Genetic aetiology of age related macular degeneration in population of Nepal: Hospital based comparative study

Abstract

Background Age related macular degeneration (AMD) is the leading cause of blindness after cataract among elderly in developing countries. AMD is the most common retinal disorder and one of the leading cause of blindness among elderly in Nepal. Various modifiable and non-modifiable risk factors have been identified for the development of AMD. Genetics of AMD has been extensively studied in the recent years and genetic susceptibility of AMD has been identified. The two major susceptibility genes for AMD are CFH (1q31) which codes for complement factor H, and ARMS2 (10q26) for which the gene product and function are poorly understood. The mutations in these genes increased the chance of AMD. Although many studies are conducted in the developed world, only limited studies are from low and middle income countries. To the best of our knowledge, there are no reported studies on genetics of AMD in Nepal. This study aimed to assess the genetic etiology of AMD among Nepalese population in a hospital setting. Methodology: This study is a hospital based cross sectional study. Patients at the age 65 years and above with all types of AMD were enrolled for AMD cases. Control groups for the AMD cases included age matched subjects at the age 65 years and above and those without AMD and other retinal pathologies that hinders the grading of AMD. The number of cases and controls necessary for this study was estimated for chi-squared tests of association and linear regression models. We estimated that recruiting 160 cases and 160 controls sufficient to identify associations between selected risk variants and AMD in the Nepalese population with a power of 95%. However, as there are no other baseline data from Nepal on genetic components, we enrolled additional 40 participants in each groups to address any unforeseen contingency such as poor image quality, problems in DNA extraction and genetic analysis etc. So, the total study participants included 200 cases of AMD and 200 cases of control in this study. Detailed history, ocular examination under mydriasis, fundus photography, macular OCT were taken from all study participants. 5 ml blood will be drawn to prepare DNA extraction and haplotype and diplotype analysis of DNA extraction were carried out to assess the genetic etiology.

Results/Conclusion: A total of 400 study participants were enrolled, which included 200 AMD cases and 200 control individuals aged 65 year and above. The mean age for AMD cases (200) was 72.86 years (SD 5.10) and the control group (200) was 72.58 (SD 5.33). The prevalence of AMD-associated loci in Nepal was ascertained. Nepali individuals show significant associations with key variants in the CFH-CFHR5, ARMS2/HTRA1, C2/CFB, and C3 loci. Nepalis exhibit a particularly high frequency of the risk allele of ARMS2/HTRA1. At the CFH-CFHR5 locus, the frequency of AMD risk at CFH rs1061170 is lower than what is observed in Europeans, but higher than what is observed in East Asians. The frequency of the protective allele CFH I62 (rs800292) is higher than what is observed in Europeans, while the incidence of the protective CFHR3/CFHR1 deletion appears comparable, assuming that the rs12144939 variant is an effective tag for the CFHR/CFHR1 deletion. Nepali haplotype structure in the CFH-CFHR5 region appears similar to that observed in Europeans and other non-African populations. AMD haplotype associations largely mirror what is observed in well-studied European cohorts.