Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4.

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoural breast cell lines. We identified putative regulatory elements, containing CCVs, which looped to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumour suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

Enhancing the Promise of Drug Repositioning through Genetics.

The development of new drugs has become challenging as the necessary investments in time and money have increased while drug approval rates have decreased. A potential solution to this problem is drug repositioning which aims to use existing drugs to treat conditions for which they were not originally intended. One approach that may enhance the likelihood of success is to reposition drugs against a target that has a genetic basis. The multitude of genome-wide association studies (GWASs) conducted in recent years represents a large potential pool of novel targets for drug repositioning. Although trait-associated variants identified from GWAS still need to be causally linked to a target gene, recently developed functional genomic techniques, databases, and workflows are helping to remove this bottleneck. The pre-clinical validation of repositioning against these targets also needs to be carefully performed to ensure that findings are not confounded by off-target effects or limitations of the techniques used. Nevertheless, the approaches described in this review have the potential to provide a faster, cheaper and more certain route to clinical approval.