age - related macular degeneration ( amd ) is the leading cause of irreversible central vision loss in elderly populations in developed countries , and 3050 million people are affected worldwide . in the united states , it has been estimated that the prevalence of amd is 13.4% among persons aged 60 years and older [ 1 , 2 ] . amd affects all retinal layers of the macula , the structure responsible for the central vision involving , in different degenerative patterns , photoreceptors , retinal pigment epithelium ( rpe ) , and bruch 's membrane . amd is primary characterized by the development of drusen , pathological extracellular deposits between rpe and bruch 's membrane mainly containing glycolipids , proteins , and cellular debris . at the level of macular area , the presence of few small hard drusen can be considered as a part of the normal tissue aging . on the other hand , amd consists of numerous and large soft drusen , rpe dystrophy , macular pigmentary changes , and/or thickening of bruch 's membrane [ 38 ] . advanced amd can manifest as either dry form or wet one . in dry amd , conversely , wet amd is characterized by the presence of choroidal neovascularization ( cnv ) with exudative and hemorrhagic phenomena leading to fibrotic scar formation [ 811 ] . amd is in fact considered a multifactorial disease , caused by the interplay between multiple acquired factors and polygenic background . recent epidemiological data have identified numerous risk factors as potential modulators of amd ; aging , cigarette smoking , previous cataract surgery , and family history of amd show strong associations with the disease , whereas higher body mass index , history of cardiovascular disease , hypertension , and higher plasma fibrinogen result in moderate amd 's risk . although family history is a well - known risk factor for amd , it is not a routine practice to alert those with a family history to the increased risk and advise them of the relevance of recognizing early symptoms . an accurate quantification of risk associated with a family history of amd has been reported in the uk population . this study confirmed that family history is a strong risk element for amd , highlighting the importance of genetic factors in the pathogenesis of amd . individuals with an affected sibling or an affected parent were reported to have a 12-fold increase in the odds of disease . odds ratio ( ors ) adjusted for age and smoking were even higher : 23% of siblings resulted to be affected by cnv or geographic atrophy with an or of 10.8 , which increased to 16.1 adjusting it for patient 's age . similar figure was previously reported in two large population - based studies , the rotterdam eye study   and the beaver dam eye study . the first reported an or of 14.3 , showing that the risk of amd increased to 19.8 if smoking was taken into account . the latter study resulted in an or of 10.3 , which probably was underestimated , as the study relied on at least one sibling being free of disease at baseline and the sibships where all siblings were affected by amd were excluded ; when only randomly selected sibships were included , the or was 26 . other studies reported family history of amd being associated with lower ors , but that could be attributed to the inclusion of cases with less severe disease [ 1720 ] . a recent uk study has documented that the onset of disease was earlier in cases who had amd affected siblings than in those without . this is typical for a complex disease with a substantial genetic component , for which the onset of disease is at a younger age in those with a family history . numerous genomic regions and a variety of candidate genes have also been seen to impact amd susceptibility . although strong associations between genetic factors and amd have been illustrated , it is likely that a significant part of the heritability of amd can not be explained through current known mechanisms [ 2123 ] . a number of genetic variants have been associated with amd , and a recent genome - wide association study ( gwas ) has provided significant ( p < 5  10 ) evidence of nineteen amd susceptibility loci . meta - analyses of gwass for amd estimated that currently identified loci account for approximately 6070% of the inherited predisposition to clinically significant amd forms [ 2427 ] . the hugely mounting number of scientific reports regarding amd - related gene variants counteracts the chance to get any unequivocal interpretation of these correlative data . in this complex scenario , which has built up more than ever in the last five years , several genes seem to be the most attractive in playing remarkable roles in different steps of amd pathogenesis [ 2437 ] . in the present review , we will focus on the best - known gene variants involved in the immunoinflammatory pathogenesis of amd , particularly considering the regulation of both complement activity and cholesterol homeostasis . the complement system is one of the main components of the innate immune response and fulfils numerous functions , such as the recognition of foreign cells , communication with and activation of adaptive immunity , and the removal of cellular debris . complement consists of over 40 proteins and cells , comprising a well - balanced network of circulating and cell - surface - bound proteins , which serve as substrates , enzymes , or modulators of a hierarchical series of extracellular proteolytic cascades . there are three well - known mechanisms of complement activation : classical , lectin , and alternative pathways . each pathway is activated by different stimuli and the initial steps that trigger the complement activation differ considerably . the final stage of the enzymatic cascade of events is the lysis of bacteria or viruses and the opsonization , which consists in a sort of marking cells or molecules to be removed by the host [ 3840 ] . the classical pathway is stimulated by the recognition of antigen - antibody complexes on foreign - cell surfaces by the hexameric complement component c1q . similar pattern - recognition receptors , that is mannose - binding lectin ( mbl ) and ficolins , bind to carbohydrate ligands on microbial intruders and initiate the lectin pathway . conversely , the alternative pathway is stimulated by the spontaneous hydrolysis of native c3 or the presence of foreign surface structures . recent findings suggest that additional processes , such as the c2-bypass and extrinsic protease pathways or properdin - mediated direct convertase assembled on microbial surfaces , can also initiate complement activation [ 4143 ] . all of the complement cascades end up in the central cleavage of c3 and in the generation of its active fragments c3a and c3b . opsonization of foreign surfaces by covalently attached c3b fulfils three major functions : cell clearance by phagocytosis;amplification of complement activation by the formation of a surface - bound c3 convertase;assemblage of the c5 convertase.cleavage of c5 results in the formation of a multiprotein pore complex ( mac , membrane - attack complex ) , which leads to cell lysis . both the covalent attachment of c3b and the stabilization of c3 convertase by the complement regulator properdin are markedly activated by hydroxyl - rich pathogen surfaces . a number of complement receptors mediate the recognition of opsonized cells by leukocytes , which induces phagocytosis and stimulation of the adaptive immune system ( b and t cells ) . finally , the anaphylatoxins c3a and c5a are released during complement activation and trigger a range of chemotactic and proinflammatory responses , such as recruitment of inflammatory cells and increase of microvasculature permeability . in this way , the complement cascade also supports and promotes the function of downstream mechanisms of the immune response [ 44 , 45 ] . cell clearance by phagocytosis ; amplification of complement activation by the formation of a surface - bound c3 convertase ; assemblage of the c5 convertase . in addition to a location - based and time - based restriction to immediate sites of activation , a finely tuned set of soluble and membrane - bound regulators ensure that any overstated action of complement on host cells is either prevented or actively inhibited . there is a large number of regulators of complement activation , including complement receptor 1 ( cr1 ) , complement factor h ( cfh ) , factor h - like protein-1 ( fhl-1 ) , c4-binding protein ( c4bp ) , decay - accelerating factor ( daf ) , and membrane cofactor protein ( mcp ) . complement is the most important pathogenic pathway of the immune system involved in amd [ 8 , 4753 ] , clearly indicating that complement activation is implicated in its pathogenesis [ 5458 ] . although amd is not a classic inflammatory disease , immunocompetent cells , such as macrophages and lymphocytes , are present in chorioretinal tissues with amd [ 59 , 60 ] . specific alteration and/or dysregulation of innate immune system are observed in amd eyes mainly at the level of complement pathway elements , such as complement components c3a and c5a , c5 and c5b-9 terminal complement complex , complement regulators or inhibitors ( i.e. , cfh , vitronectin , and clusterin ) , cr1 , mcp , and daf , but also at the level of c - reactive protein [ 6168 ] . activation products c3a , c5a , and c5b-9 are also systemically elevated in patients suffering from amd [ 6972 ] . due to genetic evidence from gwas as well as from common and rare variant analyses , the overactive alternative pathway has been investigated showing that its excessive engagement is a key component in amd pathogenesis [ 2437 , 5458 , 7377 ] . during amd , several immunopathological phenomena occur within the structures of the macular area , especially due to the pathophysiologic effects of complement system , which have a main role in the parainflammation of the aging retina [ 8 , 4753 ] . in particular , reliably because the posterior retinal layers ( i.e. , photoreceptor outer segment , rpe , and bruch 's membrane ) are more prone to environmental and/or blood - circulating oxidative stresses [ 7882 ] , they epigenetically represent the preordained site of onset of the elementary amd lesions ( drusen ) [ 38 ] . in fact , unregulated choroidal blood flow may increase the fluctuations of oxygen and/or lipids concentration , leading to elevated generation of reactive oxygen species ( ros ) [ 8082 ] . likewise , photooxidation in photoreceptors is associated with complement activation , which can increase mac formation , an important trigger of those apoptotic processes inducing retinal degeneration [ 8386 ] . in this pathogenetic context , in fact , exactly complement 's dysregulation can lead to that autologous damage which , at macular level , provokes the development of drusen : the earliest hallmarks of amd acting as foci of chronic inflammation [ 8 , 4953 ] . recent investigation array has highlighted that neural retina and rpe express most of the genes involved in cholesterol homeostasis . indeed , it has been reported that retina can synthesize cholesterol endogenously [ 88 , 89 ] and express proteins mediating cholesterol transport [ 9092 ] and removal [ 9395 ] . at the present time , detection of several cholesterol - related genes suggests that cholesterol homeostasis in the retina might be considered relatively independent of the rest of the human body . taking part , respectively , in internal and external blood - retina barriers , endothelial cells of neural retina ( nr ) and rpe cells synthesize and acquire cholesterol from low- and high - density lipoproteins ( ldl and hdl ) derived from blood circulation . however , the ratio between blood - borne cholesterol and endogenously synthesized is not well - known yet [ 87 , 96 , 97 ] . a large interindividual variability of cholesterol and lipoprotein metabolisms is unquestionable , but it is intriguing the fact that rpe has higher variations in expression of cholesterol - related genes than nr . it could be accounted for a sort of  gate - keeping  function of rpe controlling cholesterol and nutrient uptake from blood - stream to nr and reverse transport of metabolites from nr back to systemic circulation . at rpe level , this adjustment varies in each individual depending on blood lipid profile , age , gender , lifestyle , and genetic background . there are a lot of fine mechanisms of regulation pertaining to cholesterol - related genes in both nr and rpe but , despite the many experimental findings , most of them are not currently well known . at nr level , it seems that photoreceptor outer segment ( os ) deals with intraretinal cholesterol transport by means of active and passive mechanisms . the active transport of cholesterol from photoreceptor inner segment ( is ) to the os partially occurs via intracellular cholesterol transporter niemann - pick c1-like 1 [ 99101 ] . another modality of cholesterol mobilization involves scavenger receptors , especially that named scavenger receptor class b member 1 , which mediates bidirectional cholesterol flux between cells and lipoproteins ; in this manner , the photoreceptor os can uptake lipids from the hdl - like particles and offload lipids to the same particles as well [ 102107 ] . regarding the passive mechanism , it is known that photoreceptor is lies in a high - cholesterol environment than os ; hence , is can provide cholesterol for os just through passive diffusion . because of loss of efficiency in either some of these systems or phagocytosis , the cholesterol accumulates in the basal os disks dampening down the phototransduction cascade [ 106 , 108 , 109 ] . in the retina , the rpe plays a key role in cholesterol homeostasis controlling both cholesterol input and output [ 110 , 111 ] . experimental findings have indicated the presence of different pathways , even if the cholesterol offload via apolipoprotein b - mediated transport is regarded as one of the main mechanisms involved in amd pathogenesis . in fact , with aging , the apolipoprotein b - containing particles pool in the bruch 's membrane forming esterified and unesterified cholesterol - enriched lipid deposits named drusen . very little is known about amd and dysregulation of cholesterol - related genes , but it might be assumed that several affected individuals can be carrier of specific metabolic impairments in proteins determining cholesterol uptake ( e.g. , 3-hydroxy-3-methylglutaryl - coa reductase and low - density lipoprotein receptor ) and/or in those mediating cholesterol removal ( e.g. , atp binding cassette transporter 1abca1cytochromes p450 ) [ 91 , 92 ] . although further investigation is needed to better elucidate these clinicogenetic relationships , recent gwas identified four hdl - related genes as remarkable risk factors for amd : lipc ( hepatic lipase ) , cetp ( cholesteryl ester transfer protein ) , abca1 , and lpl ( lipoprotein lipase ) [ 25 , 31 , 32 ] . in several age - related vascular disorders , increased levels of oxysterols play a crucial role provoking atherosclerosis with subsequent local and chronic inflammation . homeostasis of cholesterol in blood vessel wall is of essential importance to regulate circulating cholesterol levels . a key event in the development of atherosclerosis is the uncontrolled uptake of oxidized ldl by macrophages recruited in the subendothelial space . the aberrant increasing of these lipid - loaded macrophages , termed foam cells , becomes a crucial condition causative of highly local inflammation [ 112117 ] . focusing on the lipoprotein retention in vascular wall , a parallel between atherosclerotic disease and amd is identifiable . in atherosclerosis , apolipoproteins b cross the arterial endothelium , bind to proteoglycans , undergo oxidative and nonoxidative processes , and trigger downstream events , such as foam cells build - up and cytokine release [ 112 , 118 , 119 ] . in amd , lipoprotein - like particles ( enriched with esterified cholesterol ) accumulate in the bruch 's membrane , especially in the space between the rpe basal lamina and the inner collagenous layer , forming lesions able to trigger inflammation , complement activation , and cytotoxicity ( i.e. , lipid - rich lesions , basal linear deposits and , finally , drusen ) [ 38 , 91 , 92 , 120122 ] . rpe physiologically plays a critical role in the uptake , processing , and offload of retinal lipids . it uptakes the most part of oxidized lipoproteins via scavenger receptor class b member 3 and ldl receptors from the blood circulation , but it is also able to synthesize lipoproteins endogenously . on the other hand , aged or stressed rpe is unable to properly process the oxidized lipids , when the macrophages , which normally clean up these deposits , become less efficient and are slowly intoxicated by excessive levels of 7-ketocholesterol ( 7kch ) and other oxidized lipids [ 8789 , 96 , 97 , 123 ] . 7kch is an oxidized form of cholesterol , that is , an oxysterol formed by auto - oxidation of cholesterol and cholesterol esters [ 124127 ] ; it is found in oxidized ldl deposits in the form of oxysteryl esters , covalently bound to oxidized unsaturated fatty acids [ 128130 ] . cholesteryl esters are particularly susceptible to oxidation and the cholesterol molecules in these esters can be oxidized to 7kch [ 131133 ] . in the primate retina , two main mechanisms for oxidation of cholesterol to 7kch although the levels of these metals have not been measured in oxidized lipoprotein deposits , atherosclerotic plaques are known to contain relatively high levels of them . by means of photooxidation and in presence of an adequate photosensitizer , cholesterol can be converted in a series of hydroperoxide intermediates that can further oxidize to 7kch . lipofuscin fluorophore a2e is one of the well - known photosensitizers , being involved in cholesterol ros - mediated oxidation and also in the inhibition of the normal cholesterol efflux from rpe cells [ 138140 ] . during the histopathologic evaluation of eyes affected by amd , lakkaraju and co - workers have documented that a2e induces aberrant cholesterol metabolism in rpe , which could contribute to amd onset or progression also by means of inflammatory mechanisms . since 2005 , several common variants in genes complement pathway have been consistently associated with the development of amd . the common coding variant p.tyr402his in the gene encoding complement factor h ( cfh ) was the first identified [ 64 , 141143 ] . a number of other polymorphisms in cfh , as well as in other genes involved in the alternative complement cascade , have also been demonstrated to affect amd risk , including genes for complement component 2 ( c2 ) , complement component 3 ( c3 ) , and complement factor i ( cfi ) [ 29 , 144147 ] . more recently , common variants in genes encoding for cholesterol - related pathway , such as lipc and tissue inhibitor of metalloproteinase 3 ( timp3 ) , have been reported to be associated with amd in large gwass [ 31 , 32 ] . in the next subheadings , the genes implicated in phenotypic expression of amd will be detailed , especially considering those main contributory variants at the basis of that immunoinflammatory dysregulation which , in amd patients , can be labeled as inflammaging . originally known as -1h globulin , cfh is a serum glycoprotein that regulates the function of the alternative complement pathway in fluid phase and on cellular surfaces . the binding of cfh to c3b reduces complement c3 activation , inhibits the formation of c3a , and lowers the production of il-6 . besides , cfh accelerates the decay of the alternative pathway convertase c3bbb , and also acts as a cofactor for cfi , another c3b inhibitor [ 150 , 151 ] . the cfh gene is located on chromosome 1q32 , spans 94 kb , and comprises 23 exons . the cfh gene is located within a cluster of genes encoding the regulatory complement components of the activation of c3 . fhr2 , fhr3 , fhr4 , and fhr5 and the decay - accelerating factor , c4-binding protein ( c4bpa and c4bpb ) , among others . the c.1277 t - to - c transition in exon 9 of cfh gene ( rs1061170 ) results in a substitution of histidine for tyrosine at codon 402 of the cfh protein ( p.tyr402his ) . this missense variant is located in the short consensus repeat 7 ( scr7 ) that acts as a binding site of cfh to c - reactive protein ( crp ) and heparin . the binding of cfh to crp or heparin increases cfh affinity for c3b and downregulates complement activity . the p.tyr402his can be considered to be a functional protein variant , as the p.his402 allele impairs the binding of cfh to crp , thus resulting in an enhanced complement activation and consequent tissue damage . at sites of tissue injury , the p.his402 variant does not dampen the alternative pathway of complement activation as efficiently as p.tyr402 allele [ 154158 ] . in caucasian populations of european ancestry the p.his402 allele is very common , having a gene frequency in the range of 0.3 - 0.4 . the p.his402 allele is likely replacing the major one because in early life it provides a survival advantage against streptococcal infections ; for example , microbes bind cfh to their surface to inhibit complement activation [ 46 , 159 ] . the cfh binding protein of group a beta hemolytic streptococcus has a lower affinity for p.his402 than for p.tyr402 . as a result , the host 's complement system has greater activity against the pathogen if the host expresses p.his402 , thereby reducing the microbes ' ability to counteract the alternative pathway . cfh adheres to damaged eukaryotic cells and tissue debris via the same anionic ( heparin ) binding sites that microorganisms employ to attach it to their surface [ 160162 ] . if on one hand the p.his402 allele is potentially giving some benefit , on the other hand it is one of the most significant known genetic contributor to amd disease risk . in individuals bearing a p.his402/his402 homozygous genotype , higher odds ratio ( or ) values , in the range of 3.57.4 , were found if only advanced dry and wet forms of amd were considered [ 64 , 141143 ] . the association between the p.his402/his402 genotype and amd could be explained by a reduced capacity of the p.his402 variant of cfh to bind debris in a damaged retina . differential binding of p.his402 versus p.tyr402 to multiple constituents of a damaged retina has been demonstrated for dna , rna , lipids , crp , necrotic and apoptotic cells , heparin and other glycosaminoglycans , lipofuscin , bis - retinoids , photooxidation byproducts , and amyloid beta . the common finding is that the p.his402 protein binds with a lower affinity than p.tyr402 . therefore , in the retina of a p.his402/his402 homozygous individual there is a higher level of alternative pathway activation , leading to retinal debris accumulation and ultimately amd development . recent evidence has been reported supporting the existence of multiple amd susceptible alleles in the chromosome region of the cfh gene . a case - control study of 84 single nucleotide polymorphisms located in a 123 kb genomic region in 1q32 including the cfh gene provided evidence that multiple cfh haplotypes associate with amd risk independently from p.tyr402his . functional variants within these haplotypes are likely to influence the expression of cfh gene and possibly also of other nearby genes of the c3-activation cluster . in particular , an a - to - g variant located in intron 14 of cfh gene ( rs1410996 ) has been reported to associate with amd . in the recent gwas of fritsche and co - workers , the most strongly amd - associated single nucleotide polymorphism in the cfh region  rs10737680was not in disequilibrium with p.tyr402his , which instead was tagged by a weaker signal . this evidence further supports the hypothesis that multiple functional gene variants in the cfh locus act as risk factors for amd . the c2 gene encodes for the complement component 2 , spans 18  kb , and includes 18 exons . the c2 gene maps in 6p21.33 and is adjacent to the cfb gene , which encodes for complement factor b , from which is separated by just 271 nucleotides . common variants within the c2/cfb cluster have been recently confirmed as being significantly associated with risk of developing amd . a missense g - to - c variant in exon 7 of c2 ( rs9332739 ) has a frequency of 0.067 among europeans and causes the replacement of the glutamic acid residue at codon 318 with an aspartic acid one ( p.glu318asp ) . the c - to - a substitution within intron 10 of c2 ( rs547154 ) has a frequency of 0.062 among europeans . minor alleles of both rs9332739 and rs547154 have a protective effect and reduce by half the risk for developing amd . a recent meta - analysis estimated that or of c - allele of rs9332739 was 0.55 ( 95% confidence interval ( ci ) : 0.46 , 0.65 ) , while minor allele at rs547154 carried an or of 0.47 ( 95% ci : 0.39 , 0.57 ) . the cfb : c.26 t - to - a transversion ( rs4151667 ) in exon 1 of cfb results in the substitution at codon 9 of leucine with histidine ( p.leu9his ) that has a frequency of 0.067 among europeans . a second missense variant in cfb gene , the cfb : c.95 g - to - a transition ( rs641153 ) , is located in exon 2 and determines a substitution of arginine at position 32 with a glutamine residue ( p.arg32gln ) . the minor a - allele of cfb : c.26 t - to - a and the a - allele of cfb : c.95 g - to - a carried estimated risks of 0.54 ( 95% ci:0.45 , 0.64 ) and 0.41 ( 95% ci:0.34 , 0.51 ) , respectively . haplotype analyses using two independent cohorts of amd patients identified a statistically significant common risk haplotype and two protective haplotypes . both the haplotype including minor alleles of c2:c.954 g - to - c and cfb : c.26 t - to - a ( h10 haplotype ) and the haplotype including a - allele of rs547154 variant in intron 10 of c2 and the a - allele of cfb : c.95 g - to - a ( h7 haplotype ) confer a significantly reduced risk for amd . the protective effect of h7 haplotype has been confirmed in independent studies , and evidence has been reported suggesting that minor alleles of both variants contribute independently to the protective effect . to date it is not clear if the rs547154 variant in intron 10 of c2 has a functional activity or rather is in disequilibrium with a causal variant , but it is likely that its minor allele could be associated with a lower expression of c2 . the cfb protein containing glutamine at position 32 has been reported to reduce hemolytic activity compared with the arginine containing form and to cause less efficient complement activation [ 165 , 166 ] . this lower complement response determined by h7 haplotype could possibly explain the protective effect on amd development . combined analyses of the c2/cfb haplotypes and cfh variants showed that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls . the c3 gene encodes the complement component 3 , a factor that plays important biological roles in the classical , alternative , and lectin activation pathways . the active c3 factor includes an -chain , encoded by the last 26 exons , and a -chain , encoded by the first 16 exons , having exon 16 encoding both  and -chain . mature c3 factor is obtained from the cleavage of a single chain 200  kda precursor into the  ( c3 ) and  ( c3 ) subunits that are linked by disulfide bonds . c3 factor has a critical role in the complement system , and c3 deficiency makes people more susceptible to bacterial infection . the c.304 c - to - g substitution in exon 3 of c3 gene ( rs2230199 ) is a common missense variant that causes replacement of arginine residue at codon 102 with a glycine one ( p.arg102gly ) . the p.gly102 allele has a frequency of 0.175 among europeans and is carried by more than 30% of individuals . association between p.arg102gly and amd has been confirmed in many studies on caucasian populations [ 55 , 146 , 147 , 164 , 168 , 169 ] , but not in asian populations , probably due to the lower frequency of the p.gly102 allele . among europeans , the or for amd has been reported to be 1.7 in p.arg102/gly102 heterozygotes and 2.6 in p.gly102/gly102 homozygotes , and the estimated population attributable risk for p.gly102 was 22% . the complement factor i ( cfi ) gene maps on chromosome 4q25 , spans 63  kb , and comprises 13 exons . the first eight exons encode the heavy chain of cfi , while the light chain of cfi is encoded by the last five exons . cfi is a serine protease that plays a role in the complement pathway as it cleaves and inactivates c4b and c3b . a c - to - t transition ( rs10033900 ) located 4.3  kb downstream the 3 utr of cfi gene has been shown to be independently associated with amd [ 29 , 31 ] . this variant could have a role in influencing cfi expression level or be in linkage disequilibrium with a functional regulatory variant . a locus in 10q26.13 ( loc387715 ) has been identified as the second most important locus in the etiology of amd [ 170 , 171 ] . this locus includes the age - related maculopathy susceptibility ( arms2 ) gene and the gene encoding for the high - temperature requirement factor a of serine peptidase 1 ( htra1 ) . a g - to - t transversion in exon 1 of arms2 ( rs10490924 ) is a common missense variant that replaces an alanine residue with a serine ( p.ala69ser ) . the p.ser69/ser69 homozygotes were reported to have a significant 7.6-fold increased risk of developing amd , and this association has been next confirmed in independent case - control studies . only 4.2  kb separate arms2 gene from the near htra1 gene , and the arms2:p.ala69ser variant is located just 6.3 kb from a g - to - a variant in the promoter region of htra1 gene ( rs11200638 ) . these two variants are in strong linkage disequilibrium ( r = 0.90 ) , and it is difficult to determine which one could be the causal variant in this locus . therefore , it is still under debate to definitively establish which gene , arms2 , htra1 or possibly also others , is responsible for the genetic association with amd . the htra1 protein is a 50  kda secreted enzyme that cleaves substrates involved in the complement pathway , such as clusterin , vitronectin and fibromodulin , and could theoretically play a role in the pathogenesis of amd . the g - to - a substitution in the promoter region of htra1 has been initially considered a functional variant as it is located in a conserved cpg island and resides within a putative binding site for the transcription factor adaptor - related protein complex-2 and could possibly regulate the expression level of htra1 [ 172 , 173 ] . however , later studies showed that this variant does not affect the transcription level of htra1 in several cell lines   nor alters htra1 mrna or protein expression in human retina - rpe - choroid samples . therefore , it is unlikely that rs11200638 is the functional variant that accounts for the strong association between the arms2/htra1 locus and the risk of developing amd . just 2.7  kb wide  that includes only two exons and a single intron . the encoded 107-amino acid peptide is expressed in the outer membrane of mitochondria and in the citosol . a second variant , an insertion / deletion ( indel ) polymorphism in the 3-prime untranslated region ( 3utr ) of arms2 ( arms2:c.372_815del443ins54 ) , has been strongly associated with risk of developing amd ( p = 4.1  10 ) . this indel variant removes the polyadenylation signal in the 3 utr of arms2 and replaces it with a 54  bp element known to mediate rapid mrna turnover . this variant is located between arms2:c.269 g - to - t and htra1:c.-625 a - to - g , and the haplotype including minor alleles ( t - indel - a ) was reported to be associated with a significant 3-fold increased risk for amd . considering the deleterious effect of del443ins54 indel to the expression of arms2 transcript , we could suggest that this indel polymorphism could be the actual variant causing the increased risk of amd associated with the arms2/htra1 locus . the actual function of arms2 protein is unknown , but it is thought to play a role in diseases in the elderly . arms2 transcripts have been detected in retina and in a variety of other tissues and cell lines , and it has been proposed that arms2 could play a key role in amd through mitochondrial - related pathways . so far , very little is known about the function of arms2 , and more investigations are needed to determine if variants in this gene have causal role in the pathogenesis of amd . the tissue inhibitor of metalloproteinase 3 ( timp3 ) gene belongs to a family of genes encoding for inhibitors of matrix metalloproteinases , a group of zinc - binding endopeptidases involved in the degradation of the extracellular matrix . timp3 is also a potent angiogenesis inhibitor , as it blocks the binding of vegf to vegfr2 and inhibits downstream signaling leading to vegf - mediated angiogenesis . timp3 mutations are causing a mendelian early onset form of macular degeneration often complicated by cnv , known as sorsby 's fundus dystrophy ( mim # 136900 ) . timp3 has been considered a putative candidate for amd susceptibility , but early studies failed to find association between timp3 and amd [ 178 , 179 ] . recent evidence has been reported indicating that an a - to - c substitution located far upstream ( 113  kb ) of timp3 gene ( rs9621532 ) within an intron of the synapsin iii gene ( syn3 ) is associated with a reduced risk of developing amd . this variant influences the expression of timp3 transcripts in cultured primary human fetal rpe cells , and the protective c - allele of rs9621532 was associated with mrna expression . however , the genetic association between rs9621532 and amd has not been confirmed in asian population , and the role of timp3 in amd etiology still remains controversial . the gene spans 60  kb on chromosome 15q21.3 , includes 9 exons , and encodes a hepatic triglyceride lipase which is expressed in liver . lipc enzyme is also a triglyceride hydrolase and a ligand / bridging factor for receptor - mediated lipoprotein uptake . two variants in lipc putative promoter , an a - to - g substitution ( rs493258 ) located 14 kb from lipc transcription start site and a c - to - t substitution ( rs10468017 ) 22  kb upstream of lipc , were reported to be associated with advanced amd in two independent european cohorts , indicating that common variants in lipc gene could play a role as genetic risk factor for amd [ 31 , 32 , 182 ] . these variants are thought to regulate the expression of lipc and therefore influence the metabolism of hdl cholesterol . the t - allele of rs10468017 has been reported to have a protective effect for advanced wet and dry amd by influencing lipc expression in serum and increasing hdl levels . this etiogenotypic excursus has been first and foremost aimed to speculatively interconnect two different types of gene polymorphism , which are able to alter either complement or cholesterol pathway and , consequently , to predispose to amd via inflammation and parainflammation . several clinicogenetic studies show increased or to develop amd in individuals carrying more risk genotypes [ 167 , 183 ] . in particular , the carriers of combination of peculiar cfh , arms2/hrta1 , and c2/cfb genotypes have been reported to have high or values , although significance level of these findings were relatively low , mainly due to the low number of patients included in the investigations . calculating a risk score including genetic information across the nineteen top loci resulting from a very recent gwas , fritsche and co - workers reported that a multiple combination of genotypes could distinguish amd patients from healthy controls ( area under the receiver operator curve = 0.74 ) and suggested that similar scores could be used to identify and prioritize at - risk individuals , in order to provide them preventive treatment before the disease onset . the development of an efficient tool able to predict the development of amd is strongly awaited , as it could have a remarkable impact on the health systems . however , several biases can counteract the expectation to achieve reliable data on this complex topic . many small clinicogenetic studies and , despite adequate statistical protection from multiple comparisons , some gwass are at risk of findings by chance or of overestimating marker effects [ 184 , 185 ] . therefore , correct translational information from genomic marker research to clinical practice of amd will be more rapidly available if biomedical community works together in carrying out large - scale consortium of trials designed to concomitantly verify the weight of both clinical   and genotypic   risk factors in amd patients , as recently performed by seddon and co - workers in a quite numerous sample population . before long , the validation of risk prediction models , inclusive of proteomic biomarkers , will be useful for the managing of research , clinical trials , and personalized medicine not only in amd , but also in other frequent causes of legal blindness such as diabetic retinopathy , glaucoma , and pathologic myopia . in particular , amd risk scores based only on simple sums of genotypes are unlikely to turn out effective , probably because the complex nature of amd etiology includes synergistic interactions both among gene variants and among these and environmental conditions . a more comprehensive exploratory approach on the relationship between the chief amd - risk genotypes , the underlying immunoinflammatory endophenotypes , and the networks of interaction with acquired or epigenetic factors is likely to provide , in the near future , the knowledge for the development of useful predictive algorithms , able to guide in the direction of an effective primary and secondary prevention of amd .
age - related macular degeneration ( amd ) is the most common cause of irreversible visual impairment among people over 50 years of age , accounting for up to 50% of all cases of legal blindness in western countries . 
 although the aging represents the main determinant of amd , it must be considered a multifaceted disease caused by interactions among environmental risk factors and genetic backgrounds . mounting evidence and/or arguments document the crucial role of inflammation and immune - mediated processes in the pathogenesis of amd . 
 proinflammatory effects secondary to chronic inflammation ( e.g. , alternative complement activation ) and heterogeneous types of oxidative stress ( e.g. , impaired cholesterol homeostasis ) can result in degenerative damages at the level of crucial macular structures , that is photoreceptors , retinal pigment epithelium , and bruch 's membrane . in the most recent years 
 , the association of amd with genes , directly or indirectly , involved in immunoinflammatory pathways is increasingly becoming an essential core for amd knowledge . starting from the key basic - research notions detectable at the root of amd pathogenesis , the present up - to - date paper reviews the best - known and/or the most attractive genetic findings linked to the mechanisms of inflammation of this complex disease .