To the Editor: Dr Chasman and colleagues1 recently reported the impact of genetic polymorphisms on variability in response to pravastatin using a candidate gene approach. While these findings are of considerable interest, their impact may be limited from a public policy perspective. For example, while AT heterozygotes at single-nucleotide polymorphism 12 (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase gene) had an attenuated response to pravastatin in lowering low-density lipoprotein (LDL) cholesterol, variant carriers represented only 6.7% of the population. Whether it is cost-effective to genotype 15 patients initiated on statin therapy to identify 1 patient who will have an attenuated LDL cholesterol response must be decided from a societal perspective. The fact that even those with an attenuated response had a 28-mg/dL (0.73-mmol/L) reduction in LDL cholesterol further challenges the usefulness of genotype-guided therapy in this scenario.
Pharmacogenomics of lipid-lowering therapy is further complicated in that the appropriate response phenotype is unclear. For example, pharmacogenetic studies investigating apolipoprotein E (APOE) polymorphisms suggest a gene-dose effect, with ∊2 carriers showing greater reductions in LDL cholesterol in response to statins, while ∊4 carriers are least responsive.2 - 3 In contrast, when adverse cardiovascular outcomes were examined in a substudy of the Scandinavian Simvastatin Survival Study, ∊4 carriers had the greatest reduction in death rates in response to simvastatin compared with non-∊4 carriers.4 Therefore, while ∊2 carriers may have a better response to statins using a surrogate outcome, ∊4 carriers have a better response using mortality as the outcome. Of note, these differences in risk reduction based on APOE genotype do not appear to be related to variable LDL cholesterol treatment responses.
This letter was shown to Dr Chasman, who declined to reply on behalf of the authors.—ED.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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