Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes

Prospects for Enhancing Efficacy of Radioimmunotherapy

International audienceRadioimmunotherapy has been in use for more than 20 years and has progressed significantly since its efficacy has first been demonstrated in hematology. Yet it still has limitations that prevent its large-scale clinical use. This chapter reviews recent developments to overcome these limitations including new antibody specifici-ties, pretargeting methods, fractionated injections, and the use of alpha emitters. Immuno-PET is also likely to assist in selecting patients for radioimmunotherapy, optimizing injected activities, and noninvasively monitoring therapy efficacy