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Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology. The role of genetic risk factors has been the focus of numerous studies probing for associations of genetic variants with IPF. We aimed to determine whether single-nucleotide polymorphisms (SNPs) of four candidate genes are associated with IPF susceptibility and survival in a Portuguese population. A retrospective case–control study was performed with 64 IPF patients and 74 healthy controls. Ten single-nucleotide variants residing in the MUC5B, TOLLIP, SERPINB1, and PLAU genes were analyzed. Single- and multi-locus analyses were performed to investigate the predictive potential of specific variants in IPF susceptibility and survival. Multifactor dimensionality reduction (MDR) was employed to uncover predictive multi-locus interactions underlying IPF susceptibility. The MUC5B rs35705950 SNP was significantly associated with IPF: T allele carriers were significantly more frequent among IPF patients (75.0% vs 20.3%, P < 1.0 × 10−6). Genotypic and allelic distributions of TOLLIP, PLAU, and SERPINB1 SNPs did not differ significantly between groups. However, the MUC5B-TOLLIP T-C-T-C haplotype, defined by the rs35705950-rs111521887-rs5743894-rs5743854 block, emerged as an independent protective factor in IPF survival (HR = 0.37, 95% CI 0.17–0.78, P = 0.009, after adjustment for FVC). No significant multi-locus interactions correlating with disease susceptibility were detected. MUC5B rs35705950 was linked to an increased risk for IPF, as reported for other populations, but not to disease survival. A haplotype incorporating SNPs of the MUC5B-TOLLIP locus at 11p15.5 seems to predict better survival and could prove useful for prognostic purposes and IPF patient stratification.

Key messages

  • The MUC5B rs35705950 minor allele is associated with IPF risk in the Portuguese.

  • No predictive multi-locus interactions of IPF susceptibility were identified by MDR.

  • A haplotype defined by MUC5B and TOLLIP SNPs is a protective factor in IPF survival.

  • The haplotype may be used as a prognostic tool for IPF patient stratification.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to privacy or ethical restrictions, but are available from the corresponding author on reasonable request.

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Acknowledgements

We are indebted to Instituto de Saúde Pública da Universidade do Porto (ISPUP) for providing samples from the EPIPorto cohort to be used as controls; we thank the cohort management and all participants. We acknowledge the contribution of Ana Isabel Loureiro, MD (Centro Hospitalar de Trás-os-Montes e Alto Douro) and Rui Rolo, MD (Hospital de Braga) who referred some IPF patients to our center. We are grateful to Catarina Teixeira Antunes and Joana Filipa Amorim Reis for assistance in the genotyping.

Funding

This work was supported by the Portuguese Society of Pulmonology (SPP) (Grant - SPP/Bolsa Novartis 2012) and Boehringer-Ingelheim (unrestricted research grant).

Author information

Author notes

  1. Carlos Daniel Vasconcelos and António Carlos Ferreira contributed equally to this work.

Authors and Affiliations

  1. Departamento de Pneumologia, Centro Hospitalar Universitário de São João, EPE, Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal

    Patrícia Caetano Mota, Natália Melo, Hélder Novais-Bastos, José Agostinho Marques & António Morais

  2. Faculdade de Medicina da Universidade do Porto, Porto, Portugal

    Patrícia Caetano Mota, Miguel Luz Soares, Carlos Daniel Vasconcelos, António Carlos Ferreira, Hélder Novais-Bastos, José Agostinho Marques & António Morais

  3. Laboratório de Apoio à Investigação em Medicina Molecular (LAIMM), Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

    Miguel Luz Soares, Carlos Daniel Vasconcelos & António Carlos Ferreira

  4. Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Patrícia Caetano Mota, Miguel Luz Soares, Carlos Daniel Vasconcelos, António Carlos Ferreira, Hélder Novais-Bastos, José Agostinho Marques & António Morais

  5. Oficina de Bioestatística, Ermesinde, Portugal

    Bruno A. Lima

  6. Department of Biostatistics, Epidemiology & Informatics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Elisabetta Manduchi

  7. Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Jason H. Moore

  8. Departamento de Radiologia, Centro Hospitalar Universitário de São João, EPE, Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal

    José Miguel Pereira

  9. Departamento de Anatomia Patológica, Centro Hospitalar Universitário de São João, EPE, Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal

    Susana Guimarães & Conceição Souto Moura

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  1. Patrícia Caetano Mota
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  2. Miguel Luz Soares
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Contributions

Conceptualization: P.C.M., M.L.S., J.A.M., and A.M.; methodology: P.C.M., M.L.S., A.M., and E.M.; data curation: P.C.M., M.L.S., and B.A.L.; formal analysis: P.C.M., M.L.S., B.A.L., and E.M.; investigation: P.C.M., M.L.S., C.D.V., A.C.F., N.M., H.N-B., and A.M.; validation: P.C.M., M.L.S., and J.H.M.; writing—original draft: P.C.M., M.L.S., and B.A.L.; writing—review and editing: all authors; resources: P.C.M., M.L.S., A.C.F., N.M., and H. N-B; funding acquisition: P.C.M., M.L.S., J.A.M., and A.M.; supervision and project administration: P.C.M., M.L.S., and A.M.

Corresponding author

Correspondence to Patrícia Caetano Mota.

Ethics declarations

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Centro Hospitalar Universitário de São João (CHUSJ) (CE-203–2012).

Consent to participate

Written informed consent was obtained from all individual participants in the study.

Competing interests

Patrícia Caetano Mota has received speaker fees from Boehringer-Ingelheim and research grants from Boehringer-Ingelheim and Novartis; and has participated in research with Boehringer-Ingelheim and Roche, for which her institution has been remunerated.

Hélder Novais-Bastos and António Morais have attended advisory boards for Boehringer-Ingelheim and Roche; have received speaker fees from Boehringer-Ingelheim and Roche; have participated in research with Boehringer-Ingelheim and Roche, for which their institution has been remunerated. Hélder Novais-Bastos has also received a research grant from Boehringer-Ingelheim.

The remaining authors have no relevant financial or non-financial interests to disclose.

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Mota, P.C., Soares, M.L., Vasconcelos, C.D. et al. Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival. J Mol Med 100, 1341–1353 (2022). https://doi.org/10.1007/s00109-022-02242-y

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