A functional macrophage migration inhibitory factor promoter polymorphism is associated with reduced diffusing capacity

C. Zhang, C. Ramsey, A. Berical, L. Yu, L. Leng, K. A. McGinnis, Y. Song, H. Michael, M. C. McCormack, H. Allore, A. Morris, K. Crothers, R. Bucala, P. J. Lee, M. Sauler

Research output: Contribution to journalArticlepeer-review

Abstract

Cigarette smoke exposure is the leading mod-ifiable risk factor for chronic obstructive pulmonary disease (COPD); however, the clinical and pathologic consequences of chronic cigarette smoke exposure are variable among smokers. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of COPD. Within the promoter of the MIF gene is a functional polymorphism that regulates MIF expression (-794 CATT 5– 8 microsatellite repeat) (rs5844572). The role of this poly-morphim in mediating disease susceptibility to COPD-related traits remains unknown. We performed a cross-sectional analysis of DNA samples from 641 subjects to analyze MIF-794 CATT 5– 8 (rs5844572) polymorphism by standard methods. We generated multivariable logistic regression models to determine the risk of low expressing MIF alleles for airflow obstruction [defined by forced expiratory volume in 1 s (FEV 1 )/forced vital capacity ratio <0.70] and an abnormal diffusion capacity [defined by a diffusion capacity for carbon monoxide (DL CO ) percent predicted <80%]. We then used generalized linear models to determine the association of MIF geno-types with FEV 1 percent predicted and DL CO percent predicted. The MIF-794 CATT 5 allele was associated with an abnormal diffusion capacity in two cohorts [odds ratio (OR): 9.31, 95% confidence interval (CI): 1.97– 4.06; and OR: 2.21, 95% CI: 1.03– 4.75]. Similarly, the MIF-794 CATT 5 allele was associated with a reduced DL CO percentage predicted in these two cohorts: 63.5 vs. 70.0 (P < 0.0023) and 60.1 vs. 65.4 (P < 0.059). This study suggests an association between a common genetic polymorphism of an endogenous innate immune gene, MIF, with reduced DL CO , an important measurement of COPD severity.

Original languageEnglish (US)
Pages (from-to)L400-L405
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume316
Issue number2
DOIs
StatePublished - Feb 2019

Keywords

  • COPD
  • Diffusion capacity
  • Emphysema
  • MIF
  • Macrophage migration inhibitory factor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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