Uncovering the Genetic Puzzle of Neuromyelitis Optica: How Our DNA Distinguishes NMO from Multiple Sclerosis

Neuromyelitis Optica (NMO) and Multiple Sclerosis (MS) are both inflammatory diseases of the central nervous system (CNS), but their genetic underpinnings differ significantly. While MS is often associated with the HLA DRB115 allele, NMO exhibits a strong association with the HLA DRB103 allele. This systematic review and meta-analysis by Alvarenga et al. examines the genetic susceptibilities in NMO, distinguishing it from MS and shedding light on the influence of ethnicity on HLA associations.

NMO and MS: Distinct Diseases with Overlapping Symptoms
Both NMO and MS affect young adults, particularly women, and lead to neurological impairments due to inflammation in the CNS. However, unlike MS, which predominantly affects populations in the Northern Hemisphere, NMO is more prevalent among Asians and individuals of African descent. The discovery of the NMO-IgG antibody, which targets the aquaporin-4 (AQP4) water channel, has been pivotal in differentiating NMO from MS, as this antibody is typically absent in MS patients.

The Role of HLA DRB1*03 in NMO Susceptibility
The study analyzes the HLA class II DRB1 allele, particularly DRB103, across various populations. The meta-analysis shows that patients with NMO are 2.46 times more likely to carry the DRB103 allele than controls. Notably, this association varies by ethnicity. In Latin American populations, particularly among Afro-Caribbean and Afro-Brazilian groups, DRB103:01 shows a higher prevalence in NMO patients. Among Asian populations, the DPB105:01 allele plays a more significant role, underscoring the diversity in genetic susceptibility among ethnic groups.

Key Findings Across Populations
The study reviewed 13 case-control studies from different geographic regions, including Caucasians in Europe, mestizo populations in Mexico, Afro-Caribbean groups, and Asian populations in South China, Japan, and India. Key findings include:

Western Populations: In countries like France and the Netherlands, DRB103 was associated with NMO but not with MS. However, DRB115 remained a strong risk allele for MS.

Latin American Populations: Higher frequencies of DRB103:01 were observed in NMO patients from Latin America. In contrast, MS patients in these regions were more likely to carry DRB115.

Asian Populations: The study found that DPB105:01, rather than DRB103, was the primary allele associated with NMO in Asian populations. This allele has also been implicated in other autoimmune diseases in Asia, highlighting regional genetic differences in immune-related diseases.

The Importance of AQP4-IgG Status
In NMO, the presence of AQP4-IgG antibodies, which target aquaporin-4 channels in the blood-brain barrier, is a significant biomarker. The review found that DRB103 associations were stronger in AQP4-IgG-positive NMO patients, emphasizing the relevance of this biomarker in genetic susceptibility studies. In some populations, such as those in Rio de Janeiro, DRB103 was associated with NMO regardless of AQP4-IgG status, suggesting that this allele might play a role even in the absence of the antibody.

Genetic and Environmental Interactions
The study also explored the interaction between genetic factors and environmental influences. NMO patients often share genetic predispositions with other autoimmune conditions, such as Sjögren's syndrome and systemic lupus erythematosus (SLE). This shared genetic background, often marked by HLA DRB1*03 or similar alleles, may predispose individuals to a heightened immune response, potentially leading to autoimmunity in the CNS.

Implications and Future Research Directions
This systematic review underscores the complex genetic landscape of NMO and the critical role of the HLA system in autoimmune susceptibility. These findings suggest the need for more refined genetic studies, particularly those that utilize high-resolution typing methods to further elucidate haplotypes associated with NMO. Additionally, the study recommends expanding research to include larger sample sizes and more diverse populations to better understand NMO's global genetic profile.

Conclusion
The genetic distinctions between NMO and MS support the classification of these conditions as separate autoimmune diseases with unique genetic susceptibilities. NMO’s association with DRB103 in Western and Latin American populations, contrasted with DPB105:01 in Asian populations, highlights the importance of ethnicity in genetic predispositions. This meta-analysis contributes valuable insights for future research aimed at unraveling the genetic mechanisms underlying NMO, potentially paving the way for targeted therapeutic interventions.

References:
Alvarenga, M.P., do Carmo, L.F., Vasconcelos, C.C.F. et al. Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis. Sci Rep 11, 152 (2021).