Sequence diversity in 36 candidate genes for cardiovascular disorders

Two strategies involving whole-genome association studies have been propose d for the identification of genes involved in complex diseases. The first o ne seeks to characterize all common variants of human genes and to test the ir association with disease. The second one seeks to develop dense maps of single-nucleotide polymorphisms (SNPs) and to detect susceptibility genes t hrough linkage disequilibrium. We performed a molecular screening of the co ding and/or flanking regions of 36 candidate genes for cardiovascular disea ses. All polymorphisms identified by this screening were further genotyped in 750 subjects of European descent. In the whole set of genes, the lengths explored spanned 53.8 kb in the 5' regions, 68.4 kb in exonic regions, and 13 kb in the 3' regions. The strength of linkage disequilibrium within can didate regions suggests that genomewide maps of SNPs might be efficient way s to identify new disease-susceptibility genes, provided that the maps are sufficiently dense. However, the relatively large number of polymorphisms w ithin coding and regulatory regions of candidate genes raises the possibili ty that several of them might be functional and that the pattern of genotyp e-phenotype association might be more complex than initially envisaged, as actually has been observed in some well-characterized genes. These results argue in favor of both genomewide association studies and detailed studies of the overall sequence variation of candidate genes, as complementary appr oaches.