Complement factor H: role in prediction and pathogenesis of age-related macular disease (AMD) and coronary heart disease

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Inflammation refers to the natural response of the body to an infection. For example, localised pain, redness, swelling and warmth are are well-recognised features of an infected cut and are caused by the influx of circulating white blood cells and their release of chemical mediators that help to fight invading bacteria or viruses. Perhaps surprisingly, a state of grumbling, long-lasting, low-grade, generalised inflammation may exist in all of us as we get older, without us being aware of it. This low-grade inflammation may not be caused by bacteria or viruses but rather might be triggered by dead or dying cells, or certain by-products of our metabolism. This type of inflammation, that can be assessed by measuring the concentration of certain protein markers of inflammation in a blood test, has been implicated in the development of several common diseases of later life including heart disease, diabetes, Alzheimer s disease and age-related macular disease (AMD), a common form of blindness. Recent genetic studies show that some individuals who carry a common variant form of a gene that makes a protein called complement factor H (CFH) are at higher risk of AMD and heart disease. Since CFH is a protein that can help to damp-down one part of the inflammatory response it may be that the gene variant causes lower levels of CFH, but there is much to be learnt about how the altered gene leads to disease. For such studies, it is critical to be able to measure both the genetic variation and the level of CFH in the same indidvidual from large within a large populations with, or at risk of AMD or heart disease. We have developed a rapid high-throughput blood test for CFH, and we now aim to use it to measure CFH and the genetic variants in several large groups of individuals with, or at risk of, AMD and heart disease to understand if a deficiency of this protein underlies the risk of these two disorders. If so, measuring fH itself and/or its genetic variant may help to assess an individual s risk of AMD and/or heart disease, and medicines could be designed that modify the levels of CFH or the other factors it influences to reduce the risk of developing these two common and serious disorders of later life.

Technical Summary

AMD is the commonest irreversible cause of elderly blindness in the developed world and coronary heart disease (CHD) the leading cause of death and morbidity. Inflammation is implicated in both disorders, but the link between inflammation and CHD, the more studied, is largely observational, and therefore susceptible to confounding. The naturally randomised allocation of genotypes at conception, balancing the distribution of potential confounding factors among genotypic classes, makes genetic associations less prone to biases that limit causal inference from observational studies. Consistently elevated AMD risk among carriers of common single nucleotide polymorphisms (SNPs) in the gene (OMIM: CFH Ch1q32) for complement factor H (CFH), a circulating inhibitor of complement activation, provides compelling evidence that CFH has a causal role in AMD. CFH SNPs are also linked to CHD risk, but there are fewer studies, and there are no large-scale studies of the relationship of fH level to genotypes or AMD or CHD risk. Therefore measurement of fH, or CFH genotyping, may help predict AMD or CHD risk, and fH may be a therapeutic target in these common disorders of ageing. We propose to: (1) link traditional observational studies of fH with genotyping for common polymorphisms in the CFH gene region to confirm the causal relevance of fH in AMD and investigate its potential role in the pathogenesis of CHD; (2) evaluate whether assay of fH itself, CFH genotype, or both, enhance the prediction of AMD or CHD; and (3) test associations of fH with established risk factors and novel biomarkers to evaluate the determinants of its variance in a population, and elucidate the scope for modification of its circulating concentration by available interventions.

Publications

10 25 50

 
Description UCL/ UCLH BRC
Amount £900,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start 07/2012 
End 07/2016
 
Title A high throughput assay method for factor H applicable on a population scale 
Description An nephelometric assay 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact None to date because we are currently analysing data and preparing publications 
 
Title Consortium of Age related macular degeneration case control studies 
Description A consortium of studies of AMD with clinical and biological data including DNA 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact A framework of studies has been put in place that has been the subject of a Wellcome Trust Start Grant for Clinical Lecturers; applicant Dr Sofat 
 
Description Collaboration on specificity of fH antibody with prof paul Morgan, Cardiff University 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided the antibody and helped to interpret the experiments on specificity
Collaborator Contribution Prof Morgan's group conducted experiments to delineate the specificity of the fH anybody used in the assay developed as part of the MRC Biomarker Award
Impact The data arising from this collaboration have been included in a forthcoming paper "Distribution and determinants of circulating complement factor H determined using a high-throughput immuno-nepholometric assay" in preparation for Clinical Chemistry
Start Year 2010
 
Description Collaboration with Imperial Meningitis GWAS group 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with this group on a joint paper comparing and contrasting the variants in the CFH gene region associated with AMD and meningitis together with their effect on fH level
Collaborator Contribution They coordinate the international meningococcal GWAS studies
Impact None to date
Start Year 2012
 
Description Genome wide association study for complement factor H in the MRC Fenland Study 
Organisation University of Cambridge
Department MRC Epidemiology Unit
Country United Kingdom 
Sector Multiple 
PI Contribution Measurement of fH using an assay developed s part of the biomarker award
Collaborator Contribution Allowed us to undertake a GWAS for fH based on existing Genome Wide SNP data in MRC Fenland
Impact The data analysis is underway a high impact publication is expected.
Start Year 2009
 
Title Nephelometric assay for complement factor H 
Description We developed a high-throughput nephelometric assay for complement factor H based on existing reagents 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2011
Development Status On hold
Impact The development process is currently at the stage of evaluating the diagnostic/predictive utility of fH measurement in age-related macular degeneration