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Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

Jose M. Lorenzo-Salazar, Shwu-Fan Ma, Jonathan Jou, Pei-Chi Hou, Beatriz Guillen-Guio, Richard J. Allen, R. Gisli Jenkins, Louise V. Wain, Justin M. Oldham, Imre Noth, Carlos Flores
ERJ Open Research 2019 5: 00071-2019; DOI: 10.1183/23120541.00071-2019
Jose M. Lorenzo-Salazar
1Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
10These authors contributed equally to this work
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Shwu-Fan Ma
2Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA
10These authors contributed equally to this work
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Jonathan Jou
3College of Medicine, University of Illinois, Chicago, IL, USA
10These authors contributed equally to this work
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Pei-Chi Hou
2Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA
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Beatriz Guillen-Guio
4Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
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Richard J. Allen
5Dept of Health Sciences, University of Leicester, Leicester, UK
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R. Gisli Jenkins
6NIHR Biomedical Research Centre, Respiratory Research Unit, University of Nottingham, Nottingham, UK
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Louise V. Wain
5Dept of Health Sciences, University of Leicester, Leicester, UK
7National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK
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Justin M. Oldham
8Pulmonary and Critical Care Medicine, University of California at Davis, Sacramento, CA, USA
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Imre Noth
2Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA
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Carlos Flores
1Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
4Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
9CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
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  • For correspondence: cflores@ull.edu.es
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  • FIGURE 1
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    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
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    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
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    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

  • Figures
  • Supplementary Materials
  • TABLE 1

    Clinical and demographic characteristics of idiopathic pulmonary fibrosis cases included in the discovery study

    University of ChicagoCOMETACEp-value
    Subjects1382221
    Age years69±963±869±60.02
    Male108 (78.3)14 (63.6)16 (76.2)0.46
    Ever-smoker95 (75.4)17 (77.3)15 (71.4)0.91
    FVC % pred67.2±16.772.1±12.953.9±15.48.0×10−4
    DLCO % pred47.8±16.846.4±14.233.1±19.51.7×10−3
    Transplant12 (8.7)0 (0)0.17
    Death68 (49.3)1 (4.5)3 (14.3)2.7×10−5
    Follow-up months38.5±24.836.3±2.835.1±4.00.41
    Time to death months27.8±17.99.57#4.0±2.90.06

    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

      SNVChr.Position (hg19)Effect alleleMAF#OR (95% CI)p-valueNearby geneFunction/location
      rs37163062411p15.51 213 302C0.0011942 (245.6–15 360)7.18×10−13MUC5ACSynonymous
      rs34474233¶11p15.51 219 152A0.0444.08 (2.56–6.49)2.99×10−9MUC5ACMissense (Ala5353Lys)
      rs34815853¶11p15.51 219 153A0.0444.01 (2.52–6.38)4.15×10−9MUC5ACMissense (Ala5353Lys)
      rs1280293111p15.51 236 164G0.1833.76 (2.73–5.16)3.72×10−16MUC5B8.1 kb 5′ of MUC5B
      rs3570595011p15.51 241 221T0.1086.18 (4.28–8.93)2.69×10−22MUC5B3.1 kb 5′ of MUC5B
      rs20024327311p15.51 266 716C0.2270.27 (0.17–0.43)3.55×10−8MUC5B/
      RP11-532E4.2
      Missense/intronic
      rs496307311p15.51 362 949G0.3003.23 (2.12–4.921)4.91×10−8CTD-2245O6.131 kb 3′ of CTD-2245O6.1
      rs496307211p15.51 362 953G0.3003.34 (2.19–5.11)2.63×10−8CTD-2245O6.131 kb 3′ of CTD-2245O6.1
      rs7146989211p15.51 416 119G0.4910.22 (0.15–0.31)2.15×10−16BRSK2Intronic
      rs14589817014q21.347 574 913G0.4580.47 (0.36–0.62)4.71×10−8MDGA2Intronic
      rs19983802214q21.347 574 922C0.4580.45 (0.34–0.57)7.14×10−9MDGA2Intronic
      rs1258685414q21.347 576 151T0.4280.18 (0.12–0.26)6.81×10−19MDGA2Intronic
      rs1115754314q21.347 576 203C0.3000.13 (0.07–0.22)5.97×10−14MDGA2Intronic
      rs1115754414q21.347 576 205C0.4270.30 (0.21–0.41)1.37×10−13MDGA2Intronic
      rs1258685614q21.347 576 217G0.3040.18 (0.11–0.29)3.77×10−13MDGA2Intronic
      rs1115754514q21.347 576 231T0.4630.44 (0.34–0.59)7.81×10−9MDGA2Intronic
      rs18364341514q21.347 576 246A0.1820.04 (0.01–0.12)2.77×10−8MDGA2Intronic
      rs15032284014q21.347 576 252T0.2160.13 (0.07–0.24)3.90×10−10MDGA2Intronic
      rs800546514q21.347 716 040A0.4610.37 (0.27–0.51)4.41×10−10MDGA2Intronic
      rs54345314814q21.347 751 911A0.00425.22 (8.29–76.73)1.30×10−8MDGA2Intronic
      rs1289018014q21.347 788 012G0.3930.39 (0.28–0.53)2.91×10−9MDGA2Intronic
      rs7325185714q21.347 800 734G0.1540.06 (0.02–0.14)9.59×10−10MDGA2Intronic
      rs714165314q21.347 828 946C0.3630.25 (0.17–0.37)1.65×10−11MDGA2Intronic
      rs714532914q21.347 931 577T0.3760.34 (0.24–0.49)2.59×10−9MDGA2Intronic
      rs490077014q21.347 938 755A0.4980.38 (0.28–0.53)9.10×10−9MDGA2Intronic
      rs5873132514q21.348 009 745G0.4690.34 (0.25–0.47)7.35×10−11MDGA2Noncoding transcript/intronic
      rs11581151917q21.3143 677 790C0.0704.93 (2.83–8.58)1.68×10−8RP11-707O23.17 kb 3′ of RP11-707O23.1
      rs5638376317q21.3143 682 323C0.2420.07 (0.03–0.16)1.75×10−9CTC-501O10.117 kb 5′ of CRHR1
      rs37341717q21.3143 691 173T0.2390.10 (0.05–0.20)1.24×10−10CRHR16.5 kb 5′ of CRHR1
      rs722112417q21.3143 764 301A0.2650.04 (0.02–0.09)6.70×10−14CRHR1Intronic
      rs5593813617q21.3143 798 360A0.018151.90 (62.14–371.50)3.37×10−28CRHR1Intronic
      rs1187084417q21.3144 141 279A0.2573.98 (2.82–5.62)3.85×10−15KANSL1Intronic
      rs37199652517q21.3144 183 317A0.2440.04 (0.02–0.11)2.17×10−10KANSL1Intronic
      rs14292027217q21.3144 301 840C0.2480.10 (0.05–0.20)7.45×10−11KANSL1Intronic
      rs266863717q21.3144 322 960G0.0955.32 (3.09–9.13)1.43×10−9KANSL1/LRRC37AIntergenic
      rs269661817q21.3144 325 635C0.2496.74 (4.02–11.31)5.09×10−13KANSL1/LRRC37A23 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 geneFunction/locationSNVUnconditioned p-valueConditioned p-value
        MUC5ACMissense (Ala5353Lys)rs34474233#2.99×10−94.12×10−3
        MUC5ACMissense (Ala5353Lys)rs34815853#4.15×10−96.27×10−3
        MUC5B8.1 kb 5′ of MUC5Brs128029313.72×10−160.731
        MUC5B/RP11-532E4.2Missense/intronicrs2002432733.55×10−81.44×10−4
        CTD-2245O6.131 kb 3′ of CTD-2245O6.1rs49630734.91×10−81.48×10−6
        CTD-2245O6.131 kb 3′ of CTD-2245O6.1rs49630722.63×10−82.66×10−6
        BRSK2Intronicrs714698922.15×10−161.29×10−9

        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

          SNVChr.Position (hg19)GeneEffect/
          noneffect allele
          MAFDiscoveryReplicationMeta-analysis
          OR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-value
          rs34474233111 219 152MUC5ACA/G0.0444.08 (2.56–6.49)2.99×10−93.15 (2.37–4.20)4.10×10−143.39 (2.65–4.32)2.27×10−22
          rs34815853111 219 153MUC5ACA/C0.0444.01 (2.53–6.37)4.15×10−93.16 (2.37–4.20)4.13×10−143.37 (2.64–4.30)3.02×10−22
          rs12802931111 236 164MUC5BG/A0.1833.76 (2.73–5.16)3.72×10−162.42 (2.02–2.90)6.07×10−222.96 (1.93–4.53)4.60×10−35
          rs35705950111 241 221MUC5BT/G0.1086.18 (4.28–8.94)2.69×10−224.11 (3.31–5.11)1.86×10−374.90 (3.30–7.28)9.27×10−57
          rs4963072111 362 953CTD-2245O6.1G/C0.3003.34 (2.18–5.11)2.63×10−81.29 (1.08–1.54)5.30×10−31.59 (0.38–6.65)4.91×10−8
          rs563837631743 682 323CTC-501O10.1C/T0.2420.07 (0.03–0.16)1.75×10−90.82 (0.68–0.97)2.42×10−20.24 (0.02–2.82)2.13×10−8
          rs3734171743 691 173CRHR1T/C0.2390.10 (0.05–0.20)1.24×10−100.82 (0.69–0.98)2.72×10−20.29 (0.04–2.36)1.59×10−9
          rs3719965251744 183 317KANSL1A/C0.2440.04 (0.02–0.11)2.17×10−100.80 (0.67–0.95)1.26×10−20.19 (0.01–3.44)1.98×10−9
          rs1429202721744 301 840KANSL1C/T0.2480.10 (0.05–0.20)7.45×10−110.83 (0.69–0.98)3.07×10−20.29 (0.04–2.35)1.11×10−9
          rs26966181744 325 635KANSL1/LRRC37AC/G0.2496.74 (4.02–11.31)5.09×10−131.25 (1.05–1.49)1.05×10−22.28 (0.28–18.51)4.40×10−12

          SNV: single nucleotide variant; Chr.: chromosome; MAF: minor allele frequency.

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            ERJOR-00071-2019_supplementary material 00071-2019_supplementary_material

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          Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing
          Jose M. Lorenzo-Salazar, Shwu-Fan Ma, Jonathan Jou, Pei-Chi Hou, Beatriz Guillen-Guio, Richard J. Allen, R. Gisli Jenkins, Louise V. Wain, Justin M. Oldham, Imre Noth, Carlos Flores
          ERJ Open Research Apr 2019, 5 (2) 00071-2019; DOI: 10.1183/23120541.00071-2019

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          Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing
          Jose M. Lorenzo-Salazar, Shwu-Fan Ma, Jonathan Jou, Pei-Chi Hou, Beatriz Guillen-Guio, Richard J. Allen, R. Gisli Jenkins, Louise V. Wain, Justin M. Oldham, Imre Noth, Carlos Flores
          ERJ Open Research Apr 2019, 5 (2) 00071-2019; DOI: 10.1183/23120541.00071-2019
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