TY - JOUR
T1 - Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival
AU - Mota, Patrícia Caetano
AU - Soares, Miguel Luz
AU - Vasconcelos, Carlos Daniel
AU - Ferreira, António Carlos
AU - Lima, Bruno A.
AU - Manduchi, Elisabetta
AU - Moore, Jason H.
AU - Melo, Natália
AU - Novais-Bastos, Hélder
AU - Pereira, José Miguel
AU - Guimarães, Susana
AU - Moura, Conceição Souto
AU - Marques, José Agostinho
AU - Morais, António
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
KW - Common genetic variants
KW - Haplotypes
KW - Idiopathic pulmonary fibrosis
KW - IPF survival
KW - MUC5B promoter
KW - TOLLIP
UR - http://www.scopus.com/inward/record.url?scp=85136477386&partnerID=8YFLogxK
U2 - 10.1007/s00109-022-02242-y
DO - 10.1007/s00109-022-02242-y
M3 - Article
C2 - 35986225
AN - SCOPUS:85136477386
SN - 0946-2716
VL - 100
SP - 1341
EP - 1353
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 9
ER -