Gene Variants Linked to Pulmonary Fibrosis

A variant in a gene that encodes for toll interacting protein (TOLLIP) was associated with an increased mortality risk for idiopathic pulmonary fibrosis, a rare and devastating lung disease.

The variant resulted in decreased expression of TOLLIP in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and because toll interacting protein plays a role in regulating immunity to certain stimuli, this novel finding suggests an abnormal immune response.

A team of scientists led by those at the University of Chicago Medical Center (IL, USA) carried out 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, who met standard criteria, were obtained from several US centers for each stage. The multi-institution research team looked for links between genetic markers and IPF in three separate cohorts of patients. The results were consistent in all three groups, highlighting the reproducibility of the results that could now provide investigators with a better understanding of what causes IPF.

In stage one of the GWAS, the investigators identified 20 loci from the 542 patients with IPF and 542 control individuals paired one-by-one to cases by genetic ancestry. Six single nucleotide polymorphisms (SNP) reached genome-wide significance in stage two with 544 patients, 687 control individuals. There were three TOLLIP SNP; one mucin-5B (MUC5B) SNP; one MAM domain containing glycosylphosphatidylinositol anchor 2 (MDGA2) SNP; and one signal peptide peptidase like 2C (SPPL2C) SNP. The version of TOLLIP that appears to prevent onset of the disease was also the variant that increased the risk of death in patients who did develop IPF.

Naftali Kaminski, MD, professor of medicine and cosenior author said, “The finding that one of the TOLLIP gene variants is reproducibly linked to higher mortality in IPF patients has significant implications for patient management. If an IPF patient has this variant, we might want to consider lung transplantation early in the course of the disease. It's not an ideal treatment, but it saves lives. We might be able to use the genetic markers to reveal who might need a transplant quickly.” The study was published on April 17, 2013, in the journal the Lancet Respiratory Medicine.

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