Genetic variants in RORA are associated with asthma and allergy markers in an admixed population

Abstract

Asthma and allergy affect hundreds of millions of people from childhood to old age. In most of them, the inflammatory process of respiratory allergies involves the participation of type 2 cytokines, derived from T helper-2 (Th2)-cell, and Group 2 Innate Lymphoid (ILC2) Cells. An efficient memory Th2 cell response is dependent on IL-13 produced by ILC2s, causing allergic lung inflammation and elevated serum levels of immunoglobulin E. ILC2 cells are derived from common lymphoid progenitors and their growing depends on the transcription factor RORA. The aim of this work was to identify genetic variants in RORA associated with asthma phenotypes and allergy markers. Genomic DNA samples of 1246 individuals participating from Social Changes Asthma and Allergy in Latin America Program (SCAALA) have been genotyped using Illumina Human 2.5 Omni Beadchip. Logistics regressions have been performed to analyze the association among RORA variants and asthma, skin prick tests (SPT), specific IgE and type 2 cytokine production. Twelve single nucleotide variants (SNVs) were significantly associated with atopy (P < 0.01), in which four of them, rs10162630, rs17191519, rs17270243, and rs55796775 and their haplotypes were strongly and positively associated (P < 0.001). Furthermore, these variants increased the RORA gene expression in silico analysis. Other SNVs in RORA were associated with allergy markers, atopic and non-atopic asthma. Therefore, it is believed that variants in RORA gene may influence immunologic features of asthma and allergies and could be possible targets for future treatment of allergic diseases.

Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

“…Four of the SNPs correlated with levels of tIgE in asthmatics (with the asthma risk allele associated with increased levels of tIgE, Supplementary Table 19), suggesting that these asthma risk alleles may lead to an increased Th2 immune response. This includes SNP rs1420101 in the IL1R1 locus (a gene that is known to correlate with eosinophilia 35 ), SNP rs10519067 intronic to the RORA gene (encoding a transcription factor that regulates the growth of group 2 innate lymphoids, a key cell type in the memory Th2 cell response 36 ), and SNPs rs907092 and rs2952156 in the chr17q12–21 locus. These results are consistent with previous studies that have shown both shared and unique associations between these phenotypes 37–41 .…”

The Cytokines of Asthma

“…Finally, genetic studies of asthma show that certain polymorphisms promote ILC2 development. Specifically, polymorphisms in the 15q22.2 locus are associated with asthma risk, particularly therapy-resistant asthma, and this locus contains the RORA gene that codes for the RAR-related orphan receptor-a (ROR-a) transcription factor that controls ILC2 development (Lima et al, 2019;Persson et al, 2015). Some cautionary notes about all these studies describing the presence or activation of ILC2s in asthmatics are that ILC2s are a scarce population of lymphocytes that can be contaminated by CD4 adaptive lymphocytes that downregulate TCR expression (Hinks et al, 2017) and that ILC2s are quite flexible cells that can differentiate into IFN-g-producing ILC1s in periods of exacerbation (Ohne et al, 2016;Silver et al, 2016).…”

High retinoic acid receptor-related orphan receptor A gene expression in peripheral blood leukocytes may be related to acute myocardial infarction

“…The Th2 response is derived from interleukin-13 produced by ilc2, while ilc2 cells are derived from normal lymphoid progenitor cells, and their growth depends on RORA. 20 AMI is an inflammatory disease. Inflammation increases the incidence of complications of AMI and increases the mortality rate of patients.…”

“…growth depends on RORA. 20 AMI is an inflammatory disease. Inflammation increases the incidence of complications of AMI and increases the mortality rate of patients.…”