Association of Previously Verified Gene Polymorphisms With AMD in Turkish Population

Age-related macular degeneration (AMD) remains as the most important cause of severe visual impairment of elderly people in developed countries. It is one of the best-characterized complex trait diseases. Multiple genetic and environmental factors play a role in the pathogenesis. A number of different biological pathways and related gene polymorphisms are strongly implicated in its etiology. A lot of chromosomal locations have been studied to figure out genetic risk factors responsible from the development of AMD. Most genetic variants that have been found to be related to AMD at least in one study have not been verified in subsequent studies. However in recent years, single-nucleotide polymorphisms related to the complement system and also chromosome 10q26 have strongly been elicited to predispose individuals to the susceptibility to AMD. These polymorphisms have been verified in subsequent studies. However, results from different geographic regions of the world can represent discrepancies according to ethnic populations. Aforementioned genetic tests have been commercially introduced to give the patients the risk of progression to advanced stage of AMD, and rate of the risk can be given by the genetic results together with environmental factors in USA.

Age related macular degeneration is consisted of dry and wet forms. Although wet form is responsible from severe vision loss due to AMD, dry form can progress to wet form by passage of time. The risk of AMD increases when age get older and it causes very severe central vision loss; consequently reduces considerably the quality of life in senile population. Available treatment of AMD is expensive and has economical burden. Early diagnosis of the disease has favourable impact on post-treatment prognosis. Although the basis of treatment is primarily based on the preservation of current visual acuity, it is possible to obtain improvement in visual acuity with the agents inhibiting angiogenesis in recent years. However, complete response to the treatment is not obtained approximately in one fifth of the patients. Different responses to the treatment are obtained in the remaining group. The reason for the differences at the treatment may be due to different morphological subgroups and/or diversity of genetic variants in wet AMD. . We do not at the moment know whether gen polymorphisms related to AMD established in some western population are also related to AMD in our population or whether this relationship has similar risk or protective effect for AMD. The gen variants mostly studied in relation to AMD are CFH (rs1061170 and rs1410996), LOC387715/ARMS-2 (A69S /rs10490924), HTRA-1 (rs11200638), C3 (R102G/ rs2230199), C2 E318D (rs9332739), and CFB R32Q (rs641153). A preliminary study which was published recently, carried out by our team in a single center and in a small number of patients showed that CFH and LOC387715 gen polymorphisms entertain a risk for late AMD and suggested a necessity to perform a forward study with larger population to learn definite information about our population. On the other hand, the entire eight genetic locus related to AMD will be studied first time in our population. In the introduced projects study, the relationship of eight different gen polymorphisms (CFH rs1061170 and rs1410996, LOC387715 / ARMS2 gene rs10490924, C2 gene rs9332739, CFB gene rs641153, CFI rs10033900 , HTRA-1 gene rs11200638, C3 rs2230199) will be studied in 2800 patients with high risk intermediate and late stage AMD and 2200 age-matched control subjects. Blood samples from brachial veins of the study subjects will be collected in the 5 health centers composed of Bursa Retina Eye Center and Hospitals of Afyon Kocatepe University, Dokuz Eylul University, Konya University and Uludag University within the period of 32 months. After the collection of venous samples, polymorphisms will be genotyped by "real-time PCR'' and ''pyrosequencing" genotyping systems in the genetic laboratory of Afyon Kocatepe University Medical School. Within the last 3 months of the project duration, having completed genotyping of all samples, evaluation of the study data by clinically and statistically will be made, and preparation of final report will be realized. . As a primary outcome, protective effects or the risk rate of developing the late AMD for each genetic polymorphism will be calculated by statistical analysis following the genotyping. Sub-analyses will be done to investigate any relationship between genetic polymorphism and response to the treatment. Sub-analyses will be done to determine possible differences in genetic variants between the late dry and wet AMD and also among the morphological subtypes of the wet AMD. Main study and secondary sub-studies derived from sub-analyses by further methodology will be submitted as different studies for publication. The anticipated results of the study may have impact on the management and follow-up of the patients with AMD. Because AMD is etiologically multi-factorial disease and has environmental controllable risk factor outside the genotypic features, it may be possible to early diagnosis and frequent follow-up in addition to recommending to avoid from modifiable risk factors in patients with early AMD who are genetically under the high risk of the development of late AMD according to findings obtained from our study results. It will also be possible to establish the patients with wet AMD who are resistant or sensitive to the treatment according to genotyping. Whether performing genetic tests in patients who are candidate to the late AMD in the near future is significant and meaningful for our population will be established. Our results evaluated together with the literature will make substantial contribution to better understanding of pathogenesis of AMD as well as early diagnosis and better classification or treatment choices.