Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 100; no. 9; pp. 1341 - 1353
• Main Authors: Mota, Patrícia Caetano, Soares, Miguel Luz, Vasconcelos, Carlos Daniel, Ferreira, António Carlos, Lima, Bruno A., Manduchi, Elisabetta, Moore, Jason H., Melo, Natália, Novais-Bastos, Hélder, Pereira, José Miguel, Guimarães, Susana, Moura, Conceição Souto, Marques, José Agostinho, Morais, António
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2022; Springer Nature B.V
• Subjects: Alleles; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Chromosome 11; Etiology; Fibrosis; Genetic diversity; Genetic Predisposition to Disease; Haplotypes; Health risk assessment; Human Genetics; Humans; Idiopathic Pulmonary Fibrosis - genetics; Internal Medicine; Lung diseases; Molecular Medicine; Original Article; Polymorphism, Single Nucleotide; Pulmonary fibrosis; Retrospective Studies; Risk factors; Serpins - genetics; Single-nucleotide polymorphism; Survival; Susceptibility; Haplotypes; MUC5B promoter; Common genetic variants; IPF survival; Idiopathic pulmonary fibrosis; TOLLIP
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-022-02242-y

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.