Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
Genetic risk factors and age-related macular degeneration (AMD)
Maryam Mousavi, Richard A. Armstrong
Vision Sciences, Aston University, Birmingham B4 7ET, UK Received 27 March 2013; accepted 21 June 2013 Available online 1 September 2013 Age related macular degeneration (AMD) is the leading cause of blindness in individ- Age-related macular uals older than 65 years of age. It is a multifactorial disorder and identification of risk factors degeneration (AMD); enables individuals to make lifestyle choices that may reduce the risk of disease. Collabora- tion between geneticists, ophthalmologists, and optometrists suggests that genetic risk factors play a more significant role in AMD than previously thought. The most important genes are associated with immune system modulation and the complement system, e.g., complement Complement factor H factor H (CFH), factor B (CFB), factor C3, and serpin peptidase inhibitor (SERPING1). Genes associated with membrane transport, e.g., ATP-binding cassette protein (ABCR) and voltage- dependent calcium channel gamma 3 (CACNG3), the vascular system, e.g., fibroblast growth assessment scores factor 2 (FGF2), fibulin-5, lysyl oxidase-like gene (LOXL1) and selectin-P (SELP), and with lipid metabolism, e.g., apolipoprotein E (APOE) and hepatic lipase (LIPC) have also been implicated.
In addition, several other genes exhibit some statistical association with AMD, e.g., age-related maculopathy susceptibility protein 2 (ARMS2) and DNA excision repair protein gene (ERCC6) but more research is needed to establish their significance. Modifiable risk factors for AMD should be discussed with patients whose lifestyle and/or family history place them in an increased risk category. Furthermore, calculation of AMD risk using current models should be recommended as a tool for patient education. It is likely that AMD management in future will be increas- ingly influenced by assessment of genetic risk as such screening methods become more widely available.
2013 Spanish General Council of Optometry. Published by Elsevier España, S.L. All rights Factores genéticos de riesgo y degeneración macular asociada a la edad (DMAE)
macular asociada a la La degeneración macular asociada a la edad (DMAE) constituye la causa principal de ceguera en personas mayores de 65 a˜ nos. Se trata de un trastorno multifactorial, en el que la identificación de los factores de riesgo permite a las personas la elección de aquellos estilos de vida que pueden reducir el riesgo de la enfermedad. La colaboración entre genetistas, oftalmólogos y optometristas sugiere que los factores genéticos de riesgo juegan un papel más ∗ Corresponding author.
E-mail address: (R.A. Armstrong).
1888-4296/$ – see front matter 2013 Spanish General Council of Optometry. Published by Elsevier España, S.L. All rights reserved.
Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
Genetic risk factors and age-related macular degeneration (AMD) significativo en la DMAE que lo que se pensaba hasta ahora. Los genes más importantes están Factores modificables asociados a la modulación del sistema inmune y al sistema del complemento, como el factor H (CFH), el factor B (CFB) y el factor C3 del complemento, y el inhibidor de la peptidasa tipo serpina (SERPING1). También se ha implicado a los genes asociados al transporte a través de complemento (CFH); membranas, como las proteínas cassette de unión a ATP (ABC) y la subunidad gamma 3 de los canales del calcio dependientes de voltaje (CACNG3), al sistema vascular, como el factor 2 evaluación del factor de crecimiento de fibroblastos (FGF2), la fibulina 5, los genes de tipo lisil oxidasa (LOXL1) y la selectina-P (SELP), y al metabolismo lipídico, como la apolipoproteína E (APOE) y la lipasa hepática (LIPC). Además, diversos otros genes muestran también cierta asociación estadística con la DMAE, como la proteína 2 de susceptibilidad a la maculopatía asociada a la edad (ARMS2) y el gen de la proteína de reparación de la escisión de ADN (ERCC6), aunque se precisa seguir investigando para establecer su significación. Los factores modificables del riesgo de DMAE deberán ser discutidos con los pacientes cuyo estilo de vida y/o historia familiar les sitúan en una categoría de riesgo incrementado. Además, debería recomendarse el cálculo del riesgo de DMAE utilizando los modelos actuales, como herramienta de educación al paciente. Es previsible que el tratamiento futuro de la DMAE se vea crecientemente influenciado por la evaluación del riesgo genético, y que por tanto estos métodos sean cada vez mas ampliamento aplicados.
2013 Spanish General Council of Optometry. Publicado por Elsevier España, S.L. Todos los as ‘geographic atrophy'. By contrast, in the wet form, new choroidal vessels are formed (‘neovascularisation') and ulti- Age-related macular degeneration (AMD) is the most impor- mately, retinal detachment, edema, and hemorrhage may tant cause of blindness in industrialized countries in occur resulting in degeneration of the macula.
individuals over 65 years of age. In the United Kingdom, for In the last decade, collaboration between geneticists, example, overall prevalence of late AMD is 2.4% of the pop- ophthalmologists, and optometrists has revealed signifi- ulation aged 50 years or more increasing to 4.8% cant evidence that genetic factors are involved in AMD in those 65 years of age or more and 12.2% in individuals and play a significant role in the disease alongside other greater than 80 years of a consequence, there risk factors such as smoking,exposure to are estimated to be 513,000 individuals currently in the UK sunlight.genes have now been implicated as with the visual impairment characteristic of AMD suitable possible risk factors,strongest case being made for for registration as seriously visually impaired, the number genes involved in immune modulation and the complement of female cases being greater than males. This figure is pre- system. Hence, genetic predisposition to AMD may increase dicted to rise to 679,000 by the proportion of more susceptibility to other risk factors such as smoking, diet, elderly individuals in the population continues to increase, and exposure to sunlight. The objectives of this review a phenomenon likely to be repeated in many countries.
are to discuss the results of these interdisciplinary stud- There are two forms of AMD, viz., the ‘atrophic' or ies and most specifically to identify those genes that have ‘dry' form and the ‘exudative' or ‘wet' form. The dry been associated with an increased risk of AMD. These genes form is characterized by degeneration of the macular pig- are discussed in five main categories: (1) immune modula- ment epithelium, choriocapillaris, and photoreceptor cells.
tion and the complement system, (2) membrane transport, Larger areas of degeneration result from the merging of (3) blood vessel development and vascular modulation, (4) small areas of atrophy and this state is often referred to lipid metabolism, and (5) miscellaneous genes. In addition, insights that these genes provide as to pathogenesis of AMD together with protective factors, modifiable risk factors, and risk factor assessment scores are also discussed. A list Estimated prevalence and number of cases of late- of abbreviation and acronyms used in this review is given in stage age-related macular degeneration (AMD) in the UK, CL = 95% confidence interval.
Overall prevalence 2.4% (CL: 1.7---3.3%) Genes implicated in AMD
Estimated number of cases Estimated new cases per year Many of the genes implicated as possible risk factors for AMD involve single nucleotide polymorphisms (SNP) in Projected increase by 2020 which one amino acid within the protein is substituted for Late AMD, number of females another. Many substitutions commonly result from ‘missense Late AMD, number of males mutations', i.e., the alteration of one base within a codon.
SNP may have varying consequences. Those mutations Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
M. Mousavi, R.A. Armstrong Genes involved in immune modulation and the
List of abbreviations used in the text.
Adenosine triphosphate (ATP)-binding cassette rim protein Complement system genes
Adenosine diphosphate Adenosine triphosphate Genes for the complement system protein factor H Age-related macular degeneration (CFH),B (CFB),factor 3 (C3 to exhibit the strongest associations with the risk of devel- Age Related Eye Disease Study oping higher risk of wet AMD is associated with Age-related maculopathy susceptibility polymorphisms of the CFH gene and with lower visual acu- ity strong association between CFH and bilateral Complement factor 3 dry AMD has also been is involved in Voltage-dependent calcium channel the inhibition of the inflammatory response mediated via C3b by acting both as a cofactor for cleavage of C3b to its Complement factor B inactive form, C3bi, and by weakening the active complex Complement factor H that forms between C3b and factor B. C-reactive protein Dietary glycemic index and polyanionic surface markers such as glycosaminoglycans DNA excision repair protein normally enhance the ability of CFH to inhibit complement.
Fibroblast growth factor 2 Specific mutations in CFH (e.g., Tyr402His) reduce the affin- Serum peptidase 1 ity of CFH for C3f and may also alter the ability of CFH to Intermediate density lipoprotein recognize specific glycosaminoglycans. This change results Low density lipoprotein in reduced ability of CFH to regulate the activity of com- plement proteins on critical surfaces, such as the retina, Lysyl oxidase-like 1 and may lead to an increased inflammatory response at the Mitochondrial DNA macula. By contrast, CFB is a component of the alternative Short and long arms of chromosome pathway of complement activation. When cleaved, an active Reactive oxygen species subunit is formed which is involved in the proliferation of Single nucleotide polymorphism Serpin peptidase inhibitor (SERPING1)
Genetic variants of the serpin peptidase inhibitor (SERP- ING1) gene, which regulates the activity of complement proteins, have recently been shown to be associated with which give rise to the substitution of a similar amino AMDthe protein inhibits the first components of the com- acid within a protein, such as valine for alanine, result in plement cascade and thus regulates complement activation.
little protein modification. By contrast, other substitutions may be of greater consequence, resulting in modified protein structure, through greater numbers of disulphide Genes involved in membrane transport
bridges, modified hydrophobicity and charge, which in turn, compromise protein function and interaction with ATP-binding cassette rim protein (ABCR)
other molecules. A further two types of substitution are less common but potentially more disruptive than missense Earlier studies suggested that a protein found in retinal mutations. First, a codon is modified by base substitution rod cells, viz., adenosine triphosphate (ATP)-binding cas- from one coding for an amino acid such as glutamate, to sette rim protein (ABCR), may be involved in a number a stop or termination codon (‘null mutation' or ‘nonsense of ocular disorders including Stargardt's macular dystrophy, mutation') and frequently results in a truncated protein retinitis pigmentosa (RP), cone-rod dystrophy, and AMD.
with little natural function. Second, ‘splice-site' mutations, The ABCR protein comprises two structurally related halves, i.e., a substitution in a region separating an exon from an each of which contains a section which spans the rod mem- intron can result in the incorporation of intron DNA into pro- brane, and a section which can bind to ATP, and is abundant tein synthesis, resulting in proteins markedly different from in the outer segments of rod cells but absent from cone their natural counterparts. These genetic changes often ithin the rod outer segment, the protein is local- occur as natural allelic variations within the population con- ized within the rim region of the rod membranes and aids ferring either increased risk or protection against AMD. By the movement of all-trans retinal within the contrast to SNP, copy number variation, i.e., variation in the The ABCR gene is 100 KB long and consists of 50 exons number of copies of a specific DNA sequence within a gene ranging in size from 33 to 406 full length appears to be less important, although a small number of transcript of the gene sequence was cloned in 1998 such associations with AMD have been recently allowing the gene to be located to the short arm of chromo- An alphabetical list of the major genes currently associated some 1 near to the centromere (1p21-p22.1). A large number with AMD, their functions, and locations within the genome of mutations of the ABCR gene have now been identified indi- together with their abbreviations is given in cating that ABCR is an especially ‘polymorphic' Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
Genetic risk factors and age-related macular degeneration (AMD) Genes associated with age-related macular degeneration (AMD).
Association with AMD Apolipoprotein E (APOE) Controversial, possibly with ATP-binding cassette rim protein (ABCR) Membrane transport Controversial, possibly with wet Age-related maculopathy susceptibility Wet AMD, less with dry protein 2 (ARMS2) ATP synthase (MT-ATP6) Produces ATP from ADP Complement factor H (CFH) Inhibition of inflammatory Bilateral dry, wet Complement Factor B (CFB) Component of alternative Complement factor 3 (C3) Mediates inflammatory DNA excision repair protein (ERCC6) Possible association with AMD formation at repair sites Fibroblast growth factor 2 (FGF2) Diverse biological Fibulin 5 (FBLN5) Polymerization of Elastin Hepatic lipase (LIPC Converts IDL toLDL Reduced risk of wet and dry Lysyl oxidase-like 1 (LOXL1) Connective tissue Selectin P (SELP) Pl atel et/l eucocyte Serpin peptidase inhibitor (SERPING1) Regulates complement Serum peptidase 1 (HTRA1) Regulates cell growth Transferrin (Tf) Iron binding protein Voltage-dependent calcium channel 3 L-type calcium channel five early studies, however, there was little agreement con- Voltage-dependent calcium channel
cerning the importance of the ABCR gene in AMD. A study of dry AMD in Japan concluded that there was no relation- ship between allelic variation in ABCR and the Voltage-dependent calcium channel gamma-3 (CACNG3) is a and the study of De la Paz et al.that ABCR protein subunit of the L-type calcium channel located in the was not a major risk factor. By contrast, a study of wet cell membrane and regulates trafficking and channel gat- AMDthat 4% of familial cases of AMD may be ing. Recent genetic analysis has suggested there is a gene related to ABCR. In addition, other studies have concluded associated with AMD on chromosome 16 (16p12).least that possession of some variants of the ABCR gene may five candidate genes occur in this region of the chromosome increase susceptibility to the disease.ecent studies have but the most likely to be associated with AMD is also been controversial. Hence, the presence of three sig- These data suggest a possible link between calcium ion chan- nificant mutations in ABCR was examined in eight cases of nel modulators in the photoreceptors and AMD but further wet analysis failing to identify the presence of research is necessary to establish the significance of this disease-causing mutations in the cases examined. However, ABCR mutations causing the protein to accumulate in the inner segment of rod cells have been reported to be fre- quent in patients with severe retinal dystrophies, including a small number of AMD cases.
Genes involved in blood vessel development
Hence, ABCR may influence the active transport of a wide and vascular modulation
range of drugs, metabolites, peptides, and lipids and may also be involved in the transport of retinal derivatives, phos- A number of genes linked to the development of blood pholipids, peptides, or other endogenous substrates across vessels or modulation of vascular processes have been impli- the disk membrane. Hence, disturbed transport across the cated in AMD and these genes are interesting because of the membranes of retinal cells is one possible, albeit rarer, route involvement of the vasculature in wet AMD (neovasculariza- Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
M. Mousavi, R.A. Armstrong Fibroblast growth factor 2 (FGF2)
interaction between genetics and smoking. More recently, a meta-analysis of early onset AMD has suggested an associa- Fibroblast growth factor 2 (FGF2) is a protein involved in tion with APOE various biological processes including mitosis, the develop- ment of blood vessels, wound healing, and tumor growth. In Hepatic lipase (LIPC)
a Spanish population, Brion et al.shown that although the principal genetic risk factors are ARMS2 and CFH, FGF2 gene codes for the enzyme hepatic hepatic lipase LIPC) may also be associated with some cases of dry AMD.
triglyceride lipase which is expressed in liver and the adrenal glands. The principle function of the enzyme is conversion of intermediate density lipoproteins (IDL) to low density lipoproteins (LDL). There may be an association between the Rare forms of AMD, exhibiting an autosomal dominant pat- proportion of different lipoproteins and AMD in that a spe- tern of inheritance, may be related to the fibulin-5 gene.
cific genotype of LIPC has been linked with a reduced risk Fibulin-5 is an excreted extracellular matrix protein and of both dry and wet forms of the inci- is expressed in basement membranes of epithelial cells dence of early AMD has been observed in patients with raised and developing blood vessels and is essential for the poly- C-reactive is associated with increased con- merization of elastin. AMD patients were screened and a sumption of lard and solid triglyceride levels, statistically significant correlation observed between muta- by contrast, were associated with a lower risk and there- tions of fibulin-5 and fore, certain types of lipid could be protective against AMD.
In a prospective study, association between AMD and fat intake was examined by Cho et al.otal fat intake of Lysyl oxidase-like 1 (LOXL1)
those patients who were the highest consumers was asso- ciated with increased risk of AMD. In addition, linolenic acid Lysyl oxidase-like 1 gene (LOXL1) codes for an enzyme consumption was associated with AMD whereas docosahex- involved in the development of connective tissue, including aenic acid (DHA) had a modest inverse relationship with that of blood vessels, and has been shown to be significantly AMD. Hence genes which affect lipid metabolism may alter associated with wet AMD in a Japanesea Korean pop- the balance between different types of fat in the body thus ulation although the biological basis for this association is influencing risk of AMD.
In addition to the above groups of genes, a number of genes The activity of macrophages and endothelial cell activa- of varied or unknown function show some statistical associ- tion in the pathogenesis of AMD may also be involved in ation with AMD. Their significance is more problematic and selectin gene group function as cell adhesion further research will be necessary to establish their signifi- molecules on the surface of activated endothelial cells and platelets and is involved specifically in the interactions between platelets and leucocytes. No single SNP of SELP is highly correlated with AMD, but a polymorphism of the gene Age-related maculopathy susceptibility protein 2
has been found to be statistically associated with dry Platelet and leukocyte interactions promote thrombus for- mation and are active at the sites of inflammation but how Age-related maculopathy susceptibility protein 2 (ARMS2) these processes may contribute to dry AMD, is unclear.
is a mitochondrial protein, currently of unknown function, which may play a role in various diseases of the elderly Genes involved in lipid metabolism
including of the ARMS2 gene are especially associated with wet AMD and the frequency of progression from dry to wet forms of the diseaseare less associated Apolipoprotein E (APOE)
with dry AMD.a Spanish population, ARMS2 has been reported to be one of the principal risk factors for AMD.
Apolipoprotein E (APOE) is a lipid transport protein essential for the catabolism of triglyceride-rich lipoproteins. It trans- ATP synthase
ports lipoproteins, fat-soluble vitamins, and cholesterol to the lymph system and then to the blood. APOE is a poly- morphic gene with three major isoforms, viz., ATP synthase is a mitochondrial enzyme important in provid- ing energy to the cell via ATP. Mutations of the ATP synthase ˇ4. These alelic forms differ only slightly but are sufficient gene have been related to RP and this gene may also be APOE structure and function. A pooled analysis of 15 associations between implicated in some cases of AMD.
APOE alleles ˇ4 and ˇ2 with late AMD but there was no interaction with gender or smoking behavior. By contrast, Adams et al.found DNA excision repair protein (ERCC6)
an association between possession of APOE allele ˇ2 and early onset AMD, an association that was present in non or The DNA excision repair protein gene (ERCC6) interacts with previous smokers but not in current smokers suggesting an several transcription and excision repair proteins. Excision Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
Genetic risk factors and age-related macular degeneration (AMD) repair proteins remove mutations resulting from UV dam- high-risk genotypes may show detectable and specific visual age and result in the removal of a short single-stranded changes before overt pathology is present. Feigle et segment of DNA containing the mutation. A new complimen- assessed the critical fusion frequency (CFF) in individuals tary strand is then synthesized using the remaining strand as with normal vision who were carriers of high-risk variants of template. Disease can result from genetic mutations which genes such as CFH, LOC, and HTRA1. CFF mediated by rods damage DNA repair mechanisms such as ‘Cockayne's syn- and cones was significantly reduced in gene variant-positive drome', a disorder characterized by photosensitivity and a rather than gene variant-negative individuals although CFF pigment retinopathystudy has also suggested an asso- mediated by cones alone was unaffected. This was the first ciation between SNP of ERCC6 and that UV study to relate early AMD risk genotypes to visual function damage to genes which is unrepaired could be a factor.
suggesting that there may be many other gene/vision rela- tionships to be identified in AMD.
Serum peptidase 1 (HTRA1)
The serum peptidase 1 (HTRA1) gene encodes for a secreted serine protease.protein is a secreted enzyme Various nutritional factors may be involved in the patho- proposed to regulate the availability of insulin-like growth genesis of AMD including anti-oxidants and anti-oxidant factor (IGF) by cleaving IGF-binding protein. IGF binds co-factors, a number of vitamins, zinc, and anti-free radicals to insulin-like growth receptor thus initiating intracellu- such as lutein, zeaxanthin and components of the mem- lar signaling and subsequently, stimulating cell growth and brane of photoreceptor cells.of omega-3 inhibiting apoptosis (programmed cell death). Hence, HTRA1 fatty acids in combination with anti-oxidants has been sug- may inhibit cell death in the retina and mutations in this gested as a preventative no fully developed gene result in increased cell losses. Tong et double blind studies have been carried out to date to test sized the importance of gene interactions; HTRA1 plays a this hypothesis. Eating more cold-water fish rather than red significant role in AMD when it is found in combination with meat and adding nuts to the diet have all been suggested to reduce the example, Chua et al.that a 40% reduction in early AMD could be achieved by chang- ing to a diet with significantly increased fish In addition, there is evidence that supplementing the intake Transferrin (Tr) is an iron-binding blood plasma glycopro- of DHA and eicosapentaemic acid (EPA) and reducing dietary tein which controls the level of free iron in biological glycemic index (dGI) may be protective against AMD in the stress is regarded as a major risk fac- ‘Age Related Eye Disease Study (AREDS) trial.
tor for AMD and increased levels of reactive oxygen species A review of all randomized controlled trials comparing (ROS) are produced by reactions catalyzed by iron in the anti-oxidant vitamins concluded, however, that there was retina. Hence, changes in iron metabolism genes may be little benefit of any anti-oxidant combination in AMD.
involved in AMD. Recently, SNP in the Tr gene have been also concluded that there was accumulating evidence that shown to be significantly associated with AMD especially neither vitamin E nor ␤-carotene in themselves could pre- in the interactions that may occur vent or delay the onset of AMD. In addition, Delcourt et between genetic susceptibility and environmental risk fac- studied the relationship between nutrition and AMD and found that individuals taking the antioxidants, lutein, zea- xanthin, and omega-3 poly unsaturated fatty acids had a Genes and the pathogenesis of AMD
lower risk of AMD. A similar result was reported by Lecerf and contrast, Chong et meta- analysis, studied the effect of dietary anti-oxidants in nine The most important genes implicated in AMD appear to be prospective cohorts and three random clinical trials. Pooled those involved in immune modulation and the complement results suggested that vitamins A, C, and E, zinc, lutein, zea- system such as CFH, xanthin, carotene, P-cryptoxanthin, and lycopene had little strongly suggesting that inflammatory processed are impor- or no effect on preventing early AMD. However, there was tant in AMD. It has been concluded that SNP in CFH, C3, evidence that antioxidant supplements containing zinc could HTRA1, and SERPING1 together could account for 45% of prevent visual loss in individuals with early AMD.
the risk of developing AMD.associated with mem- brane transport, e.g., ABCRCACNG the vascular system, e.g., FGF2,SELPwith lipid Modifiable risk factors
metabolism, e.g., also involved. Of these, the vascular genes are of particular interest because Several studies have proposed additional lifestyle changes of the involvement in neovascularization. In addition, a to reduce the lifetime risk of AMD that should be consid- series of other putative genes of variable or unknown func- ered in patients in high genetic risk categories. Hence, high tion could be involved in AMD including ARMS2,TP fat intake may be associated with an increased risk of AMD synthase,it is likely that in both women and men. Reducing fat intake to this level many further genes will be identified.
means reducing the consumption of red meat and dairy prod- Hence, there are likely to be multiple pathways leading ucts such as whole milk, cheese, and butter which are high to the same ultimate pathology in AMD, i.e., loss of retinal in saturated fats. Higher red meat intake has been posi- photoreceptors. Nevertheless, it is possible that carriers of tively associated with early AMD whereas consumption of Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
M. Mousavi, R.A. Armstrong chicken may be negatively associated with AMD.
genetic analysis.results of the test include a risk esti- is considerable evidence that the incidence of AMD varies mate based on the genetic polymorphisms identified and with both ethnicity and geographical location which could genetic counselling support. The test has five categories be attributed in part to varying diet. Hence, the risk of AMD of risk determined by an algorithm that takes into account varies among Americans of different Asian originoverall, genetics and also smoking history. Hence, risk category 1 5.4% of Asian Americans having dry and 0.49% wet AMD, Chi- is associated with a lifetime risk of 0.65---4.6% whereas risk nese and Pakistani Americans having a significantly increased category 4 is associated with a 55---94% lifetime risk.
risk of dry AMD compared with non-hispanic whites. By con- trast, Japanese Americans have a 29% decreased risk of dry AMD.were no significant differences in the risk of wet AMD in Asian Americans of any ethnicity compared Modifiable risk factors for AMD should be discussed with with white Americans. Outside the US, a Japanese study patients whose lifestyle and/or family history place them in at that the prevalence of early AMD in an elevated risk category. Protective modifications include: individuals greater than 35 years of age was 3.5%, and of cessation of smoking, sunglass protection under conditions late AMD 0.5%, while the age-standardised prevalence in of elevated light intensity, dietary modifications to reduce the right eye was 4.1%. In rural China, prevalence of wet intake of saturated fats and increase omega 3 fatty acids.
and dry AMD is 1.45% and 1.55% respectively, increasing with Calculation of AMD risk using current models should be rec- age.overview of epidemiological studies from around ommended as a tool for patient education. Furthermore, the prevalence of early AMD is similar in the AMD management frequency may be influenced by an assess- white, black, and hispanic populations, but that whites have ment of genetic risk, as such provisions are likely to become a greater prevalence of late AMD. Hence, prevalence stud- more widely available. Interactions between different genes ies provide considerable evidence that environmental, and and between genes and the environment also play a promi- lifestyle differences among populations as well as genetic nent role in the development of AMD and are likely to be variation are likely to be involved in determining the risk of profitable areas of future research.
Risk factor assessment scores
The identification of specific genetic defects leads to the possibility of more widespread screening for AMD especially in affected families and hence, the possibility of identifying asymptomatic carriers of the disease. A review of research to date suggests that smoking is the single most important modifiable risk factor for AMD.taken collectively suggest that long-term smoking is associated with approxi- mately a doubling of the risk of late-onset AMD. Hence, it is particularly important that patients with a familial his- tory of the disease should cease smoking. A risk assessment model has been developed for advanced AMD and is avail- able for online use.on data from 2846 AMD patients followed over 9.3 years, Cox proportional hazard analysis was used to assess the significance of demographic, envi- ronmental, phenotypic, and genetic covariates. The final model incorporates age, smoking behavior, family history, and genetic variation (especially of CFH and ARMS2) to pre- dict the risk of al.constructed a genetic risk score for AMD based on 13 ‘at risk' variations of eight individual genes. AMD patients younger than 75 years of age had a significantly higher score compared with those patients older than 75. In addition, Seddon et pro- posed a prediction model for the risk of advanced AMD based on genetic, demographic and environmental variables. This model included several genetic variants including CFH, LOC, C2, CFB, and C3, all of which were related to the prevalence of advanced AMD, and all, with the exception of CFB, sig- nificantly related to the progression to advanced AMD. In addition, smoking was independently related to AMD with a multiplicative joint effect with genotype. These advances have also resulted in the development of specific screening tests for AMD, such as the ‘macula risk test' which involves taking a sample of cells from the cheek of the patient for Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
Genetic risk factors and age-related macular degeneration (AMD) Documento descargado de el 08/10/2016. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
M. Mousavi, R.A. Armstrong



CHANGEONS DE VIE FUN, DESIGN, RENAULT TWIZY 100 % ÉLECTRIQUE RENAULT TWIZY,LES TEMPS CHANGENT. N'attendez plus le futur. Twizy, l'électron libre ultramobile, réinvente AU-JOUR-D'HUI, votre vie en ville. Bi-place protecteur et confortable, électrique, ouvert, énergisant, fun, audacieux, Twizy lance la révolution électrique dans un design totalement innovant. Il se conduit avec un permis B ou sans permis à partir de 16 ans pour la version Twizy 45. Avec Twizy, faites circuler l'énergie.

Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among african women in a pre-exposure prophylaxis trial

Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 Liver and renal safety of tenofovir disoproxilfumarate in combination with emtricitabineamong African women in a pre-exposureprophylaxis trial Justin Mandala1*, Kavita Nanda2, Meng Wang2, Irith De Baetselier3, Jennifer Deese2, Johan Lombaard4,Fredrick Owino5, Mookho Malahleha6, Rachel Manongi7, Douglas Taylor2 and Lut Van Damme1,8