Аннотация:Linkage disequilibrium (LD) is the central concept of genetic association studies. Although LD has been shown not to be uniformly distributed across the genome, limited information is available about the characteristics of LD within candidate genes at large. We screened coding and regulatory regions of 50 candidate genes for cardiovascular diseases and identified 228 polymorphisms. The overall sequence diversity was 3.81 ± 0.31 × 10–4. Intragenic LD was generally very strong, with 40% of the 464 pairs of polymorphisms exhibiting a complete LD. However, if we consider ½D′½ = 0.7 as an arbitrary limit for useful LD in association studies, 26% of the pairs fell below this threshold, half of which being in negative LD, a situation where LD is even more difficult to detect. Non-synonymous coding polymorphisms, which are more likely to have a functional role, were more represented among low-frequency alleles and were more often in complete negative LD with other polymorphisms. This implies that in many situations the power to detect the effect of a non-synonymous polymorphism by measuring a nearby marker might be low. Although intragenic LD was partly a function of physical distance, gene-specific patterns of LD were observed, making it difficult to provide general guidelines for selecting the most useful polymorphisms in association studies. For all these reasons, association studies should concentrate on the overall sequence variation of functionally important regions of candidate genes and not only on a few polymorphisms. The variability of important intergenic regions identified by different approaches including comparative genomics will also have to be assessed.
