans with MS and 1,155 African Americans without MS, used as controls.

To the investigators’ surprise, they could only replicate the MS risk link in the centromere region of chromosome 1 when restricting MS cases to the 899 African Americans with MS who overlapped with a 2007 follow-up of the 2005 study.

In the remaining 406 MS cases, collected after 2007, there appeared to be a significant association of European ancestry in such region with a decreased, rather than increased, risk of MS.

Despite several analyses, the team was not able to find an explanation for these group differences, leading them to hypothesize that “the cases collected up until 2007 may have been more enriched for people with genetic susceptibility to MS than the controls.”

Based on these findings, the researchers decided to continue their study using only the 899 MS cases.

When they looked at variants previously shown to be linked to MS risk in people of European ancestry, they found that two of them — one in the CD58 gene and other in the FCRL3 gene — were sufficient to explain the ancestry association reported in the 2005 study in African Americans.

Both genes are located near the centromere of chromosome 1, but CD58 is found in the short arm of the chromosome and FCRL3 in its long arm.

The CD58 gene contains the instructions to produce CD58, a receptor protein involved in regulatory and anti-inflammatory immune responses mediated by immune T-cells and B-cells. Meanwhile, FCRL3 provides instructions to produce a receptor protein called FCRL3 whose activation is associated with pro-inflammatory responses.

“In summary, two variants involved in regulation of immune responses predict a 1.44-fold increased risk of MS in African-Americans with … European ancestry compared to baseline-risk African-Americans,” the researchers wrote, adding that this increase was “primarily driven by the CD58 variant.”

“It is remarkable that these two genetic variants by themselves, irrespective of other factors, would be sufficient to predict an increased risk in Europeans above that of Africans approximating the range that has been documented in some epidemiological studies,” the team added.

Notably, the CD58 variant was previously associated with lower CD58 levels and a stronger immune response based on TNF-alpha, a major pro-inflammatory molecule. In agreement, MS patients in remission were found to have higher CD58 levels.

Moreover, FCRL3 mutations are associated with several autoimmune diseases, and the FCRL3 variant was shown to increase FCRL3 levels in T- and B-cells. In addition, MS patients were found to have higher levels of a similar molecule, called FCRL1.

Therefore, increasing CD58 levels or suppressing FCRL3 activity may be potential therapeutic strategies for MS, the researchers noted.

The team also emphasized that “it is likely that other genetic and environmental effects have major impacts on incidence in people of both ancestries, and future work is necessary to determine how these numerous factors interact to lead to the variable prevalence rates of MS observed in different populations today,” they wrote.