Fibrinogen, C-reactive protein and coronary heart disease: does Mendelian randomization suggest the associations are non-causal?

摘要

Combining estimates of genotype-CHD associations with genotype-phenotype associations to predict phenotype-CHD associations produces values that are considerably lower than those reported from the observational studies, suggesting that reverse causation and confounding may generate the findings seen in the observational data: the confidence intervals are wide, however, as the difference in mean phenotype between genotypes is small compared to the overall spread of phenotype levels in the population. Sample sizes required to produce more precise genotype-disease estimates of association are large: in the cases examined here, sample sizes of around 30000 and 9000 cases (and the same number of controls) for fibrinogen and CRP, respectively, would be required, to have 80% power to exclude phenotype-CHD associations of 1.5 for the difference in phenotype between top and bottom thirds of the population, if there is no true phenotype-CHD association. The inferences that can be drawn from such studies are, however, more secure than those of conventional observational studies, plagued as they are by problems of reverse causation and confounding. The principles of Mendelian randomization can be expanded to many domains, and illustrate the exciting possibilities that can arise from a combination of genetic and conventional epidemiology.