Leukotriene inhibition in high-risk genotypes
- PDF / 107,382 Bytes
- 2 Pages / 612 x 792 pts (letter) Page_size
- 70 Downloads / 135 Views
other 4 weeks of follow-up. No serious adverse events were reported. Discussion: Among patients who carry putative risk variants in the FLAP or LTA4 gene, DG-031 leads to a dose-dependent reduction in levels of two of 10 biomarkers felt to be associated with risk of myocardial infarction. DG-031 reduced ionomycin-stimulated whole blood leukocyte production of LTB 4 and MPO, indicating that the drug inhibited the leukotriene pathway. These data demonstrate that pharmacologic manipulation of the LT T pathway may reduce levels of putative biomarkers of myocardial infarction risk and raise the possibility that antagonism of the pathway could modulate cardiovascular risk.
Editor’s comments As the results of large, unbiased, genome-wide association studies become available over the coming months and years, many new candidate pathways will be proposed. However, the current pace of hypothesis generation far outstrips our capacity to elucidate the causal pathways involved. These new hypotheses are sure to generate intense speculation but, to date, translating the discoveries into the ultimate goal of personalized medical care remains elusive. Hakonarson et al. attempt the leap from candidate pathway identification to clinical reality, but this study must be interpreted carefully. First, the relationship of several of the biomarkers studied to risk of cardiovascular disease independent of other clinical characteristics is not well established. Moreover, even if well established, demonstration that pharmacologic manipulation of the pathway has an impact on inflammatory biomarkers is a long way from demonstrating an impact on outcomes. It could be that biomarkers are good prognostic factors but not causal and as such their manipulation reflects the tweaking of an epiphenomenon rather than alteration of fundamental pathophysiologic processes. Only an adequately powered, randomized, placebo-controlled clinical trial can provide sufficient evidence to consider adoption of a new therapy. Moreover, even though this study examined a genetically distinct subgroup of individuals it does not constitute a true example of pharmacogenetics. Here individuals with a putative risk variant were assigned to therapy in a crossover design, but a comparator group of putative
400 Genetics
low-risk variant carriers was not included. Statistical evidence showing a difference in the effect of therapy on (in
this case) biomarker levels based on genotype would be needed to support such genotype-directed therapy.
Race and Targeted Heart Failure Drug Therapy Taylor AL, Ziesche S, Yancy C, et al.: Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004, 351:2049–2057. Rating: •Of importance. Introduction: Despite improvement in heart failure outcomes with the widespread adoption of neurohumoral blockade, self-reported black patients continue to fare poorly. Retrospective analysis of prior large heart failure trials has suggested that black patients may have a favorable response to combination vasodilator the
Data Loading...
