The MUC5B Variant Is Associated with Idiopathic Pulmonary Fibrosis but Not with Systemic Sclerosis Interstitial Lung Disease in the European Caucasian Population

Abstract

A polymorphism on the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) but not with systemic sclerosis (SSc) with interstitial lung disease (ILD). We genotyped the MUC5B promoter in the first 142 patients of the French national prospective cohort of IPF, in 981 French patients with SSc (346 ILD), 598 Italian patients with SSc (207 ILD), 1383 French controls and 494 Italian controls. A meta-analysis was performed including all American data available. The T risk allele was present in 41.9% of the IPF patients, 10.8% of the controls (P = 2×10–44), OR 6.3 [4.6–8.7] for heterozygous patients and OR 21.7 [10.4–45.3] for homozygous patients. Prevalence of the T allele was not modified according to age, gender, smoking in IPF patients. However, none of the black patients with IPF presented the T allele. The prevalence of the T risk allele was similar between French (10%) and Italian (12%) cohorts of SSc whatever the presence of an ILD (11.1% and 13.5%, respectively). Meta-analysis confirmed the similarity between French, Italian and American cohorts of IPF or SSc-ILD. This study confirms 1) an association between the T allele risk and IPF, 2) an absence of association with SSc-ILD, suggesting different pathophysiology.

Physiology of the lung in idiopathic pulmonary fibrosis

“…The occurrence of IPF-like disease in patients with mutations in components of the telomerase complex (TERT, TERC) or other telomere-associated proteins (DKC1, TINF2, RTEL1) suggests the contribution of genomic instability, defective cell homeostasis and/or cell senescence to IPF [14,17]. A gain-of-function mutant allele in the promoter regions of the gene coding the secreted mucin MUC5B is found in ∼40% of patients with sporadic idiopathic interstitial pneumonia, including patients with IPF, versus 9-10% of control subjects [18,19], although the mechanisms by which increased mucin production relates to alveolar fibrosis are not known.…”

Management of suspected monogenic lung fibrosis in a specialised centre

“…In addition to monogenic Mendelian diseases, several genetic polymorphisms increase the risk of IPF, with odds ratios up to 20 in homozygous carriers of the rare allele in the promoter of MUC5B encoding mucin-5B (figure 5) [101,102].…”

“…Indeed, a single nucleotide polymorphism in TOLLIP, associated with mortality, was linked to reduced expression of TOLLIP, and recent post hoc analysis suggests that it affects the response to N-acetylcysteine [101,102,105,106].…”

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

“…Genetic studies in familial forms of IPF led to the discovery of mutations within TERT (encoding the telomerase reverse transcriptase) and TR (encoding the telomerase RNA component), which are both required for normal telomerase activity [5]. Heterozygous mutations within TERT or TR are detected in 15% to 20% of the cases of familial forms of pulmonary fibrosis (PF), whereas they are very rarely detected in sporadic IPF (<3%) [5][6][7]. In addition to PF, mutations in the telomerase complex are associated with mucocutaneous abnormalities such as dyskeratosis congenita (abnormal skin pigmentation, nail dystrophy, oral leukoplakia), and possibly severe complications including liver cirrhosis and bone marrow failure.…”