title: 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.
authors.affiliation: Laboratory of Immunopharmacology and Molecular Biology, Federal University of Bahia, Salvador, Brazil.
authors.forename: G A
authors.initials: GA
authors.lastname: Queiroz
authors.affiliation: Laboratory of Immunopharmacology and Molecular Biology, Federal University of Bahia, Salvador, Brazil.
authors.forename: R S
authors.initials: RS
authors.lastname: Costa
authors.affiliation: Laboratory of Allergy and Acarology, Federal University of Bahia, Salvador, Brazil.
authors.forename: N M
authors.initials: NM
authors.lastname: Alcantara-Neves
authors.affiliation: Laboratory of Immunopharmacology and Molecular Biology, Federal University of Bahia, Salvador, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Nunes de Oliveira Costa
authors.affiliation: Department of Epidemiology, Oswaldo Cruz Fundation, Salvador, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Barreto
authors.affiliation: Laboratory of Immunopharmacology and Molecular Biology, Federal University of Bahia, Salvador, Brazil.
authors.forename: V L
authors.initials: VL
authors.lastname: Carneiro
authors.affiliation: Laboratory of Immunopharmacology and Molecular Biology, Federal University of Bahia, Salvador, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Figueiredo
mesh_terms: D000818:Animals; D001249:Asthma / Q000097:blood / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D006969:Hypersensitivity, Immediate / Q000235:genetics; D007073:Immunoglobulin E / Q000097:blood; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics*; D000067596:Interleukin-33 / Q000235:genetics*; D015848:Interleukin-5 / Q000235:genetics; D008297:Male; D008925:Mites / Q000276:immunology / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide; D012867:Skin / Q000276:immunology / Q000382:microbiology; D018418:Th2 Cells
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C508599:IL5 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015848:Interleukin-5; D007073:Immunoglobulin E