ArticlesGenetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study
Introduction
Idiopathic pulmonary fibrosis (IPF) has a low incidence (4·6–16·3 cases per 100 000 person-years),1, 2 but is a devastating disease of unknown aetiology that is characterised by an interstitial fibrotic process and high mortality.3 Lung transplantation is the only treatment option that successfully improves survival; immunosuppression regimens have been shown to be harmful.4 Several rare genetic variants mostly associated with familial IPF and a common single nucleotide polymorphism (SNP) of MUC5B in sporadic IPF have been identified, suggesting that genetic factors contribute to disease.5, 6 As yet, no genetic variant has been associated with IPF outcomes. Therefore, identification of genetic variants associated with susceptibility to IPF and alleles involved in the heterogeneity of disease course and mortality is an important research focus.
Mutations in TERT or TERC result in telomere shortening and are associated with both familial and non-familial IPF.7 A previous genome-wide association study (GWAS) examining about 250 000 SNPs in only 159 IPF cases8 supported this association. Rare heterozygous variants in SFTPA2 and SFTPC have also been implicated in familial IPF.9 These findings suggest that the aetiology of IPF might involve several genetic loci.
GWAS continues to be the method of choice for identification of common genetic variants associated with complex diseases.10 In view of the power of GWAS to detect expected effects for common variants with realistic sample sizes,8 we postulated that an independent GWAS of IPF would identify novel polymorphisms associated with disease susceptibility and allow assessment of whether these loci were also associated with mortality. Although new knowledge of IPF susceptibility could provide targets for novel treatment strategies, identification of genes associated with mortality in patients with IPF might draw attention to potential therapeutic targets and enable prognostication.
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Study design and samples
First, we did a three-stage GWAS (figure 1). Stage one was a discovery GWAS in European Americans for susceptibility to IPF. Identified susceptibility loci were followed up for replication in two independent case-control association studies (stages two and three). Second, we assessed the association between susceptibility loci and mortality in three case series with follow-up data selected from stages one and two (figure 1). Finally, we assessed the correlation between SNP genotypes and gene
Results
Table 1 shows the sample sizes for each stage of the GWAS. As expected, similar to a large single-centre experience for first presentation of IPF,19 the cases included in stage one had a wide range of disease severity and age (table 2). Patients in stage two had similar overall severity to those in stage one. Patients in stage three had more severe disease than did those in stages one and two, as assessed by forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO). However
Discussion
We have identified novel genetic variants residing in two genetic loci—in TOLLIP at 11p15.5 and in SPPL2C at 17q21.31—that are associated with IPF susceptibility in European Americans, and have replicated the previously identified association with an SNP in MUC5B. As far as we are aware, we have shown for the first time that one of the novel genetic variants for susceptibility—rs5743890 in TOLLIP—is also associated with IPF mortality (panel).
MUC5B and TOLLIP reside at the same genetic locus.
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