16 research outputs found
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HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations
Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/âB and -DRB1/âDQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations
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 Ă 10â6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 Ă 10â10). 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.Fil: Romero Hidalgo, Sandra. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: Flores Rivera, JosĂ©. Instituto Nacional de NeurologĂa y NeurocirugĂa; MĂ©xicoFil: Rivas Alonso, VerĂłnica. Instituto Nacional de NeurologĂa y NeurocirugĂa; MĂ©xicoFil: Barquera, Rodrigo. Max Planck Institute For The Science Of Human History; Alemania. Instituto Nacional de AntropologĂa e Historia; MĂ©xicoFil: Villarreal Molina, MarĂa Teresa. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: Antuna Puente, BĂĄrbara. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: Macias Kauffer, Luis Rodrigo. Universidad Nacional AutĂłnoma de MĂ©xico; MĂ©xicoFil: Villalobos ComparĂĄn, Marisela. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: Ortiz Maldonado, Jair. Instituto Nacional de NeurologĂa y NeurocirugĂa; MĂ©xicoFil: Yu, Neng. American Red Cross; Estados UnidosFil: Lebedeva, Tatiana V.. American Red Cross; Estados UnidosFil: Alosco, Sharon M.. American Red Cross; Estados UnidosFil: GarcĂa RodrĂguez, Juan Daniel. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: GonzĂĄlez Torres, Carolina. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: Rosas Madrigal, Sandra. Instituto Nacional de Medicina GenĂłmica; MĂ©xicoFil: Ordoñez, Graciela. NeuroimmunologĂa, Instituto Nacional de NeurologĂa y NeurocirugĂa; MĂ©xicoFil: Guerrero Camacho, Jorge Luis. Instituto Nacional de NeurologĂa y NeurocirugĂa; MĂ©xicoFil: Treviño Frenk, Irene. American British Cowdray Medical Center; MĂ©xico. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: Escamilla Tilch, Monica. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: GarcĂa Lechuga, Maricela. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: Tovar MĂ©ndez, VĂctor Hugo. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: Pacheco Ubaldo, Hanna. Instituto Nacional de AntropologĂa E Historia. Escuela Nacional de AntropologĂa E Historia; MĂ©xicoFil: Acuña Alonzo, Victor. Instituto Nacional de AntropologĂa E Historia. Escuela Nacional de AntropologĂa E Historia; MĂ©xicoFil: Bortolini, MarĂa CĂĄtira. Universidade Federal do Rio Grande do Sul; BrasilFil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerĂșFil: Bedoya BerrĂo, Gabriel. Universidad de Antioquia; ColombiaFil: Rothhammer, Francisco. Universidad de TarapacĂĄ; ChileFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Centro Nacional PatagĂłnico. Instituto PatagĂłnico de Ciencias Sociales y Humanas; ArgentinaFil: Ruiz Linares, AndrĂ©s. Colegio Universitario de Londres; Reino UnidoFil: Canizales Quinteros, Samuel. Universidad Nacional AutĂłnoma de MĂ©xico; MĂ©xicoFil: Yunis, Edmond. Dana Farber Cancer Institute; Estados UnidosFil: Granados, Julio. Instituto Nacional de la NutriciĂłn Salvador Zubiran; MĂ©xicoFil: Corona, Teresa. Instituto Nacional de NeurologĂa y NeurocirugĂa; MĂ©xic
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HLA Class I and II Blocks Are Associated to Susceptibility, Clinical Subtypes and Autoantibodies in Mexican Systemic Sclerosis (SSc) Patients
<div><p>Introduction</p><p>Human leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results. These studies need to consider the genetic admixture of the studied population. Here we used our previously reported definition of genetic admixture of Mexicans using HLA class I and II DNA blocks to map genetic susceptibility to develop SSc and its complications.</p><p>Methods</p><p>We included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population.</p><p>Results</p><p>Our study revealed that class I block HLA-C*12:03-B*18:01 was important to map susceptibility to diffuse cutaneous (dc) SSc, HLA-C*07:01-B*08:01 block to map the susceptibility role of HLA-B*08:01 to develop SSc, and the C*07:02-B*39:05 and C*07:02-B*39:06 blocks to map the protective role of C*07:02 in SSc. We also confirmed previous associations of HLA-DRB1*11:04 and âDRB1*01 to susceptibility to develop SSc. Importantly, we mapped the protective role of DQB1*03:01 using three Amerindian blocks. We also found a significant association for the presence of anti-Topoisomerase I antibody with HLA-DQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage. The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients.</p><p>Conclusion</p><p>This is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc. Our findings suggest that HLA class I and class II genes contribute to the protection and susceptibility to develop SSc and its different clinical presentations as well as different autoantibody profiles in Mexicans.</p></div
Frequency of SSc-associated autoantibodies in our SSc patients.
<p>dcSSc: diffuse cutaneous systemic sclerosis, lcSSc: limited cutaneous systemic sclerosis, Anti-RNA Pol III: anti-RNA polymerase I/III.</p><p>Frequency of SSc-associated autoantibodies in our SSc patients.</p
HLA class II genes associations with specific autoantibodies in SSc.
<p>anti-RNAP I/III: anti-RNA polymerase I/III.</p><p>HLA class II genes associations with specific autoantibodies in SSc.</p
Demographic data and organ damage according to the modified Medsgerâs Severity Scale.
<p>dcSSc: diffuse cutaneous systemic sclerosis, lcSSc: limited cutaneous systemic sclerosis, ILD: interstitial lung disease; PAH: pulmonary arterial hypertension.</p><p>Demographic data and organ damage according to the modified Medsgerâs Severity Scale.</p
Principal component analysis (PCA) plot reveals a close genetic relationship of Mexican admixed SSc patients and healthy controls (HC) from Mexico City to Native American groups.
<p>Native American populations are represented in the upper left of the graphic and Caucasian components in the right bottom area of the graphic. Amerindian components are represented in the left bottom area. Red and blue dots represent difusse and limited SSc patients respectively and the total group in represented in green. The different populations included in the PCA analysis were: Ire: Ireland, Eng: England, Ger: Germany, Aus: Austria; Spa: Spain, Ita: Italy, UK: United Kingdom, Fra: France, Azo: Azores, Sao: SĂŁo TomĂ© Island, Cam: Cameroon, Mal: Mali, Zam: Zambia, KLu: Luo from Kenia, KNa: Nandi from Kenia, Sen: Senegal, Gui: Guinea Bissau, Tar: Tarahumara, Gil: Native Americans from Gila River, Yup: Yuâpik from Alaska, Mit: Mixtec from Oaxaca, Zap: Zapotec from Oaxaca, Mix: Mixe from Oaxaca, Ser: Seri from Sonora, Nav: Navajo from New Mexico, HC: âMexican Admixed controlsâ [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126727#pone.0126727.ref026" target="_blank">26</a>].</p
Frequencies of <i>HLA-C-B</i> blocks in 234 admixed Mexican individuals (468 haplotypes).
<p>Blocks of each ancestry (Amerindian, Caucasian, Caucasian shared with other populations, African, and Asian) were defined as those found in original populations with H.F. >1,0%, and not found in other native human groups in frequencies higher than 1,0%. We consider <i>t</i> value must be â„2.0 to denote statistically significant association and thus validate ÎâČ (shaded values).</p>*<p>Similar to B*35â¶01 with a mutation at codon 207 ggc>tgc (Gly>Cys).</p>§<p>Similar to C*03â¶04 with a mutation at codon 189 gtg>atg (Val>Met).</p
Allelic frequencies of <i>HLA-A, -B, -C, -DRB1</i>, and <i>-DQB1</i> in 234 Mexicans.
*<p>Similar to B*35â¶01 with a mutation at codon 207 ggc>tgc (Gly>Cys).</p>§<p>Similar to C*03â¶04 with a mutation at codon 189 gtg>atg (Val>Met).</p>â <p>Similar to DQB1*05â¶02 with a silent mutation at codon 133 cgg>cga.</p
HLA Conserved Extended Haplotypes in 234 Mexican admixed individuals (468 haplotypes).
<p>HLA Conserved Extended Haplotypes in 234 Mexican admixed individuals (468 haplotypes).</p