Targeted analysis of genomic regions enriched in African ancestry reveals novel classical HLA alleles associated with asthma in Southwestern Europeans

Eva Suarez-Pajes,Beatriz Guillen-Guio,Xiuwen Zheng,Rafaela González-Montelongo,Ariel Callero,Itahisa Marcelino-Rodríguez,Carlos Flores,Claudio Díaz-García,Eva Perez-Rodriguez,Héctor Rodríguez-Pérez,Jose C Garcia-Robaina,Almudena Corrales,Jose M Lorenzo-Salazar

doi:10.1038/s41598-021-02893-w

Abstract

Despite asthma has a considerable genetic component, an important proportion of genetic risks remain unknown, especially for non-European populations. Canary Islanders have the largest African genetic ancestry observed among Southwestern Europeans and the highest asthma prevalence in Spain. Here we examined broad chromosomal regions previously associated with an excess of African genetic ancestry in Canary Islanders, with the aim of identifying novel risk variants associated with asthma susceptibility. In a two-stage cases-control study, we revealed a variant within HLA-DQB1 significantly associated with asthma risk (rs1049213, meta-analysis p = 1.30 × 10–7, OR [95% CI] = 1.74 [1.41–2.13]) previously associated with asthma and broad allergic phenotype. Subsequent fine-mapping analyses of classical HLA alleles revealed a novel allele significantly associated with asthma protection (HLA-DQA1*01:02, meta-analysis p = 3.98 × 10–4, OR [95% CI] = 0.64 [0.50–0.82]) that had been linked to infectious and autoimmune diseases, and peanut allergy. HLA haplotype analyses revealed a novel haplotype DQA1*01:02-DQB1*06:04 conferring asthma protection (meta-analysis p = 4.71 × 10–4, OR [95% CI] = 0.47 [0.29– 0.73]).

Highlights

Asthma is a complex respiratory disease characterized by reversible airflow obstruction and chronic inflammation of the lower respiratory tract, usually linked to allergic and atopic manifestations[1]
Association testing focused on a total of 140,955 imputed genetic variants located on the five loci enriched in African ancestry in the Canary Islands population (2q21.2-q22.3, 3p25.3, 3q26.32, 6p22.3-p21.32, and 13q21.1q21.33)
This variant is in the 3′untranslated region (3′ UTR) of the Major Histocompatibility Complex (MHC), Class II, DQ Beta 1 gene (HLA-DQB1) (Supplementary Figure S1)

Summary

Introduction

Asthma is a complex respiratory disease characterized by reversible airflow obstruction and chronic inflammation of the lower respiratory tract, usually linked to allergic and atopic manifestations[1]. In recent years the number of genetic studies in admixed populations has increased considerably, the statistical power in many of them has not been sufficient due to the large sample sizes required by GWAS to overcome the stringent significance penalties, making screening for asthma-related genes in admixed populations still a challenge[10]. The average proportion with which each parental group contributes to the genome of an admixed individual is known as global genetic ancestry, whereas the local genetic ancestry is defined as the ancestry proportion of each particular locus Studies such as admixture mapping studies allow to reveal genomic regions where local ancestry correlates with disease risk, and the main challenge remains in the subsequent fine mapping studies of these regions to identify the causal variants[17,21]. As a matter of fact, we recently performed an admixture mapping of asthma in this population, revealing a novel locus associated with asthma risk[16]

Methods

Results

Discussion

Conclusion