POLYMORPHISMS OF THE TUMOR-NECROSIS-FACTOR-ALPHA GENE, CORONARY HEART-DISEASE AND OBESITY

Background Tumour necrosis factor-alpha (TNF-alpha) is a cytokine that has multiple functions. Through its effects on lipid metabolism, coag ulation, insulin resistance and endothelial function, TNF-alpha could be involved in cardiovascular pathophysiology. Given this possibility, we hypothesized that polymorphisms of the TNF-alpha gene might be ass ociated with a predisposition to coronary heart disease (CHD). Methods The entire coding region and 1053 bp upstream of the transcription st art site of the TNF-alpha gene were screened for polymorphisms using p olymerase chain reaction-single-strand conformation polymorphism (PCR- SSCP) and sequencing. Five polymorphisms were identified: four were lo cated in the upstream region at positions -857, -851, -308, -238 from the first transcribed nucleotide and one was found in a non-translated region at position +691. Six-hundred and forty-one patients with myoc ardial infarction (MI) and 710 control subjects from the ECTIM Study w ere: genotyped. Results The genotype frequencies were similar in cases and control subjects in the high-risk population of Belfast and in Fr ance; however, the TNF-alpha/-308A allele was more frequent in Belfast than in France (0.242 vs. 0.157; P < 0.0001), and carriers of this al lele were more frequently obese than non-carriers [1.52 (1.15-1.99), P <0.004]. No associations were found for the other polymorphisms. Concl usions These results suggest that polymorphisms of the TNF-alpha gene are unlikely to contribute to CHD risk in an important way, but the TN F-alpha/-308 polymorphism should be investigated further in relation t o obesity.