Abstract
IntroductionTransforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association.MethodsPCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses.ResultsThe heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status.ConclusionsInteraction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA.
Highlights
Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation
To investigate the possible role of the transforming growth factor-beta-1 (TGFB1) gene in the development of ischaemic heart disease (IHD) in rheumatoid arthritis (RA), we have examined the association of selected single-nucleotide polymorphisms (SNP) (-509, +868, and +913) with the presence of IHD or previous myocardial infarction (MI) in a cohort of patients recruited into a study of comorbidity in RA
We have demonstrated an association of polymorphism in the TGFB1 gene with IHD and MI in RA
Summary
Transforming growth factor-beta (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association. The excess risk of cardiovascular disease (CVD) associated with rheumatoid arthritis (RA) has long been recognized [1,2,3,4]. Polymorphism in other genes in the HLA region, namely lymphotoxin A and tumor necrosis factor-alpha (TNFA) -308, has been shown to be associated with CVD in RA [12,13]. Several polymorphisms in non-HLA genes have been reported to be associated with CV conditions/ events in RA [14,15,16,17,18,19]
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