Abstract
Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10–6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10–10). Class II HLA alleles HLA-DQB1*03:01, –DRB1*08:02, –DRB1*16:02, –DRB1*14:06 and –DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.
Introduction
Neuromyelitis optica (NMO) is a chronic autoimmune inflammatory and demyelinating disease of the central nervous system (CNS), which mainly affects the optic nerve and spinal cord. Although NMO was first described in the XIX century, it was considered a clinical variant of multiple sclerosis (MS) for decades1,2. In 2004, the discovery of positive antiaquaporin-4 antibodies (AQP4-IgG) in serum of the majority of NMO patients led to significant progress in the clinical characterization of the disease, now acknowledged as a distinct entity with different immunological, clinical and epidemiological features3,4.
Although it has been difficult to establish the actual prevalence of NMO, mainly because most reports are not comparable due to differences in study design, methodological approaches, and diagnostic criteria, worldwide NMO prevalence has been estimated between 0.51 and 4.4 cases per 100,000 inhabitants6,7. The prevalence and clinical manifestations of NMO vary among different ethnic groups, and several authors have stated that NMO is more frequent in non-European populations8,9. Interestingly, the relative frequency of NMO (estimated as the ratio of NMO/(MS + NMO) cases) has been found to decrease gradually in South America from North (Venezuela) to South (Argentina). Because ethnicity also changes gradually from North to South in this region, with the proportion of European individuals being lower in Venezuela and higher in Argentina, the authors suggested that ethnic origin influences NMO frequency in Latin America10. To date there are no population-based studies of the prevalence of NMO in Mexico, and there is a single study estimating NMO prevalence at 1.3 per 100,000 inhabitants based on the NMO/(MS + NMO) relative frequency at a referral center in Mexico City12.
Like many other autoimmune diseases, NMO is a multifactorial disorder that results from complex interactions between genetic and environmental factors. Recent studies have reported associations of NMO with genetic variation in the Human Leukocyte Antigen (HLA) genome region in chromosome 6, particularly with class II alleles, showing ethnical and geographical differences: The DRB1*03:01 allele has been associated with NMO in European13,14,15,16, Brazilian17,18, Afro-Caribbean19 and Mexican patients20; DRB1*16:02 in Southern Han Chinese21, Japanese22 and in Southern Brazilian patients23; DQB1*04:02 in a European-ancestry cohort13,24; and DRB1*04:05 in Southern Brazilians23. Moreover, candidate gene studies have reported associations with variation in non-HLA genes such as AQP4 and others involved in immune function (PD-1, IL-17, IL-7R, CD6 and CD58)24,25,26,27,28. Of the latter, only AQP4 gene variation has been analyzed in various populations by sequencing promoter and/or coding regions of the gene attempting to identify variants involved in the pathogenesis of NMO. However, the association of AQP4 gene variation with NMO remains unclear, with inconsistent findings among populations29,30,31,32,33,34.
Because the Mexican population of today resulted from a complex and ongoing admixture process involving mainly Native American and European genetic components, we hypothesized that Native American ancestry also contributes to NMO susceptibility in Mexican patients. We thus used genome-wide microarray data, HLA high-resolution typing and AQP4 gene sequencing data to explore genetic ancestry and to seek genetic variants conferring susceptibility to NMO in Mexican patients.
Results
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