Polymorphisms in the thrombopoietin gene are associated with risk of myocardial infarction at a young age

Five polymorphisms in the thrombopoietin (TPO) gene were identified, one in the 5' untranslated region (UTR) (C1796T), two within intron 5 (C4830A and A4877C), and two in the 3' UTR (A5713G and A6160T). The allele frequencies were determined in a group of 450 healthy middle aged men from the UK and found to be 0.46 for 1796T, 0.38 for 4830A, 0.004 for 4877C, 0.47 for 5713G and 0.07 for 6160T. Genotypes for the three common polymorphisms were dete rmined in a group of 176 young male Swedish survivors of a myocardial infar ction (MI) and 186 age-matched controls and a group of 156 young Italian su rvivors of an MI and 147 age and sex matched controls. In both the Swedish and the Italian studies polymorphisms were found to be associated with incr eased risk of MI. In the Swedish sample the frequency of 4830A was signific antly higher in controls (0.40) compared with patients (0.29) (P = 0.003), with an odds ratio for AA homozygotes of 0.48 (0.25-0.92; P = 0.03) compare d with CC homozygotes. In the Italian sample the frequency of 5713G was sig nificantly lower in controls (0.31) compared with cases (0.40) (P = 0.03), with an odds ratio for GC homozygotes of 2.29 (1.08-4.89; P = 0.03) compare d with AA homozygotes. These risk associations are consistent since 4830A a nd 5713A show strong allelic association. After adjusting for other measure d risk factors the effect on risk was still significant in the Italian samp le 2.39(1.02-5.58), but not in the Swedish sample 0.46 (0.16-1.32). The obs ervation of frequency differences between cases and controls in two indepen dent samples strongly suggests that the TPO gene is involved as a risk fact or for developing MI at a young age, but the identified polymorphisms are p robably acting as markers for an unidentified functional mutation elsewhere in the gene locus. (C) 2001 Elsevier Science Ireland Ltd. All rights reser ved.