Complement Factor H Variant Y402H Is a Major Risk Determinant for Geographic Atrophy and Choroidal Neovascularization in Smokers and Nonsmokers

Sepp, Tiina; Khan, Jane C.; Thurlby, Deborah A; Shahid, Humma; Clayton, David; Moore, Anthony T.; Bird, Alan C.; Yates, John R.

doi:10.1167/iovs.05-1143

Cited by 169 publications

(87 citation statements)

References 18 publications

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“…Haplotype analysis showed that a SNP in the CFH gene that results in a tyrosine to histidine substitution at amino acid 402 in the Factor H protein can account for up to 50% of AMD cases in the human population, a number approaching 50,000,000 worldwide. Follow-up reports have since confirmed these findings in additional cohorts in the United States (212,223), Iceland (224), the United Kingdom (225), and France (226). Interestingly, the major CFH risk haplotype in the Japanese population appears to be different than that reported in other populations, although the protective haplotype is the same (227).…”

Section: Molecular Genetics Of Amd and Disease Associationsmentioning

confidence: 85%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

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Section: Molecular Genetics Of Amd and Disease Associationsmentioning

confidence: 85%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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“…16,17 A number of complement system proteins, complement activators and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD 12,[39][40][41][42] and of geographic atrophy and choroidal neovascularization, the hallmark of advanced AMD. 43 Genetic studies revealed highly significant associations between AMD and variants of several complement pathway-associated genes, including complement factor H, complement factor H-related 1 and 3, complement factor B, complement component 2 and complement component 3. [39][40][41][42]44 Associations between markers of inflammation (such as C-reactive protein) and AMD have been observed in some 45,46 but not all 47 previous epidemiological studies.…”

Section: Discussionmentioning

confidence: 99%

Reconsidering the connection between vitamin D levels and age-related macular degeneration

Golan

Shalev

Treister

et al. 2011

Eye

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“…Recently, it was found that variants in the CFH and LOC 387715 genes are the major genetic factors that predispose individuals to AMD. Although the allele frequency of CFH polymorphism varies among different populations (Grassi et al 2006;Li et al 2006;Conley et al 2006), and is not associated with AMD in the Japanese population (Gotoh et al 2006), many independent studies strongly suggest that it is an important etiological factor for both geographic atrophy and choroidal neovascularization (Sepp et al 2006). Polymorphism in the second major gene LOC 387715 is strongly associated with smokers (Schmidt et al 2006) although some studies did not find significant differences in risk allele frequency and smoking (Rivera et al 2005;Conley et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…However, several recent genome scan studies have identified susceptibility loci on 1q, 3p, 6q, 9q and 10q (Barral et al 2006). Recently, several independent studies reported a strong association of the variant Y402H in the complement factor H (CFH) gene on 1q32, and the A69S variant in the LOC 387715 gene (on 10q26) as major risk factors predisposing individuals to both forms of AMD (Haines et al 2005;Klein et al 2005;Edwards et al 2005;Rivera et al 2005;Sepp et al 2006). In addition, a whole genome association study has identified a variant in the promoter region of the HTRA1 gene (on 10q26) that may also play a key role in AMD susceptibility Yang et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Assessment of the contribution of the LOC387715 gene polymorphism in a family with exudative age-related macular degeneration and heterozygous CFH variant (Y402H)

Shastry

2007

J Hum Genet

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Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly population in developed countries. The etiology of AMD is not completely understood but environmental and genetic factors have been implicated in the disease. Recently it has been documented that variations in the complement factor H (CFH) and LOC 387715 genes are the major risk factors that predispose individuals to dry and wet AMD. To investigate further the genetic contribution to AMD, we have analyzed the LOC 387715 gene in a non-smoking family with an exudative AMD and a heterozygous mutation (Y402H) in the CFH gene. Direct sequencing of the amplified product of exon 1 of the LOC 387715 gene identified a previously reported missense mutation (A69S) in this family. The affected individual is homozygous for the mutation and this sequence alteration was not identified in six age-matched controls. On the basis of this and other results it is tempting to speculate that the combined effect of variants in the CFH and LOC 387715 genes may contribute to the AMD phenotype in this family. Further studies on these and other susceptibility genes may provide clues on variable phenotypes, new preventive strategies and treatment options for AMD.

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Complement Factor H Variant Y402H Is a Major Risk Determinant for Geographic Atrophy and Choroidal Neovascularization in Smokers and Nonsmokers

Abstract: The CFH Y402H variant is strongly associated with both GA and CNV in the U.K. population. This association is similar in smokers and nonsmokers. Heavier smokers with the CC genotype may be at particular risk.

Cited by 169 publications

References 18 publications

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Reconsidering the connection between vitamin D levels and age-related macular degeneration

Assessment of the contribution of the LOC387715 gene polymorphism in a family with exudative age-related macular degeneration and heterozygous CFH variant (Y402H)

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