Figures
- FIGURE 1
Regional association plots of a) 11p15.5, b) 14q21.3 and c) 17q21.31 with annotations of previously detected signals (rs35705950 in chromosome 11, rs7144383 in chromosome 14 and rs17690703 in chromosome 17). Chromosomal position is shown in Mb. Significance is represented on a −log10(p-value) scale. A threshold minor allele frequency in controls of 0.05 was used to stratify the results derived by common versus low-frequency variants. Colours reflect linkage disequilibrium (r2) values against the top hit on each region according to the European population data from the 1000 Genomes Project.
- FIGURE 2
Detailed pile-up view of sequence reads mapping and Sanger sequencing results of the two MUC5AC variants affecting the missense change.
- FIGURE 3
Linkage disequilibrium plot of r2 and D′ estimates in the discovery study for the risk variants in MUC5AC, MUC5B and TOLLIP. Each diamond of the linkage disequilibrium plot represents a pairwise comparison, with its values schematically symbolised by a colour gradient, ranging from red (stronger linkage disequilibrium) to white (reduced linkage disequilibrium).
Tables
- TABLE 1
Clinical and demographic characteristics of idiopathic pulmonary fibrosis cases included in the discovery study
University of Chicago COMET ACE p-value Subjects 138 22 21 Age years 69±9 63±8 69±6 0.02 Male 108 (78.3) 14 (63.6) 16 (76.2) 0.46 Ever-smoker 95 (75.4) 17 (77.3) 15 (71.4) 0.91 FVC % pred 67.2±16.7 72.1±12.9 53.9±15.4 8.0×10−4 DLCO % pred 47.8±16.8 46.4±14.2 33.1±19.5 1.7×10−3 Transplant 12 (8.7) 0 (0) 0.17 Death 68 (49.3) 1 (4.5) 3 (14.3) 2.7×10−5 Follow-up months 38.5±24.8 36.3±2.8 35.1±4.0 0.41 Time to death months 27.8±17.9 9.57# 4.0±2.9 0.06 Data are presented as n, mean±sd or n (%), unless otherwise stated. FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide. #: mean.
- TABLE 2
Association results reaching genome-wide significance in the discovery study
SNV Chr. Position (hg19) Effect allele MAF# OR (95% CI) p-value Nearby gene Function/location rs371630624 11p15.5 1 213 302 C 0.001 1942 (245.6–15 360) 7.18×10−13 MUC5AC Synonymous rs34474233¶ 11p15.5 1 219 152 A 0.044 4.08 (2.56–6.49) 2.99×10−9 MUC5AC Missense (Ala5353Lys) rs34815853¶ 11p15.5 1 219 153 A 0.044 4.01 (2.52–6.38) 4.15×10−9 MUC5AC Missense (Ala5353Lys) rs12802931 11p15.5 1 236 164 G 0.183 3.76 (2.73–5.16) 3.72×10−16 MUC5B 8.1 kb 5′ of MUC5B rs35705950 11p15.5 1 241 221 T 0.108 6.18 (4.28–8.93) 2.69×10−22 MUC5B 3.1 kb 5′ of MUC5B rs200243273 11p15.5 1 266 716 C 0.227 0.27 (0.17–0.43) 3.55×10−8 MUC5B/
RP11-532E4.2Missense/intronic rs4963073 11p15.5 1 362 949 G 0.300 3.23 (2.12–4.921) 4.91×10−8 CTD-2245O6.1 31 kb 3′ of CTD-2245O6.1 rs4963072 11p15.5 1 362 953 G 0.300 3.34 (2.19–5.11) 2.63×10−8 CTD-2245O6.1 31 kb 3′ of CTD-2245O6.1 rs71469892 11p15.5 1 416 119 G 0.491 0.22 (0.15–0.31) 2.15×10−16 BRSK2 Intronic rs145898170 14q21.3 47 574 913 G 0.458 0.47 (0.36–0.62) 4.71×10−8 MDGA2 Intronic rs199838022 14q21.3 47 574 922 C 0.458 0.45 (0.34–0.57) 7.14×10−9 MDGA2 Intronic rs12586854 14q21.3 47 576 151 T 0.428 0.18 (0.12–0.26) 6.81×10−19 MDGA2 Intronic rs11157543 14q21.3 47 576 203 C 0.300 0.13 (0.07–0.22) 5.97×10−14 MDGA2 Intronic rs11157544 14q21.3 47 576 205 C 0.427 0.30 (0.21–0.41) 1.37×10−13 MDGA2 Intronic rs12586856 14q21.3 47 576 217 G 0.304 0.18 (0.11–0.29) 3.77×10−13 MDGA2 Intronic rs11157545 14q21.3 47 576 231 T 0.463 0.44 (0.34–0.59) 7.81×10−9 MDGA2 Intronic rs183643415 14q21.3 47 576 246 A 0.182 0.04 (0.01–0.12) 2.77×10−8 MDGA2 Intronic rs150322840 14q21.3 47 576 252 T 0.216 0.13 (0.07–0.24) 3.90×10−10 MDGA2 Intronic rs8005465 14q21.3 47 716 040 A 0.461 0.37 (0.27–0.51) 4.41×10−10 MDGA2 Intronic rs543453148 14q21.3 47 751 911 A 0.004 25.22 (8.29–76.73) 1.30×10−8 MDGA2 Intronic rs12890180 14q21.3 47 788 012 G 0.393 0.39 (0.28–0.53) 2.91×10−9 MDGA2 Intronic rs73251857 14q21.3 47 800 734 G 0.154 0.06 (0.02–0.14) 9.59×10−10 MDGA2 Intronic rs7141653 14q21.3 47 828 946 C 0.363 0.25 (0.17–0.37) 1.65×10−11 MDGA2 Intronic rs7145329 14q21.3 47 931 577 T 0.376 0.34 (0.24–0.49) 2.59×10−9 MDGA2 Intronic rs4900770 14q21.3 47 938 755 A 0.498 0.38 (0.28–0.53) 9.10×10−9 MDGA2 Intronic rs58731325 14q21.3 48 009 745 G 0.469 0.34 (0.25–0.47) 7.35×10−11 MDGA2 Noncoding transcript/intronic rs115811519 17q21.31 43 677 790 C 0.070 4.93 (2.83–8.58) 1.68×10−8 RP11-707O23.1 7 kb 3′ of RP11-707O23.1 rs56383763 17q21.31 43 682 323 C 0.242 0.07 (0.03–0.16) 1.75×10−9 CTC-501O10.1 17 kb 5′ of CRHR1 rs373417 17q21.31 43 691 173 T 0.239 0.10 (0.05–0.20) 1.24×10−10 CRHR1 6.5 kb 5′ of CRHR1 rs7221124 17q21.31 43 764 301 A 0.265 0.04 (0.02–0.09) 6.70×10−14 CRHR1 Intronic rs55938136 17q21.31 43 798 360 A 0.018 151.90 (62.14–371.50) 3.37×10−28 CRHR1 Intronic rs11870844 17q21.31 44 141 279 A 0.257 3.98 (2.82–5.62) 3.85×10−15 KANSL1 Intronic rs371996525 17q21.31 44 183 317 A 0.244 0.04 (0.02–0.11) 2.17×10−10 KANSL1 Intronic rs142920272 17q21.31 44 301 840 C 0.248 0.10 (0.05–0.20) 7.45×10−11 KANSL1 Intronic rs2668637 17q21.31 44 322 960 G 0.095 5.32 (3.09–9.13) 1.43×10−9 KANSL1/LRRC37A Intergenic rs2696618 17q21.31 44 325 635 C 0.249 6.74 (4.02–11.31) 5.09×10−13 KANSL1/LRRC37A 23 kb 5′ of KANSL1 SNV: single nucleotide variant; Chr.: chromosome; MAF: minor allele frequency. #: MAF in Europeans from the 1000 Genomes Project (low-frequency variants in italic); ¶: because of their complete linkage disequilibrium, these variants can be merged into rs71464134. The functional information provided corresponds to the predicted change for the merged reference sequence.
- TABLE 3
Association results of 11p15.5 with or without conditioning on rs35705950
Nearby gene Function/location SNV Unconditioned p-value Conditioned p-value MUC5AC Missense (Ala5353Lys) rs34474233# 2.99×10−9 4.12×10−3 MUC5AC Missense (Ala5353Lys) rs34815853# 4.15×10−9 6.27×10−3 MUC5B 8.1 kb 5′ of MUC5B rs12802931 3.72×10−16 0.731 MUC5B/RP11-532E4.2 Missense/intronic rs200243273 3.55×10−8 1.44×10−4 CTD-2245O6.1 31 kb 3′ of CTD-2245O6.1 rs4963073 4.91×10−8 1.48×10−6 CTD-2245O6.1 31 kb 3′ of CTD-2245O6.1 rs4963072 2.63×10−8 2.66×10−6 BRSK2 Intronic rs71469892 2.15×10−16 1.29×10−9 The rs371630624 variant at MUC5AC was excluded from this analysis as it was not supported by Sanger sequencing. #: these variants can be merged into rs71464134.
- TABLE 4
Variants showing nominal significance in the replication study, with the same direction of effects as in the discovery study and that met the genome-wide significance level in the meta-analysis
SNV Chr. Position (hg19) Gene Effect/
noneffect alleleMAF Discovery Replication Meta-analysis OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value rs34474233 11 1 219 152 MUC5AC A/G 0.044 4.08 (2.56–6.49) 2.99×10−9 3.15 (2.37–4.20) 4.10×10−14 3.39 (2.65–4.32) 2.27×10−22 rs34815853 11 1 219 153 MUC5AC A/C 0.044 4.01 (2.53–6.37) 4.15×10−9 3.16 (2.37–4.20) 4.13×10−14 3.37 (2.64–4.30) 3.02×10−22 rs12802931 11 1 236 164 MUC5B G/A 0.183 3.76 (2.73–5.16) 3.72×10−16 2.42 (2.02–2.90) 6.07×10−22 2.96 (1.93–4.53) 4.60×10−35 rs35705950 11 1 241 221 MUC5B T/G 0.108 6.18 (4.28–8.94) 2.69×10−22 4.11 (3.31–5.11) 1.86×10−37 4.90 (3.30–7.28) 9.27×10−57 rs4963072 11 1 362 953 CTD-2245O6.1 G/C 0.300 3.34 (2.18–5.11) 2.63×10−8 1.29 (1.08–1.54) 5.30×10−3 1.59 (0.38–6.65) 4.91×10−8 rs56383763 17 43 682 323 CTC-501O10.1 C/T 0.242 0.07 (0.03–0.16) 1.75×10−9 0.82 (0.68–0.97) 2.42×10−2 0.24 (0.02–2.82) 2.13×10−8 rs373417 17 43 691 173 CRHR1 T/C 0.239 0.10 (0.05–0.20) 1.24×10−10 0.82 (0.69–0.98) 2.72×10−2 0.29 (0.04–2.36) 1.59×10−9 rs371996525 17 44 183 317 KANSL1 A/C 0.244 0.04 (0.02–0.11) 2.17×10−10 0.80 (0.67–0.95) 1.26×10−2 0.19 (0.01–3.44) 1.98×10−9 rs142920272 17 44 301 840 KANSL1 C/T 0.248 0.10 (0.05–0.20) 7.45×10−11 0.83 (0.69–0.98) 3.07×10−2 0.29 (0.04–2.35) 1.11×10−9 rs2696618 17 44 325 635 KANSL1/LRRC37A C/G 0.249 6.74 (4.02–11.31) 5.09×10−13 1.25 (1.05–1.49) 1.05×10−2 2.28 (0.28–18.51) 4.40×10−12 SNV: single nucleotide variant; Chr.: chromosome; MAF: minor allele frequency.
Supplementary Material
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ERJOR-00071-2019_supplementary material 00071-2019_supplementary_material
