Dataset Information

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

ABSTRACT:

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk.

Methods

We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10^-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report.

Results

The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies.

Conclusion

Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

SUBMITTER: Guillen-Guio B

PROVIDER: S-EPMC10402235 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Guillen-Guio Beatriz B Paynton Megan L ML Allen Richard J RJ Chin Daniel P W DPW Donoghue Lauren J LJ Stockwell Amy A Leavy Olivia C OC Hernandez-Beeftink Tamara T Reynolds Carl C Cullinan Paul P Martinez Fernando F Booth Helen L HL Fahy William A WA Hall Ian P IP Hart Simon P SP Hill Mike R MR Hirani Nik N Hubbard Richard B RB McAnulty Robin J RJ Millar Ann B AB Navaratnam Vidya V Oballa Eunice E Parfrey Helen H Saini Gauri G Sayers Ian I Tobin Martin D MD Whyte Moira K B MKB Adegunsoye Ayodeji A Kaminski Naftali N Shwu-Fan Ma M Strek Mary E ME Zhang Yingze Y Fingerlin Tasha E TE Molina-Molina Maria M Neighbors Margaret M Sheng X Rebecca XR Oldham Justin M JM Maher Toby M TM Molyneaux Philip L PL Flores Carlos C Noth Imre I Schwartz David A DA Yaspan Brian L BL Jenkins R Gisli RG Wain Louise V LV Hollox Edward J EJ

medRxiv : the preprint server for health sciences 20230724

<h4>Introduction</h4>Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the <i>HLA-DQB1</i> gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if ...[more]

PMID: 37546732

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Project description:BackgroundIdiopathic 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.MethodsFirst, 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.FindingsIn 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.InterpretationNovel 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.FundingNational Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.

Dataset Information

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Introduction

Methods

Results

Conclusion

Publications

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Similar Datasets

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