Genetics

Predisposing genes in ILD  

Aim of this project is to identify genes that confer susceptibility to interstitial lung disease and identify genetically defined clinical disease phenotypes.

Most ILD's are complex diseases, occurring in genetically susceptible patients that have encountered an environmental trigger. Since decades clusters of family members with two or more relatives suffering from specific forms of ILD have been documented. This observation suggests that a patient's genetic constitution predisposes to certain forms of ILD. To understand the biological mechanisms involved, we investigate the genetic basis of disease in families and sporadic patients,  and study the molecular and cellular consequences of these genetic differences.

Project group: C.H.M. van Moorsel, J.C. Grutters

More information to be obtained from primary investigator:
Coline van Moorsel, PhD, associate professor
c.van.moorsel@antoniusziekenhuis.nl

Clinical course, outcome and genetic  associations in patients with Löfgren's syndrome

The aim of this study is to characterize the factors that determine onset and outcome of Löfgren's syndrome.

Sarcoidosis is a multisystemic granulomatous disorder with a wide variation in onset, clinical manifestation and disease outcome. Doctor Löfgren was the first to describe an acute and benign form of sarcoidosis, with bilateral hilar lymphadenopathy, fever, erythema nodosum and/or joint symptoms, which was later named after him: Löfren's syndrome.

Although the cause of Löfgren's syndrome is unknown, a genetic predisposition in combination with a common environmental agent responsible for triggering the immunological reactions is likely to be involved in disease development.

Genetic associations in Löfgren's syndrome have been found for particular human leukocyte antigen (HLA): HLA-DRB1*0301 and HLA-DQB1*0201. It has also been reported that carriers of these alleles face good prognostic outcomes.

This study reviews a large number of Dutch patients with Löfgren's syndrome, of whom clinical and radiological aspects, prognosis and genetics are sampled to accurately describe the clinical course of Löfgren's syndrome. The study especially focusses on possible interactions with genetic factors and the development of molecular biomarkers for Löfgren's syndrome.

Project group: B. Karakaya, C.H.M. van Moorsel, J.C. Grutters

More information to be obtained from primary investigator:
Bekir Karakaya, MD 
b.karakaya@antoniusziekenhuis.nl

Telomere biology in IPF  

This study explores the role of telomere biology in Idiopathic pulmonary fibrosis (IPF). Telomeres are non-coding protein-bound tandem repeat structures at the end of chromosomes. Chromosomes shorten during each cell division as a result of the DNA replication mechanism. This shortening would lead to chromosomal instability, but stability is maintained by the telomeres which can be shortened without initial consequences. Cells will avoid chromosomal damage stress by going into senescence or apoptosis when telomeres over time reach a critically short length. In order to retain replicative capacity, the protein-RNA complex telomerase elongates telomeres in certain tissues. Recent studies have already implicated telomere biology in a number of (lung) diseases.

The familial form of IPF is expected to have a genetic component underlying the disease. This is confirmed by the discovery of several mutations in familial IPF patients including mutations in TERT and TERC, the genes respectively coding for the protein and RNA component of telomerase. Analysis of IPF patients with mutations in TERT or TERC revealed a diminished telomerase activity and prematurely shortened telomere length in blood leukocytes. Further analysis of sporadic patients not carrying the mutation showed that all these patients had shorter leukocyte telomere length compared to healthy controls. This indicates that telomere shortening could play a role in the pathogenesis of IPF not only in familial IPF but also in the general development of IPF.

In this study, we set out to measure telomere biology in IPF patients. For this purpose we use PBMC's and lung tissue from IPF patients(sampled for diagnostic purposes or residual material after lung transplantation).

Project group: R. Snetselaar, C.H.M. van Moorsel, M. van Oosterhout, J.C. Grutters

More information to be obtained from primary investigator:
Reinier Snetselaar MSc
r.snetselaar@antoniusziekenhuis.nl

IIP, drugs and pharmacogenetics 

Pulmonary fibrosis can be caused by the use of certain therapeutic drugs which have been prescribed for other diseases. In this research project we investigate whether the occurrence of idiopathic interstitial pneumonia (a subtype in ILD) is related to the use of these drugs. We particularly focus on pharmacogenetic predictors that may be useful to identify patients who are at risk of developing an idiopathic interstitial pneumonia while using other therapeutic drugs.

Project group: H. Crommelin, V. Deneer, C.H.M. van Moorsel, J.C. Grutters

More information to be obtained from primary investigator:
Heleen Crommelin, MSc
h.crommelin@antoniusziekenhuis.nl