Variants in ARID5B Gene Are Associated with the Development of Acute Lymphoblastic Leukemia in Mexican Children
Authors: Reyes-León Adriana , Fernández-García Diana , Ramírez-Martínez Maribel , Amaro-Muñoz David , Velázquez-Aragón José Antonio , Salas-Labadía Consuelo , Zapata-Tarres Marta , Velasco-Hidalgo Liliana , Lopez-Santiago Norma , López-Ruíz Mayra Ivette , Malavar-Guadarrama Mónica Anabell , Cardenas-Cardos Rocio , Paredes-Aguilera Rogelio Alejandro , Dean Michael , Rivera-Luna Roberto , Perez-Vera Patricia 
Published: October 2019

Abstract
Introduction: Acute lymphoblastic leukemia (ALL) is the most common subtype of leukemia diagnosed in children under 18 years. According to the statistics of the Popular Medical Insurance Program in Mexico, the ALL incidence is 79.8 cases per million per year, and it is significantly increasing. Recently, several SNPs of ARID5B gene have been associated with ALL susceptibility and are more strongly related with ALL risk in Hispanics. However, these observations are not necessarily representative of the situation in Mexico, since the proportion of Mexican patients included in these studies is unknown. It is essential for us to know if the genetic variants of ARID5B confer susceptibility to the development of the disease in our population and if these variants contribute to the higher incidence of childhood ALL in Mexico.
Aim: The purpose of this study was to determine the association between the SNPs rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488 of ARID5B gene with the susceptibility to develop ALL in Mexican children.
Methods: The study included 384 controls and 298 children with ALL recruited at Instituto Nacional de Pediatria in Mexico city and Hospital de Especialidades Pediatricas de Tuxtla Gutierrez, Chiapas, Mexico. This study was reviewed and approved by the Institutional Research and Ethics Committees from both participant Institutions in accordance to the ethical principles of the Declaration of Helsinki. Volunteers, parents, or legal tutors of patients were previously informed about the study, and before the biological samples were collected, they provided a signed, written informed consent letter to participate. Genomic DNA was extracted from peripheral blood and saliva samples. Genotyping analysis was performed by real-time polymerase chain reaction (RT-PCR) using a pre-designed TaqMan assay for 7 SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488) of ARID5B. Genotypic and allelic frequencies were calculated to compare the differences between controls and patients (Fisher's exact test). The odds ratio (OR) was calculated to determine the association between SNPs and ALL susceptibility. Ancestry analysis was conducted for controls and patients (STRUCTURE program), and Haplotype analysis (Haploview program).
Results: The estimated proportion of Native American and European ancestry was not statistically different between controls and patients; all SNPs in ARID5B were in Hardy-Weinberg equilibrium. The frequency of the risk alleles was higher in patients than in controls, but only 3 SNPs showed statistically significant differences (p<0.05). The SNPs rs10821936, rs10994982, and rs7089424 were associated with ALL and pre-B ALL susceptibility, and rs2393732 was specifically associated with pre-B ALL. No association betwwen SNPs of ARID5B gene and T-ALL was found. The CAG haplotype (rs10821936, rs10994982, and rs7089424) was strongly associated with ALL risk in our population. The SNPs rs10821936, rs10994982, rs7089424, and rs2393732 were significantly associated with an increased risk for developing childhood ALL, specifically pre-B ALL.
Conslusions: The frequency of the risk alleles was higher than in Hispanic children with ALL.
Each SNP of ARID5B confers an individual effect on the risk for developing the disease, and the CAG haplotype was strongly associated with ALL susceptibility.
The genetic background of our population could be positively influencing the susceptibility to ALL development, specifically pre-B ALL.
The SNPs rs10821936, rs10994982, rs7089424 and rs2393732 of ARID5B gene are significantly associated with an increased risk to develop childhood ALL and this could also explain in part the high incidence of childhood ALL in Mexico.
Acknowledgments: This work was supported by the grants from Fondos del Presupuesto Federal para la Investigación (project 085/2012), Consejo Nacional de Ciencia y Tecnologia (CONACyT) - Desarrollo Cientifico para Atender Problemas Nacionales (project 216163), and in part by the Intramural Program of the National Cancer Institute.
Conflict-of-interest disclosure: The authors state that there are no conflicts of interest.

Disclosures
No relevant conflicts of interest to declare.