Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population.

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.

Aspartic acid70 in the HLA-DRB1 chain and shared epitope alleles partially explain the high prevalence of autoimmunity in Mexicans.

INTRODUCTION: Autoimmune thyroid disease (AITD) is the most common autoimmune disorder worldwide. Remarkably, it is commonly accompanied by other autoimmune diseases, such as rheumatoid arthritis (RA). The immunopathogenic mechanisms behind the coexistence of these disorders are still not completely understood. Immunogenetics influences the physiopathology of these diseases since ethnicity plays an essential role in the inheritance of susceptibility markers. METHODS: High-resolution HLA class II typing was performed using a sequence-based method. RESULTS: The allele frequency of HLA-DRB1∗04:04 and -DRB1∗03:01 were significantly increased in patients with AITD and RA compared to healthy individuals, pC â€‹= â€‹0.021, OR â€‹= â€‹2.4, 95%CI â€‹= â€‹1.19-4.75 and pC â€‹= â€‹0.009, OR â€‹= â€‹3.4, 95%CI â€‹= â€‹1.42-7.93, respectively. Remarkably, these patients have a combined risk given by susceptibility HLA-DRB1 alleles that contain the shared epitope, pC â€‹= â€‹0.03, OR â€‹= â€‹1.7, IC95% â€‹= â€‹1.07-2.76, and a lack of protective alleles carrying aspartic acid70, pC â€‹= â€‹0.009, OR â€‹= â€‹0.5, IC95% â€‹= â€‹0.32-0.84. DISCUSSION: The results suggest that patients with AITD and RA have an immunogenetic mechanism that combines the susceptibility alleles associated with both diseases. Importantly, it seems to be linked mainly to the lack of protective alleles with aspartic acid in the position 70, along with the presence of susceptibility alleles that have the sequences QRRAA, QKRAA, and RRRAA at positions 70-74. CONCLUSION: Patients with AITD and RA have a characteristic immunogenetic signature, which could be useful for determining multiple autoimmunities and assessing their relatives' risk of developing it.

Thinking Outside the Box: Innate- and B Cell-Memory Responses as Novel Protective Mechanisms Against Tuberculosis.

Tuberculosis (TB) is currently the deadliest infectious disease worldwide. Failure to create a highly effective vaccine has limited the control of the TB epidemic. Historically, the vaccine field has relied on the paradigm that IFN-γ-mediated CD4+ T cell memory responses are the principal correlate of protection in TB. Nonetheless, the demonstration that other cellular subsets offer protective memory responses against Mycobacterium tuberculosis (Mtb) is emerging. Among these are memory-like features of macrophages, myeloid cell precursors, natural killer (NK) cells, and innate lymphoid cells (ILCs). Additionally, the dynamics of B cell memory responses have been recently characterized at different stages of the clinical spectrum of Mtb infection, suggesting a role for B cells in human TB. A better understanding of the immune mechanisms underlying such responses is crucial to better comprehend protective immunity in TB. Furthermore, targeting immune compartments other than CD4+ T cells in TB vaccine strategies may benefit a significant proportion of patients co-infected with Mtb and the human immunodeficiency virus (HIV). Here, we summarize the memory responses of innate immune cells and B cells against Mtb and propose them as novel correlates of protection that could be harnessed in future vaccine development programs.

Diversity of HLA Class I and Class II blocks and conserved extended haplotypes in Lacandon Mayans.

Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.

The role of socioeconomic status in the susceptibility to develop systemic lupus erythematosus in Mexican patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well-identified as risk factors. SLE patients have different phenotypes or clinical presentations, which vary among Mexicans. This variation could be explained by ethnicity and admixture. Since socioeconomic status probably limits and change the patterns of migration, this factor could favor inbreeding and homogamy in some geographic areas. Consequently, it could alter or restrict the possibilities of admixture too. Therefore, the socioeconomic status may also have implications in the susceptibility and the clinical heterogeneity of SLE in Mexican patients. METHODS: One hundred twenty-three SLE patients and 234 healthy individuals with Mexican admixed ancestry were recruited. HLA alleles were analyzed using the HLA typing method based on Sequence-based typing (SBT). RESULTS: As expected, it was found an increased frequency of the HLA-DRB1*03:01 allele in all socioeconomic groups when compared with healthy individuals. The susceptibility allele found in the low-income SLE patients was HLA-DRB1*04:05 whereas, the susceptibility alleles for the high-income SLE patients were HLA-DRB1*07:01 (pC = 0.03, OR = 2.0) and HLA-DRB1*11:04 (pC = 0.0004, OR = 5.1). Additionally, the frequencies of two protective alleles HLA-DRB1*14:06 (pC = 0.01, OR = 0.28) and HLA-DRB1*16:02 (pC = 0.04, OR = 0.22) were found diminished. These findings correlate with the admixture differences between low-income and high-income SLE patients. The clinical manifestations showed a different distribution between both groups. Arthritis and neurological disorder were prevalent in low-income SLE patients, while the hematological disorder was prevalent in high-income SLE patients. CONCLUSIONS: These findings suggest that HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status. Due to this, the clinical manifestations vary among patients and it could be related to different admixture charge.Key Point• HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status.

Genetic diversity of HLA system in two populations from Chiapas, Mexico: Tuxtla Gutiérrez and rural Chiapas.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 173 Mexicans from the state of Chiapas living in the city of Tuxtla Gutiérrez (N = 52) and rural communities (N = 121), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in Chiapas include 12 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Chiapas are Native American (71.61 ±â€¯0.58% by ML; 53.16% of Native American haplotypes) and European (26.39 ±â€¯5.05% by ML; 25.86% of European haplotypes), and a less prominent African genetic component (2.00 ±â€¯5.20% by ML; 9.77% of African haplotypes).

Genetic diversity of HLA system in two populations from Tamaulipas, Mexico: Ciudad Victoria and rural Tamaulipas.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 148 Mexicans from the state of Tamaulipas living in Ciudad Victoria (N = 23) and rural communities (N = 125), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Tamaulipas include ten Native American, three European and one African haplotypes. Admixture estimates revealed that the main genetic components in the state of Tamaulipas are Native American (54.69 ±â€¯0.93% by ML; 47.65% of Native American haplotypes) and European (34.66 ±â€¯5.62% by ML; 33.56% of European haplotypes), and a relatively high African genetic component (10.65 ±â€¯5.05% by ML; 12.42% of African haplotypes).

Genetic diversity of HLA system in two populations from Hidalgo, Mexico: Pachuca and rural Hidalgo.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 122 Mexicans from the state of Hidalgo living in the city of Pachuca (N = 41) and rural communities (N = 81), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in Hidalgo include eight Native American and one European haplotypes. Admixture estimates revealed that the main genetic components in Hidalgo are Native American (58.93 ±â€¯2.16% by ML; 54.51% of Native American haplotypes) and European (32.49 ±â€¯2.88% by ML; 28.69% of European haplotypes), and a relatively high African genetic component (8.58 ±â€¯0.93% by ML; 6.97% of African haplotypes).

Genetic diversity of HLA system in seven populations from Veracruz, Mexico: Veracruz city, Coatzacoalcos, Córdoba, Orizaba, Poza Rica, Xalapa and rural Veracruz.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 1113 Mexicans from the state of Veracruz living in the cities of Coatzacoalcos (N = 55), Orizaba (N = 60), Córdoba (N = 56), Poza Rica (N = 45), Veracruz (N = 171), Xalapa (N = 187) and rural communities (N = 539) to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes include 12 Native American haplotypes. Admixture estimates revealed that the main genetic components are Native American (64.93 ±â€¯1.27% by ML; 55.10% of Native American haplotypes) and European (26.56 ±â€¯0.89% by ML; 28.38% of European haplotypes), and a relatively high African genetic component (8.52 ±â€¯1.82% by ML; 8.78% of African haplotypes).

Genetic diversity of HLA system in two populations from Campeche, Mexico: Campeche city and rural Campeche.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 81 Mexicans from the state of Campeche living in the city of Campeche (N = 34) and rural communities (N = 47), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Campeche include ten Native American, three European, one African and one Asian haplotype. Admixture estimates revealed that the main genetic components in the state of Campeche are Native American (65.56 ±â€¯0.96% by ML; 51.24% of Native American haplotypes), European (34.44 ±â€¯10.94% by ML; 30.25% of European haplotypes), and a virtually absent African genetic component (0.00 ±â€¯10.31% by ML; 9.26% of African haplotypes).

Genetic diversity of HLA system in two populations from Oaxaca, Mexico: Oaxaca city and rural Oaxaca.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 636 Mexicans from the state of Oaxaca living in the city of Oaxaca (N = 151) and rural communities (N = 485), to obtain information regarding allelic and haplotypic frequencies. We found that the 13 most frequent haplotypes in Oaxaca are all of putative Native American origin. Admixture estimates revealed that the main genetic components in the state of Oaxaca are Native American (73.12 ±â€¯2.77% by ML; 61.52% of Native American haplotypes) and European (17.36 ±â€¯2.07% by ML; 20.69% of European haplotypes), and a relatively high African genetic component (9.52 ±â€¯0.88% by ML; 8.94% of African haplotypes).

Genetic diversity of HLA system in two populations from Puebla, Mexico: Puebla city and rural Puebla.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 2827 Mexicans from the state of Puebla living in the city of Puebla (N = 1994) and rural communities (N = 833), to obtain information regarding allelic and haplotypic frequencies. We found that the 16 most frequent haplotypes in Puebla are all of them Native American. Admixture estimates revealed that the main genetic components in the state of Puebla are Native American (72.21 ±â€¯1.25% by ML; 63.30% of Native American haplotypes) and European (21.05 ±â€¯1.92% by ML; 23.86% of European haplotypes), and a less prominent African genetic component (6.74 ±â€¯2.20% by ML; 6.20% of African haplotypes).

Genetic diversity of HLA system in two populations from Yucatán, Mexico: Mérida and rural Yucatán.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 324 Mexicans from the state of Yucatán living in the city of Mérida (N = 192) and rural communities (N = 132), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Yucatán include 16 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Yucatán are Native American (81.54 ±â€¯4.99% by ML; 62.92% of Native American haplotypes) and European (11.50 ±â€¯15.43% by ML; 23.26% of European haplotypes), and a less prominent African genetic component (6.96 ±â€¯10.47% by ML; 5.93% of African haplotypes).

Genetic diversity of HLA system in two populations from Morelos, Mexico: Cuernavaca and rural Morelos.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 112 Mexicans from the state of Morelos living in the city of Cuernavaca (N = 82) and rural communities (N = 30), to obtain information regarding allelic and haplotypic frequencies. The most frequent haplotypes in Morelos include seven Native American, one European, one African and one Asian haplotype. Admixture estimates revealed that the main genetic components in Morelos are Native American (60.43 ±â€¯2.22% by ML; 53.57% of Native American haplotypes) and European (39.58 ±â€¯3.70% by ML; 27.68% of European haplotypes), and a virtually absent African genetic component (0.00 ±â€¯4.93% by ML; but 11.16% of African haplotypes).

Genetic diversity of HLA system in two populations from Quintana Roo, Mexico: Cancún and rural Quintana Roo.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 98 Mexicans from the state of Quintana Roo living in the city of Cancún (N = 48) and rural communities (N = 50), to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We found that the most frequent haplotypes in Quintana Roo include ten Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in Quintana Roo are Native American (80.85 ±â€¯3.70% by ML; 60.20% of Native American haplotypes) and European (15.19 ±â€¯14.25% by ML; 26.02% of European haplotypes), and a less prominent African genetic component (3.96 ±â€¯10.75% by ML; 6.63% of African haplotypes).

Genetic diversity of HLA system in two populations from Tlaxcala, Mexico: Tlaxcala city and rural Tlaxcala.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 1011 Mexicans from the state of Tlaxcala residing in the city of Tlaxcala (N = 181) and rural communities (N = 830), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes in Tlaxcala are all of Native American origin. Admixture estimates revealed that the main genetic components are Native American (75.13 ±â€¯1.56% by ML; 69.24% based on of Native American haplotypes) and European (16.10 ±â€¯4.98% by ML; 19.74% of European haplotypes), with a less prominent African genetic component (8.78 ±â€¯4.09% by ML; 4.35% of African haplotypes).

Genetic diversity of HLA system in two populations from Tabasco, Mexico: Villahermosa and rural Tabasco.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 224 Mexicans from the state of Tabasco living in the city of Villahermosa (N = 82) and rural communities (N = 142), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in Tabasco include 13 Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in Tabasco are Native American (67.79 ±â€¯1.59% by ML; 56.25% of Native American haplotypes) and European (27.21 ±â€¯3.97% by ML; 29.91% of European haplotypes), and a less prominent African genetic component (5.01 ±â€¯4.42% by ML; 8.93% of African haplotypes).

Genetic diversity of HLA system in two populations from San Luis Potosí, Mexico: San Luis Potosí City and rural San Luis Potosí.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 117 Mexicans from the state of San Luis Potosí living in the city of San Luis Potosí (N = 30) and rural communities (N = 87), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state include 13 Native American, six European, two African and two Asian haplotypes. Admixture estimates revealed that the main genetic components are Native American (52.72 ±â€¯0.66% by ML; 48.29% of Native American haplotypes) and European (34.62 ±â€¯4.28% by ML; 32.48% of European haplotypes), and a relatively high African genetic component (12.66 ±â€¯4.61% by ML; 10.26% of African haplotypes).

Genetic diversity of HLA system in three populations from Coahuila, Mexico: Torreón, Saltillo and rural Coahuila.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 684 Mexicans from the state of Coahuila living in Saltillo (N = 72), Torreón (N = 396) and rural communities (N = 216), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes found in the state of Coahuila include eight Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in the state of Coahuila are European (49.72 ±â€¯4.18% by ML; 37.49% of European haplotypes) and Native American (45.01 ±â€¯2.69% by ML; 42.98% of Native American haplotypes), while African genetic component is less apparent (5.27 ±â€¯1.88% by ML; 9.92% of African haplotypes).