Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Nakatsuka, Nathan; Patterson, Nick; Patsopoulos, Nikolaos A.; Altemose, Nicolas; Tandon, Arti; Beecham, Ashley; McCauley, Jacob L.; Isobe, Noriko; Jager, Philip L. De; Hafler, David A.; Oksenberg, Jorge R.; Reich, David

doi:10.1038/s41598-020-74035-7

Cited by 10 publications

(11 citation statements)

References 54 publications

(68 reference statements)

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“…First among the reasons for enrollment targets, there is evidence that MS may differ in both risk factors and disease severity in certain racial and ethnic groups. People who identify as African American, LatinX, Middle Eastern, and North African are reported to have increased disease activity, more lasting disability, and/or worse clinical outcomes (8)(9)(10)(11)(12)(13). Other characteristics relevant to MS including early life exposures or vitamin D levels may differ (14).…”

Section: For Againstmentioning

confidence: 99%

Is It Time for Quotas to Achieve Racial and Ethnic Representation in Multiple Sclerosis Trials?

Mateen

2021

Front. Neurol.

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Clinical trials form the bedrock of evidence upon which clinical decision making is based. In multiple sclerosis (MS), the number of disease modifying therapies (DMTs) continues to expand with the number of clinical trials growing rapidly, especially over the past two decades. Phase III trials of DMTs are usually multi-centered, spanning many countries, and involve dozens of centers and hundreds of investigators. Meanwhile, efforts to improve racial and ethnic diversity in clinical trials in general in the United States have largely failed (1, 2). Just 5% of trial participants are African American or Black in the USA (compared to 13% of the population in the last reported U.S. census) and just 1% are Hispanic/LatinX (compared to 18% of the U.S. population) (2). Clinical trials for people living with MS are no exception to this reality (3,4).Current efforts to advance health equity via phase III clinical trials in MS appear inadequate. MS research is highly sensitive to the many structural inequities experienced across the U.S.A. Although clinical trials in MS have often been considered separate from broader social, cultural, and political trends, demands for equity in all aspects of American society are rightly becoming a tour de force. Many stakeholders are beginning to re-examine who enters and leads clinical trials. Increasing scrutiny of the representativeness of people of color is therefore rightly gathering new attention by patients, investigators, and the general public as the science of MS rapidly advances.Quotas, or enrollment number targets, are one approach that may be taken to increase the number of people of color in MS clinical trials. This practice has recent precedents. Taking a sense of responsibility for racial and ethnic representativeness to a new level, one recent trial of a vaccine for SARS-CoV-2 by a U.S.-based company set targets for the enrollment of participants from specific racial and ethnic groups in the U.S. and slowed enrollment to ensure adequate representation. Others have followed this trend by publicly delaying completion of enrollment in their trial until benchmarks for representativeness are met (5, 6). These benchmarks approximate the incidence of the disease in the target population for the proposed product and recognize concentrated epidemics within epidemics. In other sectors, most prominently including corporate America, the role of target numbers or quotas for the inclusion of people of color and women on executive boards has become a matter of not only public trust and confidence, but also enforced regulation. In 2020, California bill AB 979 was passed to eliminate all-White boards of publicly traded companies headquartered in that state (7). Accountability by major companies to achieve representativeness is considered a public good and sets a new standard which clinical trials can learn from.There are reasons for and against concrete numerical enrollment targets to ensure representativeness of people of color in MS clinical trials (Table 1).

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Section: For Againstmentioning

confidence: 99%

Is It Time for Quotas to Achieve Racial and Ethnic Representation in Multiple Sclerosis Trials?

Mateen

2021

Front. Neurol.

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“…Among African American people who were heterozygotic for the HLA-DRB1*15:01 allele, carriage of an ancestrally European allele was associated with a threefold greater risk of MS than was carriage of an ancestrally African allele 59 . However, another admixture mapping study of African American people (with a partially overlapping cohort) found no evidence of excess European ancestry at the MHC despite a similar study design and comparable statistical power 14,15 . These findings should be interpreted with some caution because the admixture peak at the MHC did not pass genome-wide significance in either study.…”

Section: [H2] Hla Effects and Ancestrymentioning

confidence: 94%

“…These signals collectively explain up to ~50% of the estimated genetic heritability of MS 7,8 . However, these findings alone tell us little about the genetic architecture of MS in other ancestral populations [9][10][11][12][13][14][15] .…”

Section: [H1] Introductionmentioning

confidence: 97%

Towards a global view of multiple sclerosis genetics

et al. 2022

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Multiple sclerosis (MS) is a neuroimmunological disorder of the CNS with a strong heritable component. The genetic architecture of MS susceptibility is well understood in populations of European ancestry. However, the extent to which this architecture explains MS susceptibility in populations of non-European ancestry remains unclear. In this Perspective article, we outline the scientific arguments for studying MS genetics in ancestrally diverse populations. We argue that this approach is likely to yield insights that could benefit individuals with MS from all ancestral groups. We explore the logistical and theoretical challenges that have held back this field to date and conclude that, despite these challenges, inclusion of participants of non-European ancestry in MS genetics studies will ultimately be of value to all patients with MS worldwide.[H1] The MHC locus The role of the MHC locus (6p21) in determining MS susceptibility is wellestablished 39,40 . However, studying the role of the MHC in populations of non-European ancestry is valuable because population-specific alleles exist and haplotype structures differ between populations (Figure 1). Such studies can reveal the role of HLA alleles that are not present in European populations and clarify independent and/or shared effects of alleles that highlight core disease pathways. Differences between populations of different ancestry could also reveal a role for specific pathogens or selection pressures.Determining the precise mechanisms by which MHC variation affects MS biology has been challenging owing to the density of genes in this region, the complex linkage disequilibrium, and the existence of long-range haplotypes. A GWAS in populations of European ancestry has identified 32 statistically independent signals within the MHC locus, including class II alleles that increase risk (HLA-DRB1*15:01, HLA-DRB1*03:01,HLA-DRB1*13:03, HLA-DRB1*08:01 and HLA-DQB1*03:02), class I alleles that are protective (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), and some risk variants outside of classical HLA genes 8,41 . Gene-gene interactions also occur at this locus in populations of European ancestryseveral alleles modulate the effect of HLA-DRB1*15:01 8,41 . There is little evidence to suggest that the MHC influences MS phenotypes (for example, relapse rate, severity or relapsing-remitting versus progressive disease) besides age of onset in European populations [41][42][43] .The frequency, distribution and haplotypes of HLA alleles differ between ancestral populations (Figure 1) 44,45 . Some alleles are absent in the European population so their influence on MS risk cannot be studied in populations of European ancestry. Conversely, some MS risk alleles, such as HLA-DRB1*15:01, are rare in populations of non-European ancestry. The class II allele HLA-DRB1*04:05, which is essentially absent in populations of European ancestry, has been associated with MS in Japanese 46 , Turkish 47 , South American 48 , African American 10 , and Sicilian populations 49 . The combina...

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“… 9 , 10 There is substantial variation in the proportion of genomes of European and African ancestry in African Americans in the United States. 11 , 12 Of note, race and ethnicity are patient reported in the majority of studies evaluating differences in clinical outcomes described below.…”

Section: Disparities In Clinical Outcomes and Healthcare Accessmentioning

confidence: 99%

Advancing Care and Outcomes for African American Patients With Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) has historically been underdiagnosed and undertreated among African Americans. Recent evidence suggests that African Americans with MS have a different clinical presentation, increased disease incidence and burden, and worsened long-term outcomes versus their White counterparts. Due to limited data available for African Americans in MS clinical trials, it is difficult to make informed, generalizable conclusions about the natural history, prognosis, and therapeutic response in this population. In this narrative review, we highlight the nature and magnitude of the health disparities experienced by African Americans with MS and underscore the pressing need to increase knowledge about and understanding of MS disease manifestations in this group. Additionally, we describe the mission and objectives of the recently established National African Americans with Multiple Sclerosis Registry (NAAMSR), which is intended to be a platform to advance the care of African Americans with MS and address health disparities they may experience.

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Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Cited by 10 publications

References 54 publications

Is It Time for Quotas to Achieve Racial and Ethnic Representation in Multiple Sclerosis Trials?

Is It Time for Quotas to Achieve Racial and Ethnic Representation in Multiple Sclerosis Trials?

Towards a global view of multiple sclerosis genetics

Advancing Care and Outcomes for African American Patients With Multiple Sclerosis

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