Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

Abstract

Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis.

Aim: The aim of the present study is to overview the clinical significance of genetics in IPF.

Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a "a sporadic entity of the elderly, limited to the lungs" and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and "faces" in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure.

Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.

Keywords: MUC5B; alveolar epithelial cell; idiopathic pulmonary fibrosis; interstitial lung disease; short telomere syndrome; single nucleotide polymorphisms; surfactant-related gene mutations; telomere-related-gene mutations.

Figure 1

Major discoveries in the history of genetics: 1859: Ch. Darwin: “On the Origin of Species”; 1866: Gr. Mendel: Experiments in Plant Hybridization”; 1869: Fr. Miescher: “nuclein” (DNA); 1919: Ph. Levene: DNA structure; 1926: HJ Müller: radiation and lethal mutations; 1944: O. Avery, C. MacLeod, M. McCarty inheritance through “hereditary units”; 1950: E. Chargaff: “the total number of purines in DNA is equal to the total number of pyrimidines”; 1950s: JA Clements: physical properties of surfactant; 1953: J. Watson and F. Crick: three-dimensional double helical structure of DNA molecule; 1959: ME Avery: surfactant deficiency in RDS in premature babies; 1959: Hermansky–Pudlak syndrome; 1966: MW. Nirenberg break the genetic code; 1972: W. Fiers: first sequence of a gene; 1977: F. Sanger: sequence DNA for the first time; 1983: K. Banks Mullis: polymerase chain reaction; 2001–2003: Francis Collins: Human Genome Project; 2009: EH. Blackburn, CW. Greider, JW. Szostak: Nobel Prize “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”.

Figure 2

Discoveries in IPF genetics: 1950: IPF is reported in identical twin sisters; 1996–1998: First mutations in Hermansky–Pudlak syndrome (HPS) genes; 1997: Is there is fibrosis gene in pulmonary fibrosis? 2001: First SFTPC mutation in familiar IP; 2002: NKX2-1 mutations in brain-thyroid-lung syndrome; 2003: HPS-4 mutations; 2004: Bi-allelic ABCA3 mutations in NRD syndrome and chILD; 2005: Mutations in TERT in patients with bone-marrow failure; 2007: TERT and TERC mutations in familiar IP; 2009: SFTPA2 mutations FIP and adenocarcinoma families, 2010: ELMOD2 SNP polymorphism in IPF; 2011: A common SNP in the promoter region of the gene MUC5B: the strongest polygenic risk factor for sporadic IPF and familiar IP; 2011: IL8 SNP polymorphism in IPF; 2012: CDKN1A, 1L1RN, TP53 SNP polymorphisms in IPF; 2013: ATP11A, DPP9, DSP, FAM13A, HLA-DRB1, MAPT, MUC2, OBFC1, TERC, TERT, MDGA2, SPPL2C, TGFB1, TOLLIP, TLR3 SNP polymorphisms in IPF; 2014: DKC1 mutation in familiar IP; 2014: TMEM173 mutations in SAVI, 2015: RTEL1, PARN and TINF2 mutations in familiar IP; 2015: COPA mutations in COPA syndrome; 2015: IND, LRRC34 SNP polymorphisms in IPF; 2016 SFTPA1 mutations in FIP and/or adenocarcinoma families; 2016: NAF1 mutations in pulmonary fibrosis-emphysema; 2017: AKAP13 SNP polymorphism in IPF; 2018: HPS-2 gene mutations: fibrosing lung disease early in childhood; 2019: ZCCHC8 mutations in FIP; 2020: NOP10 and NHP2 mutations in FIP; 2022: POT1 mutation in FIP; 2022: KNL1, NPRL3, STMN3, RTEL1, and an intergenic variant in 10q25.1 in IPF; 2022: KIF15 mutations in IPF; 2022: RPA1 mutations in pulmonary fibrosis and STS.