Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study

Abstract

Summary Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF. Methods First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10−8) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes. Findings In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r2=0.07], rs5743894 [r2=0.16], and rs5743890 [r2=0.01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1.72 [95% CI 1.24–2.38]; p=0.0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0.097), 40% in those with the minor allele of rs111521887 (p=3.0 × 10−4), and 50% in those with the minor allele of rs5743894 (p=2.93 × 10−5) compa...

The MUC5B Promoter Polymorphism Is Associated With Idiopathic Pulmonary Fibrosis in a Mexican Cohort but Is Rare Among Asian Ancestries

“…[1][2][3] Th e MUC5B promoter polymorphism was originally reported to be associated with IPF by Seibold et al, 3 nine loci outside of the MUC5B locus were reported by Fingerlin et al, 1 and two SNPs within TOLLIP were reported by Noth et al 2 We chose not to genotype a third reported SNP within TOLLIP , since it was found to be in high linkage disequilibrium ( r 2 5 0.97) with one of the other genotyped TOLLIP SNPs (rs111521887). 2 …”

“…[3][4][5] Of note, a promoter polymorphism in MUC5B has been confi rmed by multiple studies as a common risk factor with the largest genetic eff ect on development of pulmonary fi brosis, estimated to increase risk by sixfold for people who are heterozygous for the polymorphism and by 20-fold for those who are homozygous . [1][2][3]6,7 Th e identifi cation of these loci, and of the MUC5B polymorphism, in particular, have changed perspectives on the pathogenesis of pulmonary fi brosis, motivated additional research on the risk factors for pulmonary fi brosis, and generated new targets for pharmacologic therapies. 3,[8][9][10] While research on the genetics of pulmonary fi brosis is making great progress, these studies share an important limitation: All were conducted in populations of non-Hispanic white subjects only.…”

Idiopathic pulmonary fibrosis biomarkers: clinical utility and a way of understanding disease pathogenesis

“…117 Finally, a more recent genome-wide association study identified a common single-nucleotide polymorphism in TOLLIP, a toll-interacting protein felt to play a role in innate immune system regulation, that correlates with increased mortality. 118 Clearly, these biomarkers have tantalizing utility in early prognostication and perhaps even identifying patients at risk for development of IPF. Similar studies have been identifying additional genetic variants that, with further investigation, will likely broaden the genetic understanding of IPF and possibly serve similar functions as biomarkers.…”

Idiopathic Pulmonary Fibrosis: Clinical Behavior, Pathogenic Mechanisms and Therapeutic Approach

“…Almost at the same time, Noth et al 15 reported a three-stage GWAS, with stage one being a discovery GWAS and stages two and three independent case-control studies. Their results confirmed previously reported gene variants, including MUC5B and TERT SNPs, and revealed novel variants in toll interacting protein (TOLLIP, (rs111521887, rs5743894, rs5743890; 11p15.5) and signal peptide peptidase like 2C (SPPL2C, rs17690703; 17q21.31) associated with IPF susceptibility.…”