Pharmacogenetics and interstitial lung disease

Abstract

Purpose of review Interstitial lung disease (ILD) is comprised of a heterogeneous group of disorders with highly variable natural histories and response to therapies. Pharmacogenetics focuses on the variability in drug response due to the presence of genetic factors that influence drug metabolism or disease activity. In this article, we review relevant drug-specific and disease-specific polymorphisms that may influence therapeutic response, and then highlight a recently identified drug-gene interaction in patients with idiopathic pulmonary fibrosis (IPF). Recent findings The emergence of high-throughput genomic technology has allowed for identification of gene polymorphisms associated with susceptibility to specific disease states, including IPF and several connective tissue diseases known to cause ILD. IPF risk loci span a diverse group of genes, while most associated with CTD are critical to immune signaling. A recent pharmacogenetic analysis of patients enrolled in an IPF clinical trial identified a variant within TOLLIP to be associated with differential response to N-acetylcysteine therapy. Summary Though few pharmacogenetic investigations have been conducted in patients with ILD to date, ample opportunities for pharmacogenetic exploration exist in this patient population. Such exploration will advance our understanding of specific ILDs and help usher in an era of personalized medicine.

Sex and gender in interstitial lung diseases

“…Are there sex-specific pharmacogenetic differences modifying the effect of antifibrotic drugs? [85].…”

The use of chest magnetic resonance imaging in interstitial lung disease: a systematic review

“…This differentiation is important in the treatment of ILD, because anti-inflammatory medications (i.e. corticosteroids) are currently used in ILD related to collagen vascular disease in contrary to the antifibrotics pirfenidone (Roche, Basel, Switzerland) and nintedanib (Boehringer Ingelheim, Ingelheim am Rhein, Germany), which are indicated in patients with idiopathic pulmonary fibrosis (IPF) [7,8]. Thin-slices MDCT is also limited by poor reproducibility of visual scores for ILD abnormalities and lack of specific outcome measures to evaluate response to treatment [9].…”

Genomic Profiling for Predictive Treatment Strategies in Fibrotic Interstitial Lung Disease

“…Since the introduction of antifibrotic treatments into clinical practice, which have transformed our understanding of IPF, some patients have remained stable for many years, while others have experienced steady progression, and a minority have experienced rapid disease worsening. Consequently, in recent years, various biomarkers associated with the intricate cellular, biological and immunobiological pathways have been studied as potential indicators of treatment efficacy [37][38][39].…”

“…DNA samples from patients enrolled in the Anti-Coagulant Effectiveness in Idiopathic Pulmonary Fibrosis trial were used in a genome-wide association study [63]. Examination of this group revealed a possible association between warfarin treatment and the MUC5B promoter polymorphism, although the sample size was insufficient for formal interaction testing [39]. Notably, among the genotyped study participants, a greater number of deaths were observed in individuals with the polymorphism who received warfarin compared to those who received placebo (6 on warfarin vs. 1 on placebo), suggesting a possible interaction.…”

“…Three allelic variants of TPMT, TPMT2, TPMT3A and TPMT3C, account for 80-90% of individuals with low or intermediate TPMT activity [86,87]. International clinical recommendations and guidelines differ on the determination of TPMT status prior to initiation of azathioprine therapy, although regular monitoring of white blood cells is recommended as AEs may be TMPT-independent [39,88]. Patients with RA who are heterozygous for the TPMT3A allele have an increased risk of azathioprine-related haematopoietic and gastrointestinal toxicity compared to those with the wild-type allele [89,90].…”