Is complement factor H a shared risk factor for age-related
macular degeneration and cardiovascular disease?
Doctoral thesis, UCL (University College London).
Background and Aims: Inflammation is implicated in common disorders of ageing including atherosclerosis and age-related macular degeneration (AMD), although the link between inflammation and cardiovascular disease (CVD) is the more studied. The recent finding that susceptibility to AMD is increased substantially by common single nucleotide polymorphisms (SNPs) in the gene that encodes complement factor H (CFH; a circulating inhibitor of complement activation) provides evidence that inflammation in general, and complement in particular, maybe causally involved in AMD. Since AMD and atherosclerosis share similar pathological features and risk factors, including a link with inflammation, an important question arises: is complement factor H (fH) a shared risk factor for both AMD and CHD? One SNP in particular, which has the most replicated association in AMD, rs1061170, which encodes a putative functional tyrosine to histidine change (Y402H), and has been studied in both AMD and coronary heart disease (CHD). I hypothesised that genetic variants in CFH, in particular rs1061170 is associated with risk of both AMD and CHD and that this association may be mediated through changes in circulating fH concentration. I addressed this hypothesis by: (i) precisely defining the effect of the association of the rs1061170 SNP encoding Y402H in CFH on AMD risk; (ii) precisely defining the association of rs1061170 on risk of CHD events; and (iii) developing and validating a high throughput assay of circulating fH, to enable further evaluation of the nature of the association between CFH genotype and fH concentration, and fH concentration and disease; (iv) measuring fH in a population based sample to determine its non-genetic correlates and genetic determinants (v) measuring fH in case control studies of AMD and genotyping of SNPs in the CFH and related genes to determine the concordance of the genetic associations of fH and AMD. Methods: To address aims (i) and (ii), I conducted a systematic review of published studies investigating the effect of variants in CFH on AMD and CHD risk respectively, supplementing data with results from newly genotyped studies in both AMD and CHD. To address aim (iii) I developed and validated a high-throughput assay measuring circulating fH, which I used to undertake studies in aim (iv) in which I measured fH in a population based sample with an existing range of blood and lifestyle measures as well as anthropometric, cardiovascular, glycaemic, lipid, liver, renal, and inflammation markers. In addition to this genome wide information was also available on ~500,000 SNPs across the genome with additional imputation of un-typed SNPs, giving coverage of ~ 2 million markers across the genome. In order to achieve aim (v) I measured fH in case control studies of AMD, with additional genotyping of SNPs in the CFH and CFH related gene in order to attain a more high resolution signal of association in this genomic region for both fH concentration and AMD risk. Results: Data synthesis from published literature and newly genotyped studies, confirmed the strong association of the rs1061170 SNP with risk of AMD (per-allele odds ratio (OR) of 2.30, 99% CI 1.93, 2.73; p<0.001), in individuals of European descent, although the association was less clear in individuals of Chinese or Japanese descent. However, there was no association of rs1061170 with CHD (per-allele OR 1.01 95% CI 0.98, 1.04), or established risk factors for CHD. Adaptation of an existing commercial, low through-put assay allowed the development and validation of a high throughput assay to measure circulating fH concentrations. With an operating range of 7-1000 mg/L, this assay was reliable, repeatable and robust, enabling assay of fH in stored samples. In a large population study, novel associations of fH with lipids, apo-lipoproteins and indices of adiposity were identified and genetic determinants localised to the CFH/CFHR gene cluster on Chromosome 1. In case-control analysis, there was no association of fH concentration with AMD risk. Conclusions: Genetic variation in CFH, and in particular the effect of the most replicated rs1061170 SNP is robustly associated with AMD with little attenuation in the effect size as data has accrued. However the effect of the same SNP is not associated with CHD. Circulating fH is associated with a range of cardio-metabolic biomarkers and regulated by common genetic variants in the vicinity of the encoding gene on chromosome 1. However fH itself is not associated with risk of AMD, suggesting the genetic association of CFH with AMD is mediated through altered fH function or perhaps through an fH-related protein encoded by an adjacent gene.
|Title:||Is complement factor H a shared risk factor for age-related macular degeneration and cardiovascular disease?|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Copyright restricted material comprising of two published articles has been removed from the e-thesis.|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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