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, 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
Abstract
Cigarette smoke exposure is the leading modifiable 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 CATT5-8 microsatellite repeat) ( rs5844572 ). The role of this polymorphim 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 CATT5-8 ( 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 (FEV1)/forced vital capacity ratio <0.70] and an abnormal diffusion capacity [defined by a diffusion capacity for carbon monoxide (DLCO) percent predicted <80%]. We then used generalized linear models to determine the association of MIF genotypes with FEV1 percent predicted and DLCO percent predicted. The MIF-794 CATT5 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 CATT5 allele was associated with a reduced DLCO 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 DLCO, an important measurement of COPD severity.
Trial registration: ClinicalTrials.gov NCT00608764.
Keywords: COPD; MIF; diffusion capacity; emphysema; macrophage migration inhibitory factor.
Conflict of interest statement
Yale University has applied for patent protection for the clinical utility of MIF genotype determination. R. Bucala is listed as coinventor on this application.
Source: PubMed