Increased low density lipoprotein cholesterol (LDL-C) levels in plasma is a risk factor for cardiovascular disease, the leading cause of mortality.  Genetic factors which predispose to increased LDL-C concentration have been identified by large genome-wide association studies, reproducibly showing an unanticipated association of a variant in the gene encoding the iron regulatory protein HFE. This could result from several alternative mechanisms, including the genetic association of the variant in the HFE gene with another variant, or the regulation of LDL-C levels by iron.  Body iron levels can be readily manipulated, therefore understanding the mechanism is relevant to the modulation of LDL-C levels and prevention of cardiovascular disease.

The same HFE variant that is associated with LDL-C levels in the general population has been widely studied as it is present in two copies in the rare "single gene" iron loading disease, haemochromatosis.  I participate in the review of haemochromatosis genetic testing and supervision of research projects at the Anthony Nolan Laboratories, Royal Free Hospital and in the curation of databases interpreting variants in HFE and other genes in the context of phenotypes of iron loading and haemochromatosis.

Regulation of gene expression by iron is being investigated, both directly and as mediated by known iron responsive elements, potential novel iron responsive signatures, microRNAs and epigenetic changes such as DNA methylation, influencing the expression of LDL-C  - associated genes.  I am participating in the investigation of genetic mechanisms for regulation of iron with colleagues in the UCL - London School of Hygiene and Tropical Medicine - Edinburgh - Bristol Consortium, along with other research groups (UCLEB Plus), by discovery and conditional analysis of the loci associated with serum ferritin levels, as an index of body iron stores, and red blood cell  traits.