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

TitleGenetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.
Publication TypeJournal Article
Year of Publication2013
AuthorsNoth I, Zhang Y, Ma S-F, Flores C, Barber M, Huang Y, Broderick SM, Wade MS, Hysi P, Scuirba J, Richards TJ, Juan-Guardela BM, Vij R, Han MLK, Martinez FJ, Kossen K, Seiwert SD, Christie JD, Nicolae D, Kaminski N, Garcia JGN
JournalLancet Respir Med
Volume1
Issue4
Pagination309-317
Date Published2013 Jun
ISSN Number2213-2600
KeywordsAdult, Aged, DNA, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Idiopathic Pulmonary Fibrosis, Linkage Disequilibrium, Male, Middle Aged, Phenotype, Retrospective Studies, Survival Rate, United States
Abstract

<p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>FINDINGS: </b>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 [r(2)=0·07], rs5743894 [r(2)=0·16], and rs5743890 [r(2)=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)) compared with homozygous carriers of common alleles for these SNPs.</p><p><b>INTERPRETATION: </b>Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease.</p><p><b>FUNDING: </b>National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.</p>

DOI10.1016/S2213-2600(13)70045-6
Alternate JournalLancet Respir Med
PubMed ID24429156
PubMed Central IDPMC3894577
Grant ListU01 HL105371 / HL / NHLBI NIH HHS / United States
P01 HL98050 / HL / NHLBI NIH HHS / United States
R01 HL95397 / HL / NHLBI NIH HHS / United States
R01 HL087115 / HL / NHLBI NIH HHS / United States
RC2 HL101740 / HL / NHLBI NIH HHS / United States
F32 HL009961 / HL / NHLBI NIH HHS / United States
UL1 RR024999 / RR / NCRR NIH HHS / United States
R01 HL1081619 / HL / NHLBI NIH HHS / United States
U10 HL080513 / HL / NHLBI NIH HHS / United States
HL080513 / HL / NHLBI NIH HHS / United States
R01 HL095397 / HL / NHLBI NIH HHS / United States
HL101740 / HL / NHLBI NIH HHS / United States
RC2 HL096845 / HL / NHLBI NIH HHS / United States
R01 HL096845 / HL / NHLBI NIH HHS / United States
P50 HL0894932 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
RC1 HL09961 / HL / NHLBI NIH HHS / United States
RC1 HL099619 / HL / NHLBI NIH HHS / United States