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A fundamental and novel insight into the pathophysiology of hypertension or just another dubious genetic association study?

Although this finding is interesting and may have fundamental relevance to the pathophysiology of the metabolic syndrome, several issues warrant further discussion. Genetic association studies can be problematic and plagued by poor reproducibility. There is always a concern that ‘positive publication bias’ can create a falsely elevated impression of a potential genotype– phenotype interaction. However, the PPARa ProAla polymorphism has stood the test of time better than most, certainly in terms of its association with protection from type 2 diabetes. Altshuler et al. [2] evaluated 16 published genetic associations to type 2 diabetes and related subphenotypes using a family-based design to control for population stratification and replication samples to increase power. Analyses involving 3000 subjects demonstrated that the PPARa ProAla was the only polymorphism with a consistent and significant association, with the Pro allele being linked with a 1.25-fold risk of diabetes. Because the Pro allele is much more common (85% frequency), this relatively modest association could potentially translate into a large population attributable risk.