Single nucleotide polymorphisms in multiple novel thrombospondin genes maybe associated with familial premature myocardial infarction

Background-Recent advances in high-throughput genomics technology have expa nded our ability to catalogue allelic variants in large sets of candidate g enes related to premature coronary artery disease. Methods and Results-A total of 398 families were identified in 15 participa ting medical centers; they fulfilled the criteria of myocardial infarction, revascularization, or a significant coronary artery lesion diagnosed befor e 45 years in men or 50 years in women. A total of 62 vascular biology gene s and 72 single-nucleotide polymorphisms were assessed. Previously undescri bed variants in 3 related members of the thrombospondin protein family were prominent among a small set of single-nucleotide polymorphisms that showed a statistical association with premature coronary artery disease. A missen se variant of thrombospondin 4 (A387P) showed the strongest association, wi th an adjusted odds ratio for myocardial infarction of 1.89 (P=0.002 adjust ed for covariates) for individuals carrying the P allele. A variant in the 3' untranslated region of thrombospondin-2 (change of thymidine to guanine) seemed to have a protective effect against myocardial in individuals homoz ygous for the variant (adjusted odds ratio of 0.31; P=0.0018). A missense v ariant in thrombospondin-1 (N700S) was associated with an adjusted odds rat io for coronary artery disease of 11.90 (P=0.041) in homozygous individuals , who also had the lowest level of thrombospondin-1 by plasma assay (P=0.00 19). Conclusions-This large-scale genetic study has identified the potential of multiple novel variants in the thrombospondin gene family to be associated with familial premature myocardial infarction. Notwithstanding multiple cav eats, thrombospondins specifically and high-throughput genomic technology i n general deserve further study in familial ischemic heart disease.