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

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.