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Polymorphisms in the Tropomyosin TPM1 Short Isoform Promoter Alter Gene Expression and Are Associated With Increased Risk of Metabolic Syndrome

Lookup NU author(s): Professor Ann Daly

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Abstract

BACKGROUND Inflammation contributes to the development of atherosclerotic lesions in the metabolic syndrome. Tropomyosin isoform expression is altered in this disease and has a role in inflammatory cell plasticity, motility, and insulin sensitivity. We determined the frequency of haplotype carriage of three single-nucleotide polymorphisms (SNPs) in the short isoform promoter of the TPM1 gene in 300 normal controls and 500 metabolic syndrome patients. The effect of each haplotype on tropomyosin gene expression was assessed. METHODS PCR-restriction fragment length polymorphism assays were developed for each polymorphism. Promoter activity was measured using luciferase assays in the insulin-sensitive human embryonic kidney (HEK) 293 and the monocyte THP-1 lines. RESULTS The SNPs -111(1/C), -426(T/C), and -491(A/G), relative to the TPM1 short isoform transcription start site, occurred in haplotypes ATT, GCT, GTT, and GTC, and were in strong linkage disequilibrium. AU had a frequency of 66%. The presence of -491G, which conforms to a predicted binding site for transcription factor AML-1, caused a decrease in gene expression of 24% in the HEK 293 cells. In the THP-1 cells, haplotypes GTC and GTC gave 24% lower expression, whereas haplotype GCT gave expression at wild-type levels, The carriage of a -491G allele gave an odds ratio of 1.4(95% CI 1.02-1.8) for the metabolic syndrome (P < 0.03). CONCLUSIONS A polymorphism in the TPM1 short isoform promoter region is predicted to alter transcription factor binding, alters gene expression and is associated with the metabolic syndrome. This could affect inflammatory cells and cytoskeleton-mediated insulin signaling.


Publication metadata

Author(s): Savill SA, Leitch HF, Daly AK, Harvey JN, Thomas TH

Publication type: Article

Publication status: Published

Journal: American Journal of Hypertension

Year: 2010

Volume: 23

Issue: 4

Pages: 399-404

Print publication date: 01/04/2010

ISSN (print): 0895-7061

ISSN (electronic): 1941-7225

Publisher: Elsevier

URL: http://dx.doi.org/10.1038/ajh.2009.278

DOI: 10.1038/ajh.2009.278


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