On the interpretation of genetic association studies

This editorial refers to "Association of RANTES G-403A gene polymorphism with increased risk of coronary arteriosclerosis by E. Simeoni et al. on page 1438 and "Asociation of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction by K. Edfeldt et al. on page 1447†Genetic association studies seek to relate variation in human DNA sequence with a disease or trait. Compared with linkage analysis, the association study design provides greater power to detect common genetic variants conferring susceptibility to complex phenotypes such as atherosclerosis and myocardial infarction (MI).1 In a case-control study, a common and convenient association study design, the frequency of a harmful genetic variant is expected to be greater among cases than controls (a protective variant is less frequent in cases). Though the case-control design may be simple, interpreting the results of these genetic association studies has been far less straightforward.In this issue, the results of two case-control association studies are reported. Simeoni et al.2 investigated the relationship between polymorphisms in four candidate genes and coronary atherosclerosis detected at coronary angiography. They report that a variant in the C—C chemokine Regulated Upon Activation, Normal T-cell Expressed and Secreted (RANTES) gene, G-403A, is associated with coronary atherosclerosis. Specifically, the A allele frequency was higher in 2694 cases with coronary atherosclerosis compared to 530 controls free of coronary atherosclerosis ( p =0.041). Meanwhile, Edfeldt et al.3 studied the relationship between two coding polymorphisms in the Toll-like receptor 4 (TLR4) gene and MI. They report that among the 1368 men in the study, the frequency of the co-segregating 299Gly and 399Ile alleles was higher among survivors of a first MI than in controls (uncorrected p =0.004).These two studies are extensions of exciting animal work implicating inflammatory pathways in atherogenesis. It was recently demonstrated that antagonism … *Correspondence to: Robert E. Gerszten, MD, Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA. Fax: +1-617-726-1544 (E-mail: rgerszten{at}partners.org).