Document resource
Background Adult women have a higher prevalence and greater severity of asthma, along with increased asthma-related mortality compared to men, yet the underlying molecular and genetic mechanisms remain poorly understood.Methods To investigate sex-specific characteristics and mechanisms in asthma, we analysed clinical, transcriptomic, proteomic, metabolomic, and metagenomic data from 568 adult participants in the pan-European U-BIOPRED cohort. Differential expression analysis, functional enrichment analysis, and weighted gene co-expression network analysis (WGCNA) were conducted.Results In mild/moderate asthma, clinical characteristics among women and men were largely comparable, but women exhibited a higher prevalence of type 2-low phenotypes ( p = 0.013), characterised by lower FeNO levels (p < 0.001) and reduced blood eosinophil counts (p = 0.004). Women also showed higher CRP levels (p = 0.042) and prevalence of a history of lung infections (p = 0.026). In severe asthma, sex-related differences were more pronounced. Men with severe asthma displayed more pronounced pulmonary dysfunction, including greater declines in spirometry values (p < 0.001), increased residual volume (p < 0.001), and elevated mucin production. In contrast, women with severe asthma experienced a greater symptom burden (p = 0.005) and more frequent exacerbations (p = 0.005), along with an increased prevalence of comorbidities, including allergic rhinitis and psychiatric disorders. In women with severe asthma, bronchial biopsy transcriptomic analysis revealed enhanced airway remodelling and impaired mitochondrial and ciliary function, while blood transcriptomics indicated stronger innate and adaptive immune responses with enhanced T-cell activation. Moreover, proteomic analysis showed heightened type 2 immune activity in female patients with severe asthma, evidenced by increased expression of TSLP, CCL11, and increased GZMB, suggesting increased cytotoxicity. Sputum metagenomic profiling further revealed a higher prevalence of airway infections in women with severe asthma, with a higher prevalence of Haemophilus, Moraxella, and Pseudomonas species. Clinical data and metabolomic analyses showed comparable medication usage and corticosteroid adherence between sexes. Interestingly, circulating androgen levels were inversely associated with asthma severity in both sexes.Abstract T4 Table 1Sex differences in clinical characteristics of mild/moderate asthma, severe asthma, and healthy controls Characteristics Healthy controls Mild/moderate asthma Severe asthma Female Male p-value* Female Male p-value# Female Male p-value& Subjects, n 39 62 44 44 237 142 Age, years 40.3 ± 2.2 38.0 ± 1.7 0.399 41.5 ± 2.2 41.8 ± 2.5 0.924 50.4 ± 0.9 54.6 ± 1.1 0.004 Age at diagnosis, years NA NA NA 16 (5, 34) 13 (6, 28) 0.956 23 (9, 40) 30 (8, 44) 0.139 Race, Caucasian 3/39 (7.7%) 4/62 (6.5%) 1.000 41/44 (93.2%) 41/44 (93.2%) 1.000 213/237 (89.9%) 129/142 (90.8%) 0.897 BMI, kg·m-2 23.8 ± 0.54 26.3 ± 0.44 0.001 25.2 ± 0.71 26.3 ± 0.63 0.255 30.0 ± 0.45 28.5 ± 0.44 0.026 Ex-smokers/non-smokers, n 11/28 9/53 0.154 7/37 6/38 1.000 62/175 53/89 0.030 Smoking history, pack-years 1.0 [0.6, 3.5] 0.7 [0.2, 3.0] 0.447 3.5 [1.4, 4.1] 4.3 [1.5, 4.9] 0.352 5.2 [2.0, 14.8] 13.0 [4.0, 23.0] 0.018 Spirometry Pre-bronchodilator FEV1,% pred 98.4 [92.7, 107.2] 104.3 [95.7, 111.2] 0.180 92.3 [81.8, 101.8] 91.6 [73.1, 100.6] 0.387 70.2 [52.4, 86.4] 62.7 [48.3, 77.3] 0.010 Pre-bronchodilator FVC,% pred 108.1 [99.7, 120.1] 108.7 [100.8, 114.5] 0.594 108.3 [97.3, 113.2] 104.2 [86.8, 118.5] 0.325 88.8 [75.9, 103.2] 84.8 [73.5, 97.1] 0.043 Pre-bronchodilator FEV1/FVC,% 79.8 [74.9, 83.3] 80.1 [75.3, 82.8] 0.810 75.5 [70.1, 78.8] 71.3 [63.7, 77.4] 0.094 66.7 [56.2, 75.9] 61.3 [49.2, 68.6] <0.001 Pre-bronchodilator FEF25–75%,% pred 70.9 [62.4, 95.4] 85.80 [73.1, 104.7] 0.034 60.9 [43.1, 70.1] 59.7 [44.2, 69.4] 0.932 32.1 [19.1, 52.7] 29.6 [17.6, 45.9] 0.370 Change in FEV1, post-salbutamol,% NA NA NA 7.9 [4.5, 13.4] 12.3 [6.7, 21.1] 0.009 14.0 [6.3, 22.7] 13.4 [5.2, 19.7] 0.201 Body plethysmography Airflow limitation,% 0/39 (100.0%) 0/62 (100.0%) NA 5/44 (11.4%) 10/44 (22.7%) 0.257 113/237 (47.7%) 79/142 (55.6%) 0.164 TLC,% pred 107 [96, 114] 101 [95, 107] 0.051 106 [97, 123] 106 [97, 117] 0.581 110 [100, 122] 106 [94, 112] 0.003 RV/TLC,% pred 1.6 [1.5, 1.8] 1.7 [1.4, 2.1] 0.467 1.6 [1.4, 1.9] 2.0 [1.8, 2.5] 0.001 2.2 [1.8, 2.5] 2.9 [2.5, 3.3] <0.001 sGaw, kPa-1·s-1 1.5 [1.1, 2.0] 1.7 [1.1, 2.3] 0.438 1.4 [1.1, 2.6] 1.1 [0.7, 1.8] 0.118 0.7 [0.4, 1.1] 0.8 [0.4, 1.1] 0.383 Biomarkers Blood eosinophils, 109/L 0.1 [0.06, 0.2] 0.1 [0.1, 0.2] 0.521 0.1 [0.1, 0.3] 0.2 [0.1, 0.3] 0.004 0.2 [0.1, 0.4] 0.2 [0.1, 0.4] 0.686 Blood neutrophils, 109/L 3.3 [2.7, 5.2] 2.9 [2.3, 3.9] 0.032 3.2 [2.9, 4.5] 3.3 [2.7, 4.3] 0.720 5.0 [3.7, 6.7] 4.7 [3.7, 7.1] 0.868 Sputum eosinophils,% 0.0 [0.0, 0.4] 0.2 [0.0, 0.2] 0.640 0.7 [0.2, 3.4] 1.1 [0.2, 3.0] 0.477 3.3 [0.6, 19.4] 2.4 [0.4, 16.1] 0.827 Sputum neutrophils,% 29.3 [16.5, 41.3] 42.6 [21.2, 68.7] 0.129 44.5 [27.5, 68.7] 39.1 [23.4, 60.8] 0.509 52.5 [32.2, 71.0] 57.4 [39.0, 84.8] 0.112 FeNO, ppb 16.3 [12.4, 21.6] 21.8 [15.0, 32.3] 0.017 20.0 [15.0, 28.4] 39.0 [22.0, 63.0] <0.001 24.0 [14.0, 47.3] 29.0 [20.5, 53.0] 0.013 IgE, IU/ml 16.0 [7.0, 45.2] 31.0 [10.0, 85.0] 0.143 100.0 [45.0, 188.0] 88.7 [61.2, 307.0] 0.230 108.0 [41.0, 313.1] 128.0 [51.8, 387.0] 0.055 CRP, mg/L 1.0 [0.4, 2.2] 0.6 [0.3, 1.4] 0.156 1.1 [0.5, 2.6] 0.6 [0.3, 1.1] 0.042 2.5 [1.1, 5.1] 1.9 [0.9, 4.6] 0.100 Symptoms ACQ5 NA NA NA 4.0 [2.0, 5.0] 4.5 [1.1, 7.8] 0.434 12.0 [8.0, 16.0] 10.0 [5.0, 14.0] 0.005 AQLQ NA NA NA 196.0 [172.0, 207.0] 198.0 [172.5, 209.0] 0.918 142.0 [112.3, 166.8] 153.0 [121.0, 183.5] 0.013 Exacerbations Exacerbations (past year), n NA NA NA 0.0 [0.0, 1.0] 0.0 [0.0, 0.0] 0.163 2.0 [1.0, 3.0] 2.0 [0.0, 3.0] 0.005 Severe exacerbations (past year), n NA NA NA 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.24 2.0 [1.0, 3.0] 1.0 [0.0, 2.0] 0.011 Medical histories Pneumonia or bronchitis 0/39 (0.0%) 0/62 (0.0%) NA 13/41 (31.7%) 4/42 (9.5%) 0.026 147/226 (65.0%) 78/134 (41.8%) 0.237 Emphysema or COPD 0/39 (0.0%) 0/62 (0.0%) NA 1/44 (2.3%) 2/44 (4.5%) 1.000 13/234 (5.6%) 6/141 (4.3%) 0.754 Comorbidities Allergic rhinitis diagnosed 1/38 (2.6%) 4/58 (6.9%) 0.653 22/43 (51.2%) 20/39 (51.3%) 1.000 129/224 (57.6%) 57/134 (42.5%) 0.008 Eczema diagnosed 3/39 (7.7%) 2/62 (3.2%) 0.592 15/43 (34.9%) 10/44 (22.7%) 0.310 79/234 (33.8%) 43/142 (30.3%) 0.559 GORD diagnosed 1/39 (2.6%) 3/62 (4.8%) 0.963 10/44 (22.7%) 6/43 (14.0%) 0.436 121/229 (52.8%) 54/140 (38.6%) 0.011 Hay fever diagnosed 1/38 (2.6%) 9/61 (14.8%) 0.109 25/44 (56.8%) 21/41 (51.2%) 0.764 107/224 (47.8%) 55/140 (39.3%) 0.140 Nasal polyps diagnosed 1/39 (2.6%) 2/61 (3.3%) 1.000 4/44 (9.1%) 3/44 (6.8%) 1.000 59/233 (25.3%) 69/139 (49.6%) <0.001 Non-allergic rhinitis diagnosed 0/39 (0.0%) 1/61 (1.6%) 1.000 5/42 (11.9%) 3/42 (7.1%) 0.710 32/229 (14.0%) 22/137 (16.1%) 0.695 Psychiatric disease diagnosed 3/39 (7.7%) 2/62 (3.2%) 0.592 7/44 (15.9%) 0/44 (0.0%) 0.018 30/237 (12.7%) 5/142 (3.5%) 0.005 Medications ICS NA NA NA 44/44 (100.0%) 43/44 (97.7%) 1.000 229/229 (100.0%) 138/139 (99.3%) 1.000 OCS NA NA NA 0/44 (0.0%) 0/44 (0.0%) NA 121/234 (51.7%) 78/141 (55.3%) 0.568 OCS dose, prednisolone (equ.) mg NA NA NA NA NA NA 16.4±11.0 15.7±10.7 0.667 SABA NA NA NA 30/44 (68.2%) 37/44 (84.1%) 0.132 197/232 (84.9%) 103/139 (74.1%) 0.015 LABA NA NA NA 2/44 (4.5%) 2/44 (4.5%) 1.000 226/229 (98.7%) 137/139 (98.6%) 1.000 Antibiotic NA NA NA 0/44 (0.0%) 0/44 (0.0%) NA 53/234 (22.6%) 27/142 (19.0%) 0.481 LAMA NA NA NA 0/44 (0.0%) 0/44 (0.0%) NA 50/230 (21.7%) 36/141 (25.5%) 0.475 Omalizumab NA NA NA 0/44 (0.0%) 0/44 (0.0%) NA 36/236 (15.3%) 16/141 (11.3%) 0.363 LTM NA NA NA 0/44 (0.0%) 0/44 (0.0%) NA 100/232 (43.1%) 63/142 (44.4%) 0.895 *Compare between female and male healthy controls; #Compare between female and male mild/moderate asthma; &Compare between female and male severe asthma. Abbreviations: ACQ5: Asthma Control Questionnaire-5; AQLQ: Asthma Quality of Life Questionnaire; BMI: body mass index; COPD: chronic obstructive pulmonary disease; CRP: C-reactive protein; FEF25–75%: forced expiratory flow at 25% and 75% of the pulmonary volume; FeNO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; GORD: Gastro-oesophageal reflux disease; LABA: long-acting β-agonist; LAMA: long-acting muscarinic antagonist; IgE: immunoglobulin E; ICS: Inhaled corticosteroids; LTM: Leukotriene modifier; NA: not applicable; OCS: oral corticosteroids; RV: residual volume; SABA: short-acting β-agonist; sGAW: specific airway conductance; TLC: total lung capacity.Conclusions This large-scale multi-omics study reveals significant sex differences in asthma pathophysiology. Sex specific immunopathological differences suggest sex may be relevant to the choice of biologic.On behalf of the UBIOPRED collaboration.