Published ahead of print on June 12, 2003, doi:10.1165/rcmb.2003-0024OC
© 2003 American Thoracic Society DOI: 10.1165/rcmb.2003-0024OC Monocyte Chemoattractant Protein-4 Core Promoter Genetic VariantsInfluence on YY-1 Affinity and Plasma LevelsCombined Program in Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, and Respiratory Physiology Program, Harvard School of Public Health, Boston, Massachusetts Address correspondence to: Craig M. Lilly, Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis Street, PBB 3rd Floor Clinics Building, Boston, MA 02115. E-mail: clilly{at}partners.org
Monocyte chemoattractant protein-4 (MCP-4) is a CC chemokine implicated in the recruitment of eosinophils, monocytes, and T-lymphocytes in diseases of mucosal inflammation, including asthma. We tested the hypothesis that there is a genetic basis for differences in MCP-4 expression among individuals by evaluating the effects of core promoter variants on MCP-4 expression. We identified two single-nucleotide T-to-C polymorphisms in the MCP-4 core promoter that occur 896 and 887 base pairs preceding the transcription initiation site. The –887 variant alters a consensus binding motif for the transcription factor YY-1. Electrophoretic mobility shift assay demonstrated that YY-1 containing nuclear extracts from tumor necrosis factor-
Abbreviations: base pairs, bp • electrophoretic mobility shift assay, EMSA • interleukin, IL • monocyte chemoattractant protein-4, MCP-4 • peripheral blood mononuclear cells, PBMCs • polymerase chain reaction, PCR • tumor necrosis factor- This article has been cited by other articles:
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–stimulated peripheral blood mononuclear cells had greater avidity for the wild-type (YY-1 motif intact) sequence than for the variant sequence. Increasing doses of a YY-1 expression vector induced significantly greater reporter activity from MCP-4 core promoter expression constructs of the wild-type compared with the variant sequence in transient transfection experiments. The external validity of these observations was demonstrated by measuring plasma levels of MCP-4 from individuals with the alternative forms of the gene. Individuals bearing haplotypic variants of the MCP-4 core promoter that avidly bind the transcription factor YY-1 had higher plasma levels of MCP-4 than did individuals with variants with lower binding avidity (490, 360, and 360 pg/ml; P < 0.01). Our findings suggest that the MCP-4 core promoter YY-1 binding motif is functional, modulates the transcriptional regulation of the MCP-4 gene, and that part of the variance in the systemic expression of MCP-4 is determined by core promoter genetic variants. 
