Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD

A proposed architecture and method of operation for improving the protection of privacy and confidentiality in disease registers

BACKGROUND: Disease registers aim to collect information about all instances of a disease or condition in a defined population of individuals. Traditionally methods of operating disease registers have required that notifications of cases be identified by unique identifiers such as social security number or national identification number, or by ensembles of non-unique identifying data items, such as name, sex and date of birth. However, growing concern over the privacy and confidentiality aspects of disease registers may hinder their future operation. Technical solutions to these legitimate concerns are needed. DISCUSSION: An alternative method of operation is proposed which involves splitting the personal identifiers from the medical details at the source of notification, and separately encrypting each part using asymmetrical (public key) cryptographic methods. The identifying information is sent to a single Population Register, and the medical details to the relevant disease register. The Population Register uses probabilistic record linkage to assign a unique personal identification (UPI) number to each person notified to it, although not necessarily everyone in the entire population. This UPI is shared only with a single trusted third party whose sole function is to translate between this UPI and separate series of personal identification numbers which are specific to each disease register. SUMMARY: The system proposed would significantly improve the protection of privacy and confidentiality, while still allowing the efficient linkage of records between disease registers, under the control and supervision of the trusted third party and independent ethics committees. The proposed architecture could accommodate genetic databases and tissue banks as well as a wide range of other health and social data collections. It is important that proposals such as this are subject to widespread scrutiny by information security experts, researchers and interested members of the general public, alike

Global Boundary Stratotype Section and Point (GSSP) for the Anthropocene Series: Where and how to look for potential candidates

International audienc

An Examination of the Golden Ratio in Nature and Music

The Golden Ratio, also known as the Golden Section, exists as a proportion of lengths. Calculated to be approximately 1.61803, the Golden Ratio is closely related to the Fibonacci numbers and other topics in mathematics such as the continued fraction. In addition to its relationship to the Fibonacci numbers, the Golden Ratio is closely connected to many geometric shapes including the regular pentagon, the regular pentagram, certain rectangles, and the dodecahedron. Often thought to have an aesthetically pleasing effect, the Golden Ratio can be found in objects in nature, paintings, music composition, and musical instruments