Mai-Jun - Sociedade Brasileira de Oftalmologia

Importance of genetic polymorphisms in the response to age-related macular degeneration treatment195INTRODUÇÃOAge-related macular degeneration (AMD) is adegenerative disorder that affects the centralretina and involves the Bruch’s membrane, theretinal pigment epithelium (RPE) and thephotoreceptors. (1,2) It is characterized by a progressive,painless loss of central vision associated with ageing.AMD is considered the leading cause of irreversibleblindness and responsible for a low quality of life in theaffected population. (1,3) In the United States of Americapopulation aged 40 years and older, the estimatedprevalence of any AMD is 6.5%. (4) The disease is usuallyclassified into dry and wet types, responsible for 15%and 85% of cases, respectively. In the dry form, visualloss is usually gradual and is characterized by subretinaldeposits called drusen or retinal pigment epithelial(RPE) abnormalities, including hyper orhypopigmentation. Larger drusen may become confluentand evolve into drusenoid RPE detachments, which canprogress to geographic atrophy and less frequently towet AMD. Wet AMD (also called exudative orneovascular AMD) occurs when choroidal neovascularmembrane grows under the RPE or between the RPEand neurosensory retina, leading to subretinalhemorrhage and subsequent scar tissue formation. (1,2)Etiological research suggests that AMD is acomplex disease, caused by the actions and interactionsof multiple genes and environmental factors such assmoking and hypertension. (5,6) Recent studies have shownthat some genetic polymorphisms are associated withAMD. A genetic variation in the complement factor H(CFH) gene on chromosome 1q32 is one of the moststudied gene polymorphisms related to AMD. Thispolymorphism (rs 1061170) results in a tyrosine-tohistidinesubstitution at amino acid position 402 (Y402H)in the CFH protein. (7-33) The A69S polymorphism (rs10490924) within the gene LOC387715 on chromosome10q26 that leads to an alanine-to-serine substitution wasalso found to confer an increased risk for developmentof AMD. (33-50) Some papers suggested that the vascularendothelial growth factor (VEGF) gene could play a rolein the pathogenesis of AMD. (51,58) However, manydifferent single nucleotide polymorphisms (SNPs) weretested and limited sample sizes and diverse ethnic originof cases and controls were studied to ensure a statisticallyvalid conclusion. It has also been demonstrated thatcommon CFH and LO387715 polymorphisms wereindependently related to progression from early orintermediate stages to advanced forms of the disease. (59)Herein, we review the main published studies thatevaluate the response to the treatment of AMD relatedto genetic polymorphisms.Klein et al. made a retrospective analysis ofparticipants of a randomized, controlled clinical trial, theAge-Related Eye Disease Study (AREDS) toinvestigate the possible association between the responseto oral antioxidants and zinc with genetic polymorphisms.The AREDS study enrolled 4757 participants from 11clinical centers and established that a combination ofzinc and antioxidants (B-carotene, vitamin C, and vitaminE) produced a 25% reduction in development of AMDover 5 years and a 19% reduction in severe vision loss inindividuals determined to be at high risk of developingthe advanced forms of the disease. A treatmentinteraction was observed between the CFH Y402H highriskgenotype and supplementation with antioxidants pluszinc (p = 0.03). An interaction (p = 0.004) was observedin the AREDS treatment groups taking zinc whencompared with the groups taking no zinc, but not in groupstaking antioxidants compared with those taking noantioxidants (p = 0.59). There were no significanttreatment interactions observed with LOC387715. (60)Other authors have studied the effect of theLOC387715, CFH and VEGF genotypes on the responseto photodynamic therapy (PDT) with controversialresults. (61,68) Goverdhan et al. genotyped a total of 557cases with AMD and 551 normal controls for the CFHY402H. Twenty-seven PDT-treated patients werefollowed up for 15 months and individuals with differentCFH genotypes were then analyzed for any associationwith visual change following PDT. The number of patientscarrying the high-risk C allele was 70.4% in thoserequiring PDT as compared to 52.3% in the non-PDTgroup (p=0.011), and presence of the CC genotypesignificantly increased the risk of PDT (p=0.015). Thedegree of visual loss following PDT was significantlyhigher in the CFH CC genotype group (p=0.038); 50%of CC cases and 45% of the CT cases lost 15 or moreETDRS letters at final follow-up. In conclusion, theyshowed that patients homozygous for the CFH high riskallele seem to have worse outcome after PDT. (61)Brantley et al. also found a potential relationship betweenCFH genotype and response to PDT. However, theyshowed that patients with the CFH TT genotype (T: nonriskallele) fared significantly worse with PDT than thosewith the CFH TC and CC genotypes. (62) Other studies didnot show significant association between CFHpolymorphism and PDT response for neovascularAMD. (63,64) For LOC387715, two important studies haveRev Bras Oftalmol. 2012; 71 (3): 194-8