IL33 and IL1RL1 variants are associated with asthma and atopy in a Brazilian population

Abstract

Atopic asthma is a chronic inflammatory disease in airways resulting from genetic and environmental factors, characterized by production of the Th2 cytokines interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13). Interleukin-33 (IL-33) appears to be a potent inducer of Th2 immune response. This occurs when IL-33 binds and activates its receptor, the membrane ST2 (ST2L) in mast cells, dendritic cells, basophils, eosinophils, innate lymphoids and Th2 cells, leading to the release of these cytokines and intensifying allergic inflammation. Polymorphisms in the IL33 and IL1RL1 can act as protective or risk factors for asthma and/or allergy in humans. No study was conducted to replicate such findings in a European and African descendent mixed population. DNA was extracted from peripheral blood from 1223 subjects, and the samples were genotyped using Illumina 2.5 Human Omni Beadchip. We tested for possible associations between SNPs in the IL33 and ST2 with asthma and allergy markers such as specific IgE (sIgE), IL-5 and IL-13 production and skin prick test (SPT). Logistics regressions were performed using PLINK software 1.07. The analyses were adjusted for sex, age, helminth infection and ancestry markers. The G allele of IL33 SNP rs12551256 was negatively associated with asthma (OR 0.71, 95% CI: 0.53-0.94, P = 0.017). In contrast, the A allele of IL1RL1 rs1041973 was positively associated with IL-5 production (OR 1.36, 95% CI: 1.09-1.84, P = 0.044), sIgE levels (OR 1.40, 95% CI: 1.07-1.84, P = 0.013) and positive SPT (OR 1.48, 95% CI: 1.08-2.03, P = 0.014), for Blomia tropicalis mite. The same allele, in atopic subjects, was associated with decreased production of soluble ST2 (sST2) (P < 0.05). Moreover, expression quantitative trait loci (eQTL) analysis suggests that rs1041973 and rs873022 regulate the expression of IL1RL1 gene. This latest SNP, rs873022, the T allele, was also associated with a lower production of sST2 in plasma of Brazilians. The genetic risk score for rs1041973 and rs16924161 demonstrated a higher risk for SPT positivity against B. tropicalis, the greater the number of risk alleles for both SNPs. Our findings demonstrate a robust association of genetic variants in IL1RL1 and IL33 SNPs with allergy markers and asthma.

The family of the interleukin‐1 receptors

“…A strong linkage of the loci for IL‐1R4, as well as its ligand IL‐33, has been reported especially for allergic asthma (reviewed in ), and recent studies underscore this finding in different populations. Loss‐of‐function mutations in IL‐33 in allergic patients as well as in IL‐1R4 were identified, supporting the findings in genome‐wide association studies that identified the IL‐33/IL‐1R4 pathway as the most relevant factor in allergy . Besides allergic asthma, increased levels of IL‐33 have been found in many disorders associated with acute or chronic inflammation (reviewed in ) such as in the intestine (reviewed in ) and arthritis.…”

“…Loss-of-function mutations in IL-33 in allergic patients 193 as well as in IL-1R4 [194][195][196] were identified, supporting the findings in genome-wide association studies that identified the IL-33/IL-1R4 pathway as the most relevant factor in allergy. 190 Besides allergic asthma, increased levels of IL-33 have been found in many disorders associated with acute or chronic inflammation (reviewed in 197) such as in the intestine (reviewed in 198) and arthritis.…”

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

“…The analyses were performed under an additive model and the Odds Ratio (OR) was estimated, as well as 1000 permutations procedures was used to estimate the statistical significance of multiple correlation tests in the genetic association analysis [29,30]. Results obtained from this analysis having a confidence interval of 99.0% and a P-value less than 0.01 were considered statistically significant.…”

Interleukin‐33 polymorphisms and serum concentrations in mycosis fungoides

“…IL‐33 is also implicated in allergy and asthma . For example, single nucleotide polymorphisms (SNPs) in the IL‐33 gene were associated with the development of allergic rhinitis and asthma . IL‐33/ST2 signaling may also promote local progression and metastasizing of myeloproliferative neoplasms, gastric cancer, colon cancer, and breast cancer …”