Nasal epithelium as a proxy for bronchial epithelium for smoking-induced gene expression and expression Quantitative Trait Loci

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 1; pp. 314 - 317.e15
• Main Authors: Imkamp, Kai, Berg, Marijn, Vermeulen, Cornelis J., Heijink, Irene H., Guryev, Victor, Kerstjens, Huib A.M., Koppelman, Gerard H., van den Berge, Maarten, Faiz, Alen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2018; Elsevier Limited
• Subjects: Airway management; Asthma; Epithelium; Gene expression; Genome-wide association studies; Genomes; Quantitative trait loci; Smoking; Studies
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.01.047

Recent studies have suggested that nasal brushings may provide a less invasive source of airway epithelial cells that closely approximate the bronchial airways.1-3 This approach is starting to be adopted in gene expression profiling and expression Quantitative Trait Locus (eQTL) studies. [...]it is currently unknown whether the cellular composition (including inflammatory cells) of nasal and bronchial brushings differs. The correction for multiple testing was done transcriptome-wide using Storey's q value method according to the GTEX eQTL protocol.E1Genome-wide association studies SNP selection The SNPs were selected from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas) and an additional study that was not included in the NHGRI-EBI Catalog at the time of this current study.E2 All SNPs selected had a P value of less than 1 × 10−8 in their respective genome-wide association study. Table E2 provides an overview of the studies included from the NHGRI-EBI Catalog.E3-E19 SNP Proxy r2 Minor Major MAF Trait Gene Bronchial Nasal Q Q P value Reference β SD P value FDR β SD P value FDR rs2305480 rs2872507 1 G A 0.512 Childhood asthma GSDMB −0.306 0.040 3.101 × 10−10 1.907 × 10−06 −0.506 0.049 7.303 × 10−14 1.365 × 10−09 9.998 1.568 × 10−03 4 rs2955083 rs2999068 1 A G 0.160 Lung function (FEV1/FVC) RUVBL1 0.168 0.025 1.068 × 10−08 3.841 × 10−05 −0.010 0.044 8.137 × 10−01 9.638 × 10−01 12.372 4.359 × 10−04 5 rs62070270 rs3110495 0.838 G A 0.507 Lung function (FEV1/FVC) SSH2 −0.188 0.031 1.190 × 10−07 2.872 × 10−04 −0.022 0.033 5.043 × 10−01 9.454 × 10−01 13.442 2.461 × 10−04 6 rs17707300 rs27741 0.824 A G 0.431 Lung function (FEV1) TUFM 0.104 0.018 2.326 × 10−07 5.116 × 10−04 0.046 0.019 1.660 × 10−02 6.814 × 10−01 4.911 2.669 × 10−02 5 rs3117098 G A 0.313 Asthma HLA-DRB5 1.456 0.254 4.908 × 10−07 9.623 × 10−04 1.206 0.249 1.229 × 10−05 1.516 × 10−02 0.494 4.821 × 10−01 7 rs2381416 rs7848215 0.885 A G 0.264 Asthma IL33 0.368 0.070 2.522 × 10−06 3.756 × 10−03 0.272 0.080 1.286 × 10−03 3.134 × 10−01 0.816 3.665 × 10−01 8 rs2509961 rs11553576 0.813 G A 0.361 Lung function (FEV1) INTS5 0.130 0.027 1.123 × 10−05 1.264 × 10−02 0.031 0.023 1.752 × 10−01 8.909 × 10−01 7.791 5.251 × 10−03 6 rs62070270 rs4429345 0.967 G A 0.458 Lung function (FEV1/FVC) EFCAB5 0.161 0.035 2.191 × 10−05 2.135 × 10−02 0.047 0.026 7.880 × 10−02 8.350 × 10−01 6.836 8.932 × 10−03 6 rs9268516 A G 0.236 Asthma HLA-DQA1 −0.584 0.130 3.757 × 10−05 3.245 × 10−02 −0.658 0.134 9.638 × 10−06 1.260 × 10−02 0.157 6.918 × 10−01 7 rs721917 G A 0.410 Lung function (FEV1) DYDC2 0.289 0.065 4.097 × 10−05 3.452 × 10−02 0.201 0.061 1.780 × 10−03 3.591 × 10−01 0.975 3.235 × 10−01 5 rs11658500 A G 0.167 Lung function (FEV1/FVC) PCGF2 0.193 0.044 5.459 × 10−05 4.266 × 10−02 0.267 0.044 1.466 × 10−07 4.029 × 10−04 1.414 2.344 × 10−01 6 rs34864796 rs13207082 0.841 G A 0.076 Lung function (FEV1) HIST1H2BL −0.220 0.053 1.263 × 10−04 7.709 × 10−02 −0.530 0.078 1.146 × 10−08 4.877 × 10−05 10.806 1.012 × 10−03 6 rs987870 G A 0.118 Asthma HLA-DPA1 −0.303 0.074 1.601 × 10−04 9.022 × 10−02 −0.381 0.084 3.782 × 10−05 3.544 × 10−02 0.485 4.860 × 10−01 9 rs3129890 G A 0.313 Asthma LY6G6C 0.149 0.040 4.407 × 10−04 1.694 × 10−01 0.380 0.075 5.672 × 10−06 8.341 × 10−03 7.386 6.575 × 10−03 7 rs204993 G A 0.326 Asthma RNF5P1 0.153 0.051 4.047 × 10−03 4.650 × 10−01 0.322 0.055 4.100 × 10−07 9.483 × 10−04 5.077 2.425 × 10−02 7 rs17513135 A G 0.215 Lung function (FEV1/FVC) PABPC4 −0.079 0.027 5.265 × 10−03 5.049 × 10−01 −0.133 0.022 2.423 × 10−07 6.148 × 10−04 2.404 1.210 × 10−01 6 Table I eQTL associated with asthma and lung function Number of patients, n 77 Age (y) 36.06 (16.23) BMI (kg/m2) 23.73 (3.50) Sex: male/female 41/36 Pack-years 8.68 (13.4) Current smokers, n (%) 41 (53.2) Never-smokers, n (%) 36 (46.8) FEV1 % predicted 108.14 (10.49) Reversibility % from baseline 3.82 (3.05) FEV1/FVC 83.06 (6.37) RV % predicted 93.74 (17.46) TLC % predicted 104.04 (9.42) RV/TLC % predicted 85.62 (12.38) Table E1 NORM subject characteristics First author Date Study Disease/trait Reference Hirota T July 31, 2011 Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population Asthma E3 Bønnelykke K November 17, 2013 A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations Asthma (childhood onset) E4 Nieuwenhuis MA July 20, 2016 Combining genome-wide association study and lung eQTL analysis provides evidence for novel genes associated with asthma Bronchial hyperresponsiveness in asthma E5 Lutz SM December 3, 2015 A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry Postbronchodilator FEV1/FVC ratio Postbronchodilator FEV1 E6 Torgerson DG July 31, 2011 Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations Asthma E7 Moffatt MF September 23, 2010 A large-scale, consortium-based genome-wide association study of asthma Asthma E8 Sleiman PM December 23, 2009 Variants of DENND1B associated with asthma in children Asthma E9 Noguchi E July 21, 2011 Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations Asthma E10 Almoguera B September 9, 2016 Identification of four novel loci in asthma in European and African American populations Adult asthma E11 Moffatt MF July 26, 2007 Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma Asthma E12 Ramasamy A September 28, 2012 Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA Asthma E13 Forno E May 2, 2012 Genome-wide association study of the age of onset of childhood asthma Asthma (childhood onset) E14 Ding L July 5, 2013 Rank-based genome-wide analysis reveals the association of ryanodine receptor-2 gene variants with childhood asthma among human populations Asthma (childhood onset) E15 Wan YI May 5, 2012 Genome-wide association study to identify genetic determinants of severe asthma Asthma E16 Pickrell JK May 16, 2016 Detection and interpretation of shared genetic influences on 42 human traits Asthma E17 Yan Q May 1, 2017 A meta-analysis of genome-wide association studies of asthma in Puerto Ricans Asthma E18 Wain LV February 6, 2017 Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets Lung function (FEV1) Lung function (FEV1/FVC) E19 Table E2 GWAS on asthma and lung function Gene Bronchial brushes Nasal brushes logFC P value FDR logFC P value FDR SEC14L3 −1.412 4.690 × 10−10 4.440 × 10−08 −1.038 6.897 × 10−04 2.918 × 10−02 CYP2A13 −1.284 6.600 × 10−17 3.940 × 10−14 −0.833 3.260 × 10−05 4.946 × 10−03 C3 −1.090 4.300 × 10−08 1.930 × 10−06 −1.068 1.300 × 10−07 1.510 × 10−04 MROH9 −1.081 2.790 × 10−10 2.800 × 10−08 −0.790 3.214 × 10−04 1.887 × 10−02 SAA1 −1.018 3.049 × 10−03 1.400 × 10−02 −1.400 1.320 × 10−06 7.633 × 10−04 CTNNAL1 −0.920 1.740 × 10−10 1.910 × 10−08 −0.747 4.790 × 10−05 6.332 × 10−03 SAA2 −0.851 1.807 × 10−03 9.256 × 10−03 −1.037 8.510 × 10−09 2.400 × 10−05 TEX26 −0.642 1.610 × 10−05 2.357 × 10−04 −0.715 1.441 × 10−03 4.410 × 10−02 SLC28A2 −0.558 6.346 × 10−04 4.167 × 10−03 −0.876 6.530 × 10−06 1.945 × 10−03 ALDH1A3 0.550 4.210 × 10−08 1.900 × 10−06 0.532 1.491 × 10−04 1.215 × 10−02 CRISP3 0.564 1.141 × 10−03 6.493 × 10−03 0.726 5.040 × 10−06 1.743 × 10−03 TFF1 0.604 2.390 × 10−05 3.212 × 10−04 0.808 3.260 × 10−05 4.946 × 10−03 TIMP3 0.634 8.620 × 10−10 7.360 × 10−08 0.706 5.550 × 10−06 1.820 × 10−03 DNASE1L3 0.634 5.810 × 10−08 2.490 × 10−06 0.706 1.690 × 10−05 3.345 × 10−03 BPIFA2 0.793 5.800 × 10−11 7.530 × 10−09 0.608 3.710 × 10−07 3.046 × 10−04 UGT1A6 0.860 5.070 × 10−08 2.240 × 10−06 0.651 5.790 × 10−09 1.900 × 10−05 SCEL 0.878 6.800 × 10−10 5.990 × 10−08 0.894 2.880 × 10−05 4.804 × 10−03 C1QTNF9B-AS1 1.053 1.130 × 10−09 9.210 × 10−08 0.642 1.306 × 10−03 4.182 × 10−02 UGT1A10 1.069 1.920 × 10−06 4.340 × 10−05 0.554 7.750 × 10−05 8.090 × 10−03 FAM177B 1.123 2.110 × 10−09 1.630 × 10−07 0.743 1.013 × 10−04 9.511 × 10−03 STATH 1.272 1.454 × 10−04 1.319 × 10−03 0.892 3.430 × 10−08 6.380 × 10−05 LOC344887 1.735 1.350 × 10−18 1.330 × 10−15 0.733 1.130 × 10−09 7.890 × 10−06 H19 2.116 4.000 × 10−17 2.550 × 10−14 0.564 7.800 × 10−06 2.135 × 10−03 SLC7A11 2.715 5.110 × 10−17 3.150 × 10−14 0.973 1.600 × 10−09 7.890 × 10−06 CYP1A1 3.299 9.830 × 10−11 1.170 × 10−08 2.784 1.230 × 10−09 7.890 × 10−06 AKR1B10 3.642 9.880 × 10−21 1.770 × 10−17 0.867 1.300 × 10−06 7.633 × 10−04 CYP1B1 4.168 1.640 × 10−17 1.160 × 10−14 2.447 4.340 × 10−12 8.550 × 10−08 Table E3 Overlapping genes differentially expressed in smokers and never-smokers in both nasal and bronchial brushes (FC ± 1.5, FDR < 0.05) No.