Because of the critical consequences about the visual loss caused by AMD, especially advanced AMD (atrophic/dry or neovascular/wet), it is necessary to study its etiology and mechanism, then to development early diagnostic methods and effective treatment. Nowadays, VEGF inhibitors are widely recognized as effective drugs in clinical application for CNV (wet AMD) [3, 70, 71], instead of dry AMD. Therefore, to identify some novel detection markers and target drugs for different types of AMD is the current and future research focus on the direction. In the introduction section, we have enunciated the genetic factors may help us to search potential high-risk group about AMD, which can be prevented and treated in advance. In our analysis, we chose the HTRA1 gene, which can regulate some kinds of growth factors. Rs11200638 polymorphism in HTRA1 is the most common SNP, which is getting noticed. Mori et al. first investigated the association between HTRA1 gene rs11200638 polymorphism and risk of AMD [47]. Other more following researchers duplicated their work in different populations and different types of AMD. However, results were confounding, even within same populations, though two published meta-analysis. It is well known that meta-analysis provides a means for effectively increasing the size of the sample by pooling data from individual correlation studies, thus enhancing the statistical power of the analysis to estimate genetic effects [72], which used this method to demonstrate statistically significant genetic associations.
Two previous meta-analysis [73, 74] about rs11200638 polymorphism and AMD have been reported, however, each study has its limitations. For example, Tang et al. just included fourteen case-control studies, two studies [65, 67] were not consistent with HWE, and Tuo et al. actually reported four-source case-control studies, which shouldn’t be combined together [74]. Chen et al. also performed a meta-analysis in the same year including 14 case-control studies, similar limitations were existed [73]. After year of 2008, newly added studies have been published, and to perfect the above deficiencies, we performed an updated meta-analysis to come to a more convincing conclusion about HTRA1 gene rs11200638 polymorphism and AMD susceptibility.
To the best of our knowledge, this is the comprehensive and systematic meta-analysis exploring the associations between HTRA1 gene rs11200638 polymorphism and AMD risk; it involved about 8101 AMD individuals and 7215 controls. Increased associations were found in the whole group, in Asian and Caucasian subgroups, source of control subgroup, and dry/wet sub-types of AMD, different genotyping methods (Sequencing, TaqMan, PCR-RFLP and MassARRAY MALDI-TOF), which means that A-allele or AA genotype is the risk factor for AMD, in other words, if individuals carry on this SNP from peripheral blood test, which may indicate that it is possible to increase the occurrence of AMD for them in present time or at some point in the future. Therefore, it can offer us some preventions to intervene, or carry out treatments as soon as possible. To sum up, we wish to use this method to reduce the incidence of AMD and improve the cure rate of early treatment. In addition, the power of present study was 1.00, which suggested our conclusions were stable and convincing.
In addition, the online analysis system-String was applied to predict potential and functional partners related to HTRA1, which can help us to better understand the value for detection and concern. Finally, ten genes were predicted. Among them, the highest score of association was ACAN (0.943), however, so far, no research has been reported between this gene and AMD and interaction between this gene and HTRA1. Future research should be payed attention to above information, which may be in favor of AMD early detection/prevention and intervention. In other partners, ARMS2 and CFH have been shown to associate with AMD. The ARMS2 and HTRA1 genes are located nearby on the 10q26 chromosome in a strong linkage disequilibrium. Significant association was observed that ARMS2 rs10490924 was related response to ranibizumab treatment among wet AMD subjects [68]. CFH gene T1277C polymorphism is strong associated with both wet and dry AMD and may be contribute to the inflammation in the pathogenesis of AMD [75]. As for the rest interaction genes (CLPP, CTRC, YME1L1, HSPD1, RPL34, CLPX and PLEKHG4) both had moderate score and no literature to support. In a word, we should deep explore these partners of HTRA1 gene, and gene-gene interactions in the development of AMD in the next step.
There are some inherent limitations of our study should be declared. First, further studies should focus on Mixed and African populations, which was vacant in present analysis. Second, gene-gene and gene-environment interactions were not well analyzed. It is possible that specific environmental and lifestyle factors alter the associations between HTRA1 rs11200638 polymorphism and AMD, including age, diabetes, smoking, familial history, and hypertension. Third, vision is the most concerned-clinical indicator of AMD, future studies should include the value of the vision and analyze the relationships between rs11200638 polymorphism and the degree of visual impairment, which may help us to better detect disease progression.
In conclusion, our present meta-analysis suggests that HTRA1 rs11200638 polymorphism may be powerful associated with AMD risk, which may be as a clinical biomarker for detection.