Heterogeneity of Genetic Admixture Determines SLE Susceptibility in Mexican

Susana Hernández-Doño; Juan Jakez-Ocampo; José Eduardo Márquez-García; Daniela Ruiz; Víctor Acuña-Alonzo; Guadalupe Lima; Luis Llorente; Víctor Hugo Tovar-Méndez; Rafael García-Silva; Julio Granados; Joaquín Zúñiga; Gilberto Vargas-Alarcón

doi:10.3389/fgene.2021.701373

Heterogeneity of Genetic Admixture Determines SLE Susceptibility in Mexican

Front Genet. 2021 Aug 3:12:701373. doi: 10.3389/fgene.2021.701373. eCollection 2021.

Affiliations

¹ Immunogenetics Division, Department of Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
² Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
³ Molecular Biology Core Facility, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
⁴ Department of Dermatology, Hospital General Dr. Manuel Gea González, Mexico City, Mexico.
⁵ Laboratory of Physiology, Biochemistry, and Genetics, Escuela Nacional de Antropología e Historia, Mexico City, Mexico.
⁶ Department of Endocrinology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁷ Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁸ Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
⁹ Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico.
¹⁰ Research Direction, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City, Mexico.

Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well identified as risk factors. SLE patients present different clinical phenotypes, which are partly explained by admixture patterns variation among Mexicans. Population genetic has insight into the high genetic variability of Mexicans, mainly described through HLA gene studies with anthropological and biomedical importance. A prospective, case-control study was performed. In this study, we recruited 146 SLE patients, and 234 healthy individuals were included as a control group; both groups were admixed Mexicans from Mexico City. The HLA typing methods were based on Next Generation Sequencing and Sequence-Based Typing (SBT). The data analysis was performed with population genetic programs and statistical packages. The admixture estimations based on HLA-B and -DRB1 revealed that SLE patients have a higher Southwestern European ancestry proportion (48 ± 8%) than healthy individuals (30 ± 7%). In contrast, Mexican Native American components are diminished in SLE patients (44 ± 1%) and augmented in Healthy individuals (63 ± 4%). HLA alleles and haplotypes' frequency analysis found variants previously described in SLE patients from Mexico City. Moreover, a conserved extended haplotype that confers risk to develop SLE was found, the HLA-A^∗29:02∼C^∗16:01∼B^∗44:03∼DRB1^∗07:01∼DQB1^∗02:02, pC = 0.02, OR = 1.41. Consistent with the admixture estimations, the origin of all risk alleles and haplotypes found in this study are European, while the protection alleles are Mexican Native American. The analysis of genetic distances supported that the SLE patient group is closer to the Southwestern European parental populace and farthest from Mexican Native Americans than healthy individuals. Heterogeneity of genetic admixture determines SLE susceptibility and protection in Mexicans. HLA sequencing is helpful to determine susceptibility alleles and haplotypes restricted to some populations.

Keywords: HLA; HLA-DRB1∗03:01; Mexican; admixture; conserved extended haplotype; heterogeneity; population genetics.