Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results.

Finding the genetic causes for complex diseases is a challenge. Expression studies have shown that the level of expression of many genes is altered in disease compared with normal conditions, but what lies behind these changes? Linkage studies provide hints as to where in the genome the genetic triggers – the mutations – might be located. Fine-mapping and association studies can give yet more information about which genes, and which changes in the genes, are involved in the disease. Recent examples show that single-nucleotide polymorphisms (SNPs), which are variations at the single-nucleotide level within an individual's DNA, in the regulatory regions of some genes constitute susceptibility factors in many complex diseases. This article discusses the nature of regulatory SNPs (rSNPs) and techniques for their functional validation, and looks towards what rSNPs can tell us about complex diseases.