Does HLA explain the high incidence of childhood-onset type 1 diabetes in the Canary Islands? The role of Asp57 DQB1 molecules
Authors: Nóvoa-Medina Yeray , Marcelino-Rodriguez Itahisa , Suárez Nicolás M. , Barreiro-Bautista Marta , Rivas-García Eva , Sánchez-Alonso Santiago , González-Martínez Gema , Quinteiro-González Sofía , Domínguez Ángela , Cabrera María , López Sara , Pavlovic Svetlana , Flores Carlos ,   Gran Canarian Diabetes and Obesity Research Group, Rodriguez-Benitez Carlota , Ageno-Alemán Héctor , Perera-Hernández Cristina , de Elejabeitia-Cortezo Catalina , Franco-Mateu Nieves , Rodríguez Gonzalez Ana María , Leon-Olmo Victor Manuel , Aitoutouhen-Infante Fátima , Pérez-López Sade , Alonso-Falcón Saula del Pino , Bolaños-Alzola Acoraida , García-Suárez Zeltia , Perdomo-Delgado Inés , Ayala-Martínez Sara , Valenzuela-Alvarez Laura , Caballero-Estupiñán Elena , Rúa-Figueroa Celia , Travieso-Hermoso Claudia , García-Delgado Yaiza , Azcoitia Pablo , Arroyo Sara Quintana , Rodríguez Carlos , López-Plasencia Yaiza , Pérez-Martín Nuria , Sánchez-Hernández Rosa María , López-Madrazo María José , Déniz Alejandro , Tozzi Rossella , Boronat-Cortés Mauro , Valverde-Tercedor Carmen , Zamora-Zamorano Garlene , Jiménez-Monzón Roberto , Hernández-Baeza Luisa , Dávila-Batista Verónica , Gil Yaiza , Gil Jorge Oliver , Soage-Villegas Romina , Bueno-Montoro Sofia , Guanche-Sicilia Aitana , Santos-Morán Brenda , Santana-Medina Jesús , Ojeda-Elías Sofía , Melian-Cordovez Beatriz , Corona-Lopez Marina , Macías-Dolz Marta , Betancort-Avero Saray , Rodriguez-Déniz Samuel , Puga-Morales Ana , Bowler-Parminter Rose , Ferrera Fernandez María de los Angeles , Rodriguez-Sánchez Rocio , Wägner Ana M. 
Published: September 2024

Abstract
The Canary Islands inhabitants, a recently admixed population with significant North African genetic influence, has the highest incidence of childhood-onset type 1 diabetes (T1D) in Spain and one of the highest in Europe. HLA accounts for half of the genetic risk of T1D.

Aims
To characterize the classical HLA-DRB1 and HLA-DQB1 alleles in children from Gran Canaria with and without T1D.

Methods
We analyzed classic HLA-DRB1 and HLA-DQB1 alleles in childhood-onset T1D patients (n = 309) and control children without T1D (n = 222) from the island of Gran Canaria. We also analyzed the presence or absence of aspartic acid at position 57 in the HLA-DQB1 gene and arginine at position 52 in the HLA-DQA1 gene. Genotyping of classical HLA-DQB1 and HLA-DRB1 alleles was performed at two-digit resolution using Luminex technology. The chi-square test (or Fisher's exact test) and odds ratio (OR) were computed to assess differences in allele and genotype frequencies between patients and controls. Logistic regression analysis was also used.

Results
Mean age at diagnosis of T1D was 7.4 ± 3.6 years (46% female). Mean age of the controls was 7.6 ± 1.1 years (55% female). DRB1*03 (OR = 4.2; p = 2.13–13), DRB1*04 (OR = 6.6; p ≤ 2.00–16), DRB1* 07 (OR = 0.37; p = 9.73–06), DRB1*11 (OR = 0.17; p = 6.72–09), DRB1*12, DRB1*13 (OR = 0.38; p = 1.21–05), DRB1*14 (OR = 0.0; p = 0.0024), DRB1*15 (OR = 0.13; p = 7.78–07) and DRB1*16 (OR = 0.21; p = 0.003) exhibited significant differences in frequency between groups. Among the DQB1* alleles, DQB1*02 (OR: 2.3; p = 5.13–06), DQB1*03 (OR = 1.7; p = 1.89–03), DQB1*05 (OR = 0.64; p = 0.027) and DQB1*06 (OR = 0.19; p = 6.25–14) exhibited significant differences. A total of 58% of the studied HLA-DQB1 genes in our control population lacked aspartic acid at position 57.

Conclusions
In this population, the overall distributions of the HLA-DRB1 and HLA-DQB1 alleles are similar to those in other European populations. However, the frequency of the non-Asp-57 HLA-DQB1 molecules is greater than that in other populations with a lower incidence of T1D. Based on genetic, historical and epidemiological data, we propose that a common genetic background might help explain the elevated pediatric T1D incidence in the Canary Islands, North-Africa and middle eastern countries.