Background

ALSPAC is a vital resource in the study of child development and has contributed to much influential work on the topic of child development and paediatric disease.

Age-related macular degeneration (AMD) is the most frequent cause of blindness in Europe and accounts for severe visual loss in around 25 million people worldwide.(1) It is characterised by reduction in visual acuity and contrast sensitivity with subsequent loss of central vision. There are two categories of AMD: wet (neovascular and exudative) and dry. Wet AMD accounts for 90% of blindness due to AMD (2) and if untreated results in an average loss of approximately 4 lines of visual acuity with 2 years of disease onset.(3) Timely identification and treatment of those with neovascular ARMD improves visual outcomes.(4) The economic burden of AMD in terms of direct and indirect costs is significant.(5)

A meta analysis by Chakravarthy et al in 2010 found that risk factors for AMD include major risk factors (with a strong, consistent association): increasing age, current cigarette smoking, previous cataract surgery and family history of AMD. Risk factors with a moderate and consistent association include history of cardiovascular disease, hypertension, raised plasma fibrinogen and high body mass index. Weak, inconsistent association was found between AMD and gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease and serum total and HDL cholesterol and triglyceride levels.(4) The same study identified 73 potential risk factors for late age-related macular degeneration including nine genetic factors. Increased sun exposure and low dietary intake of zinc and vitamin E were also highlighted by Smith et al using data pooled from three continents.(6)

More recently the link between genetics, environment and AMD has become far better understood with the discovery of potential AMD susceptibility genes. One such gene is Complement Factor H (CFH), a variant of which is rs1061170 (T1277C, Y402H) which is characterised by substitution of histidine for tyrosine at codon 402 on the long arm of chromosome 1, region 31. This is a missense mutation, which results in altered binding of the CFH protein to sulphated polysaccharides and may contribute to the pathogenesis of AMD through complement dysregulation. In individuals of European descent the Y402H variant was found to confer a 2-fold higher risk of late AMD per copy.(7,8)In homozygous individuals, those with neovascular AMD may have a decreased treatment response, particularly to anti-VEGF agents, when compared to individuals who are homozygous for the T-allele.(9) Along with another common variant (rs1410996), Y402H is thought to explain around 17% of AMD liability.(10)

There is evidence that chronic low-grade inflammation is key in the pathogenesis of AMD.(11) Raised serum inflammatory markers have been identified as possible indicators of increased risk of developing AMD, including C-reactive protein (CRP), interleukins (IL)-2 and -6, tumour necrosis factor (TNF)-a, soluble intercellular adhesion molecule (sICAM)-1 and C3a-desArg as have raised levels of urinary pro-inflammatory cytokines, including transforming growth factor (TGF)-b1 (OR 1.24 CI 1.02-1.50; Pless than 0.031) and macrophage chemoattractant protein (MCP)-1 (OR 1.07 CI 1.02-1.12 pless than 0.008) in early AMD and MCP-1 (OR 1.10 CI 1.03-1.17 pless than 0.003) in geographic atrophy.(11,12) Linked to this is the finding of the Blue Mountains Eye study that there is reduced renal function in AMD demonstrated by decreased estimated glomerular filtration rate and creatinine clearance.(13) Urinary MCP-1 levels above median levels were 2.5 times more likely to be found in individuals who were heterozygous or homozygous for the C-allele (Y402H) (Pless than 0.040).

The study team are experienced in working with ALSPAC data and among them have a wealth of epidemiological, genetic and ophthalmological clinical experience. The existing ALSPAC data contains snps directly associated with the Complement factor H and we will therefore be able to address the research question with existing data. This is a proposal for a small pilot study of the potential association between complement factor H genotype and AMD-related traits, which will inform the direction of future work.