Original Article
Association between MUC5B and TERT polymorphisms and different interstitial lung disease phenotypes

https://doi.org/10.1016/j.trsl.2013.12.006Get rights and content

TERT and MUC5B polymorphisms have been associated consistently with idiopathic pulmonary fibrosis (IPF) in recent genomewide genetic studies. However, it remains unclear how both loci contribute to the susceptibility to different entities of sporadic interstitial lung disease (ILD). We sought to test the associations of the 2 polymorphisms with IPF and non-IPF ILD entities in a white population. Associations between 2 polymorphisms in TERT (rs2736100) and MUC5B (rs35705950) and IPF or non-IPF sporadic ILD were tested using 227 patients with ILD and 689 control subjects. Genotypic data were also correlated with pulmonary functions measured in patients with ILD. As a result, rs2736100 and rs35705950 were associated significantly and independently with ILD as a single phenotype (Odds ratio [OR], 1.29; 95% confidence interval [CI], 1.04–1.60; P = 2 × 10−2; and OR, 2.22; 95% CI, 1.69–2.92; P = 7 × 10−9; respectively). When considering IPF and “other ILD” (non-IPF) separately, rs35705950 had a stronger association with IPF (OR, 3.2; 95% CI, 2.21–4.63; P = 1.2 × 10−10) than with other ILD (OR, 1.72; 95% CI, 1.22–2.42; P = 1.2 × 10−3). In contrast, rs2736100 was associated with other ILD (OR, 1.43; 95% CI, 1.11–1.85; P = 6.2 × 10−3) but not with IPF (OR, 1.08; 95% CI, 0.78–1.49; P > 0.05). Rs35705950 correlated significantly with increased pulmonary function (P < 0.05). It was also associated with ILD without airflow obstruction in both the IPF and other ILD groups (P < 0.01 for both), and conferred the highest risk for IPF without airflow obstruction (OR, 4.46; 95% CI, 2.60–7.66; P = 4.5 × 10−9). Our study suggests that although both loci confer independent risks for ILD, rs35705950 may, in particular, contribute differentially to IPF and other ILD entities. Our study further highlights the genetic and phenotypic heterogeneity of ILD.

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Ethics statement

Samples used in this study were collected with approval of institutional review boards of the Lung Tissue Research Consortium and the University of Chicago. Written informed consent was obtained from each participant. The Purdue University institutional review board has approved this study. The study was carried out in compliance with the Helsinki Declaration.

Study subjects

DNA extracted from peripheral blood of patients with ILD (n = 227) was obtained from the Lung Tissue Research Consortium. All patients

Demographic data and environmental covariates

We compared the distribution of demographic and environmental covariates data between each ILD subset and the normal lung control group. Significant differences were observed in the distribution of age, gender, and smoking status, but not BMI data. We also compared the difference in the data distribution between the IPF and non-IPF other ILD group. Only the distribution of age data was observed to be significantly different between these 2 groups (P = 0.01; Table I). These factors were then all

Discussion

Our study, for the first time, tested the associations between the TERT and MUC5B polymorphisms, and different sporadic ILD entities in a white population. Although the sample size is moderate, our findings confirmed that both polymorphisms confer susceptibility independently to ILD as an overall phenotype, with the MUC5B locus conveying a higher risk than the TERT polymorphism. Our results confirmed the findings that have been reported previously in genomewide studies.11, 12, 14, 15 However,

Acknowledgments

Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.

This study was supported in part by the National Institutes of Health/National Heart, Lung, and Blood Institute grant (R03 HL097016) (WL) and a startup fund (WL) by the Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University.

The authors thank the Lung Tissue Research Consortium (http://www.ltrcpublic.com) and the Translational

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