Meta-analysis of genome scans of age-related macular degeneration

Fisher, Sheila; Abecasis, Gonçalo R.; Yashar, Beverly M.; Zareparsi, Sepideh; Swaroop, Anand; Iyengar, Sudha K.; Klein, Barbara E. K.; Klein, Ronald; Lee, Kristine E.; Majewski, Jacek; Schultz, Dennis W.; Klein, Michael L.; Seddon, Johanna M.; Santangelo, Susan L.; Weeks, Daniel E.; Conley, Yvette P.; Mah, Tammy S.; Schmidt, Silke; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Gorin, Michael B.; Schulz, Heidi L.; Pardi, Fabio; Lewis, Cathryn M.; Weber, Bernhard H. F.

doi:10.1093/hmg/ddi230

Cited by 210 publications

(130 citation statements)

References 55 publications

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“…Previously several groups reported that the AMD 10q locus has been associated with both GA and wet AMD phenotypes. [13][14][15][16] Our expanded findings are in agreement with these findings.…”

Section: Discussionsupporting

confidence: 91%

HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration

Cameron¹,

Yang²,

Gibbs³

et al. 2007

Cell Cycle

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Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two types of degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA. This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.

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Section: Discussionsupporting

confidence: 91%

HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration

Cameron¹,

Yang²,

Gibbs³

et al. 2007

Cell Cycle

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“…Genome-wide linkage analyses of extended families with AMD have identified a number of chromosomal loci that are linked to AMD. The most consistent of these occurs at chromosome 1q31 (210). Between 15% and 40% of multiplex AMD families segregated with a disease gene in the 1q31 region (204).…”

Section: Molecular Genetics Of Amd and Disease Associationsmentioning

confidence: 99%

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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“…The chromosome 1q32 region has long been considered to possess a susceptibility locus for AMD [29]. Edwards, Haines, Klein, Hageman and their colleagues [30][31][32][33] recently reported in four independent studies that the tyrosine to histidine at position 402 (Y402H) SNP in the CFH gene in the 1q32 region increases the risk of AMD.…”

Section: Complement Components and Complement Regulatory Proteins In mentioning

confidence: 99%

Immunopathological aspects of age-related macular degeneration

2008

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Age-related macular degeneration (AMD) represents a leading cause of blindness worldwide. While the clinical and histopathological aspects of AMD are well characterized, its etiology and pathogenesis remain unclear. Recent findings suggest a role for immunologic processes in AMD pathogenesis, including the age-related generation of extracellular deposits inside the Brusch membrane and beneath the retinal pigment epithelium, recruitment of macrophages for clearance of these deposits, complement activation, recruitment of tissue-destructive macrophages, microglial activation and accumulation, and proinflammatory effects of chronic inflammation by Chlamydia pneumoniae. This review discusses the evidence for the role of inflammation in human AMD and in animal models of AMD.

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Meta-analysis of genome scans of age-related macular degeneration

Cited by 210 publications

References 55 publications

HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration

HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Immunopathological aspects of age-related macular degeneration

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