Polymorphisms and haplotypes of TOLLIP and MUC5B are associated with susceptibility and survival in patients with fibrotic hypersensitivity pneumonitis

P C Mota; M L Soares; A C Ferreira; R F Santos; J C Rufo; D Vasconcelos; A Carvalho; S Guimarães; F Vasques-Nóvoa; C Cardoso; N Melo; A T Alexandre; D Coelho; H Novais-Bastos; A Morais

doi:10.1016/j.pulmoe.2024.01.002

Polymorphisms and haplotypes of TOLLIP and MUC5B are associated with susceptibility and survival in patients with fibrotic hypersensitivity pneumonitis

Pulmonology. 2024 Feb 2:S2531-0437(24)00007-2. doi: 10.1016/j.pulmoe.2024.01.002. Online ahead of print.

Authors

P C Mota¹, M L Soares², A C Ferreira³, R F Santos⁴, J C Rufo⁵, D Vasconcelos³, A Carvalho⁶, S Guimarães⁷, F Vasques-Nóvoa⁸, C Cardoso¹, N Melo⁹, A T Alexandre⁹, D Coelho¹, H Novais-Bastos¹, A Morais¹

Affiliations

¹ Departamento de Pneumologia, Centro Hospitalar Universitário de São João, EPE, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
² Laboratório de Apoio à Investigação em Medicina Molecular (LAIMM), Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Portugal; LAIMM, Núcleo de Recursos Laboratoriais, Unidade de Gestão de Conhecimento, Departamento de Recursos Comuns, Faculdade de Medicina da Universidade do Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. Electronic address: mlsoares@med.up.pt.
³ Laboratório de Apoio à Investigação em Medicina Molecular (LAIMM), Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
⁴ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Escola Superior de Saúde - Instituto Politécnico do Porto, Portugal.
⁵ Indoor Air Quality and Respiratory Health Lab, Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal; EPIUnit - Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal; Center for Translational Health and Medical Biotechnology Research (T.Bio), Escola Superior de Saúde, Instituto Politécnico do Porto, Porto, Portugal.
⁶ Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Departamento de Radiologia, Centro Hospitalar Universitário de São João, EPE, Porto, Portugal.
⁷ Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Departamento de Anatomia Patológica, Centro Hospitalar Universitário de São João, EPE, Porto, Portugal.
⁸ Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Departamento de Medicina Interna, Centro Hospitalar Universitário de São João, EPE, Porto, Portugal; UnIC@RISE, Department of Surgery and Physiology, Portugal.
⁹ Departamento de Pneumologia, Centro Hospitalar Universitário de São João, EPE, Porto, Portugal.

PMID: 38309995
DOI: 10.1016/j.pulmoe.2024.01.002

Abstract

Introduction and objectives: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with diverse clinical features that can present a fibrotic phenotype similar to idiopathic pulmonary fibrosis (IPF) in genetically predisposed individuals. While several single nucleotide polymorphisms (SNPs) have been associated with IPF, the genetic factors contributing to fibrotic HP (fHP) remain poorly understood. This study investigated the association of MUC5B and TOLLIP variants with susceptibility, clinical presentation and survival in Portuguese patients with fHP.

Material and methods: A case-control study was undertaken with 97 fHP patients and 112 controls. Six SNPs residing in the MUC5B and TOLLIP genes and their haplotypes were analyzed. Associations with risk, survival, and clinical, radiographic, and pathological features of fHP were probed through comparisons among patients and controls.

Results: MUC5B rs35705950 and three neighboring TOLLIP variants (rs3750920, rs111521887, and rs5743894) were associated with increased susceptibility to fHP. Minor allele frequencies were greater among fHP patients than in controls (40.7% vs 12.1%, P<0.0001; 52.6% vs 40.2%, P = 0.011; 22.7% vs 13.4%, P = 0.013; and 23.2% vs 12.9%, P = 0.006, respectively). Haplotypes formed by these variants were also linked to fHP susceptibility. Moreover, carriers of a specific haplotype (G-T-G-C) had a significant decrease in survival (adjusted hazard ratio 6.92, 95% CI 1.73-27.64, P = 0.006). Additional associations were found between TOLLIP rs111521887 and rs5743894 variants and decreased lung function at baseline, and the MUC5B SNP and radiographic features, further highlighting the influence of genetic factors in fHP.

Conclusion: These findings suggest that TOLLIP and MUC5B variants and haplotypes may serve as valuable tools for risk assessment and prognosis in fibrotic hypersensitivity pneumonitis, potentially contributing to its patient stratification, and offer insights into the genetic factors influencing the clinical course of the condition.

Keywords: Fibrosis; Genetic variants; Haplotypes; Hypersensitivity pneumonitis; MUC5B; Survival; Susceptibility; TOLLIP.