Publications

Work-related asthma is common among adult asthmatics, either asthma initially caused by work (occupational asthma) or pre-existing asthma worsened by work factors (work-exacerbated asthma). Appropriate management depends on both correct diagnosis and on recognition of etiology. Following a systematic literature review, the American College of Chest Physicians enpaneled a group of experts that reviewed this material, extended the literature review, and developed a "Consensus Statement on the Diagnosis, and Management of Work-Related Asthma", published in 2008. This article addresses the main practical aspects of that Consensus Statement, including clinical clues to diagnosis of work-related asthma from the medical history, exposure assessment, targeted diagnostic tests, and directed patient management. The range and importance of preventive measures are also addressed.

Regulatory T cells (TREG) are a subset of CD4+ T cells with a critical role in the prevention of autoimmunity. Whether defects in TREG contribute to the pathogenesis of rheumatoid arthritis (RA) is unclear. However, a variety of approved and experimental drugs for RA may work, in part, by promoting the function or increasing numbers of TREG. Furthermore, animal studies demonstrate that direct injection of TREG ameliorates a wide range of experimental models of inflammatory and autoimmune diseases. Thus, cell-based therapy with TREG has the potential to produce durable disease remission in patients with RA.

The Pharmacogenomics Center of the University of California, San Francisco (CA, USA) fosters research and educational activities focused on the genomic basis for variation in drug response. Investigators in the Center conduct multidisciplinary and multicenter research on a diverse array of clinically used drugs with the goal of understanding the genetic factors that contribute to variation in therapeutic and adverse drug response. The Center houses the large NIH-supported Pharmacogenomics of Membrane Transporters Project, which is a leader in understanding genetic variation in membrane transporters that are important in clinical drug response. Center investigators study racially and ethnically diverse populations, are pioneers in the education of PharmD, MD and PhD students in pharmacogenomics, and have led the establishment of unique graduate and postdoctoral training programs focused on pharmacogenomics. A key emphasis of the Center is on biological mechanisms with a goal of facilitating the development of safer and more effective medications.

OBJECTIVES

Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations.

METHODS

We measured luciferase activities of the six common promoter haplotypes of MATE1 using in-vitro and in-vivo reporter assays.

RESULTS

Haplotypes that contain the most common variant (mean allele frequency in four ethnic groups: 0.322), g.-66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, activating protein-1 (AP-1) and activating protein-2 repressor (AP-2rep), were predicted to bind to the promoter in the region of g.-66T>C. Results from electrophoretic mobility shift assays showed that the g.-66T allele, exhibited greater binding to AP-1 than the g.-66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.-66T>C. These data suggest that the reduced transcriptional activity of g.-66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.-66T>C in comparison with samples from individuals who were homozygous for the g.-66T allele.

CONCLUSION

Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.-66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.