Title: Using genetic data to understand the causes of age-related macular degeneration
Funder: Dunhill Medical Trust

Abstract: AMD is the commonest cause of blindness in those aged> 60 years old in the western world, and will become a major public health burden worldwide given a projected increase in the ageing population. Preventing or slowing the progression of AMD remains a major health challenge because of the poor understanding of the aetiology of AMD. Lipids have been linked to AMD, however prospective or randomised studies have not reliably established a causal link. We will use 3 approaches to establish a causal link between circulating lipid sub-fractions and AMD using existing and novel data. First we will use linked electronic health care records across health care settings to establish the largest observational study (n~120000) to examine the link between routinely measured lipids (LDL-C, HDL-C and TRGs) and AMD risk. Temporal records and 400 million years of person follow-up data will allow estimation of risk of incident AMD and adjustment of relevant factors limiting previous studies (e.g. medication use). Second we will use a genetic approach to assess the causal link of single nucleotide polymorphisms (SNPs) that alter circulating levels of LDL-C, HDL-C and TRG’s in a publically available data set (n~15000) of late AMD and studies where new genotyping of relevant SNPs can or has been carried out. Third we will test if measures of lipoproteins other than routinely measured LDL-C, HDL-C and TRGs may aid dissection of the lipid pathways involved in AMD, based on the identification from GWAS of genes encoding lipid handling. These measures, till now, have not been available in a reliable and repeatable method. However using NMR based methods this is now possible. We will test the association of ~220 metabolites measured using this platform including lipoprotein intermediates with AMD. These measures have already been carried out in the Cambridge Eye study, but we will extend these measures to other AMD studies with saved serum; ~5000 case-control datasets. We will then use a genetic approach, to overcome reverse causality or confounding that might limit case-control measures. We have already identified SNPs (appendix) that underlie circulating levels of a range of ~220 lipid sub-fractions and metabolites in ~40,000 participants from the UCLEB Consortium and ALSPAC mothers and children (manuscript in preparation). We will use these SNPs as instruments to study the causal relevance of lipoprotein sub-fractions AMD using two-stage Mendelian randomisation analysis, exploiting large, publically available and newly generated genetic AMD data sets.

Lay abstract: Age-related macular degeneration (AMD) is the most common cause of blindness in individuals over 60 years in the western world. As people are living longer AMD will become a major public health burden. Visual loss is troubling in persons of any age, however in elderly individuals it is also associated with a loss of independent living, increase in other conditions associated with aging and an increased reliance on social care. There are few treatments that have been shown to work in AMD largely because the causes are unknown. Existing treatments are limited to the least common form of AMD and is limited in availability and expensive. We are interested in understanding the causes that lead to AMD and identifying changes in the eye that predispose to AMD so that these might be used to prevent AMD using drugs that interfere with these pathways. We are particularly interested in the role of circulating lipids. These are fats that have an important role in normal functioning of many cells and are carried around the body in the bloodstream. High levels of lipids are well known to predispose to heart attacks, and taking medication that reduces these fats (e.g. statins) can help reduce the rate of heart attacks. The first sign that someone is developing AMD is that spots containing lipids can be seen at the back of the eye. However studies have not yet shown a link between lipid levels and AMD. This is because often studies are small and measures of lipids have not been carried out carefully enough. A more direct link has now emerged from studies where genes that influence the levels of circulating lipids have been shown to alter AMD risk. In the current study we aim to estimate how measurements of circulating lipids affect the risk of AMD by using electronic data generated during routine interactions with the health care system and supplementing this by testing if genes that affect circulating lipids also affect AMD. This is of value because we will be able to better estimate the risk of lipids in AMD, and might help us conduct better trials on existing (e.g. statins) or newer drugs that are cheap, widely available and easy to take (e.g. tablets versus injections into the eye).

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE