Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype

Abstract

Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95–19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27–547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22–438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91–0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01–9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45–79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12–117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52–519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14–142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94–89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77–804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88–0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31–100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01–9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

Phenotype wide association study links bronchopulmonary dysplasia with eosinophilia in children

“…33,34 Aligning with our genetic ndings, decreased sST2 levels have been implicated in asthma with type 2 in ammation. 34,35 These observations have led to ongoing efforts to develop pharmacological interventions targeting IL-33-ST2L signaling for use in asthma. 36 Paradoxically, increased as opposed to decreased sST2 expression has been found in patients with asthma and type 2 in ammation.…”

IL1RL1 polymorphisms rs12479210 and rs1420101 are associated with increased lung cancer risk in the Chinese Han population

“…Second, we downloaded ped and info files of mutation sites in IL1RL1 in the Chinese Han Beijing (CHB) population from 1000 Genome Project through VCF to PED Converter window ( http://grch37.ensembl.org/Homo Sapiens/Tools/VcftoPed), and we used Haploview software to screen SNPs with Hardy-Weinberg equilibrium (HWE) > 0.05, minor allele frequency (MAF) > 0.05, and min genotype frequency >75%, r 2 > 0.8. Finally, based on previous studies associated with respiratory diseases ( Ferreira et al, 2011 ; Shrine et al, 2019 ; Sun et al, 2019 ; Wu et al, 2021 ; Li et al, 2022 ; Rojo-Tolosa et al, 2023 ) and primer design, a total of six SNPs in the IL1RL1 gene were randomly selected ( Supplementary Table S1 ). The potential role of SNPs was predicted using RegulomeDB ( https://regulomedb.org/ ), HaploReg ( https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php ), and Genotype-Tissue Expression (GTEx) Portal databases ( https://gtexportal.org ).…”

“…05, and min genotype frequency >75%, r 2 > 0.8. Finally, based on previous studies associated with respiratory diseases (Ferreira et al, 2011;Shrine et al, 2019;Sun et al, 2019;Wu et al, 2021;Li et al, 2022;Rojo-Tolosa et al, 2023) and primer design, a total of six SNPs in the IL1RL1 gene were randomly selected (Supplementary Table S1). The potential role of SNPs was predicted using RegulomeDB (https://regulomedb.org/), HaploReg (https://pubs.broadinstitute.org/mammals/haploreg/ haploreg.php), and Genotype-Tissue Expression (GTEx) Portal databases (https://gtexportal.org).…”