Genetic association studies using single nucleotide polymorphisms (SNPs) and insertion/deletion variants are a common feature on the atherosclerosis research landscape. A recent Medline search using the terms “[gene] AND [polymorphism] AND [X],” where X was “atherosclerosis,”“vascular biology,” thrombosis,” or “lipoprotein,” found 4000 original articles. Furthermore, the yearly number of new reports has been growing exponentially since 1983 (Figure). The allure of SNPs, the release of millions of SNP-based markers from dedicated consortia, and the availability of cost-effective high-throughput detection methods are converging to create a potential explosion of genetic association studies in atherosclerosis. Although the standards and quality seem to be improving, there is nevertheless a risk that SNP-based association analyses will squander academic trust and scientific resources owing to unsatisfactory design and/or analysis. Like all experimental designs and model systems, genetic association studies in human samples have strengths and limitations. 1–3 Their potential strengths include the simplicity of design, ease of noninvasive sampling, reliability and cost-effectiveness of genotyping, uncomplicated statistical analysis, and the potential for clear interpretation and direct relevance to human biology. But many factors collude to undermine confidence in association studies. Often the initial publication of a positive association is followed by reports of non-replication or refutation. There can be good reasons for non-replication, including complexity of mechanisms, multiplicity of causative genes, confounding by gene-environment interactions, and context-dependency of the associations. However, the pattern of non-replication of genetic associations is frequent, familiar, and disconcerting. An index of the tenuous nature of genetic associations in atherosclerosis is that few DNA markers are in routine clinical use, such as in risk stratification protocols, although the application of markers for disease prediction is admittedly distinct from their use in experimental hypothesis testing. Limiting the potential to publish false-positive (FP) or false-negative (FN) results can be achieved in many ways. For instance, one journal recently expanded its editorial criteria for rapid rejection to include “genetic association studies related to complex disorders, including... atherosclerotic heart disease”(http://www. jci. org/misc/jcipoli. pdf).

This policy can be justified as an effective means to eliminate the likelihood of ever publishing a false, non-replicable result from a genetic association study. However, the bath water could hold an occasional baby. In general, the principle of editorial scrupulousness and placing restrictions on the publication of genetic association studies is valid in the current research environment, but might there be some standards for association studies that would not close the door on their publication, while simultaneously maximizing confidence in their validity? It is hoped that this editorial will stimulate a dialogue among the contributors, editorial staff, and readers