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Joe Butler, Yit Yang, Luminita Paraoan; Population Attributable Risk of Known AMD Genetic Risk Factors Based on the 1000 Genomes Project. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6166.
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© ARVO (1962-2015); The Authors (2016-present)
This analysis aims to dissect the contribution of known genetic risk factors for age-related macular degeneration (AMD). Using data from the 1000 Genomes Project we gain insights into the contribution of each genetic risk factor across different populations.
Five non-synonymous SNPs with known risk to AMD were considered, these were: CFH (Y402H), ARMS2 (A69S), C3 (R102G), C2 (E186D,E318D) and CST3 (A29T). The allele frequencies in African, Asian, European and American populations were estimated using the Variation Pattern Finder from the 1000 Genomes Project. For each SNP the effect size was evaluated from previously reported data; the odds ratio is assumed to be the same throughout all four populations. The population attributable risk (PAR) was calculated based on the estimates of allele frequencies, odds ratio and disease prevalence. AMD prevalence in each of the four populations was informed by a previous epidemiology study. To determine which allele is ancestral and which is derived, the chimpanzee reference sequence was compared with the human reference sequence (GRCh37/hg19). The PAR was calculated for the derived allele as opposed to the ancestral allele. If the frequency of the derived allele is higher in cases than controls then it is a risk allele; if it is higher in controls it is protective.
In the population of European descent CFH had the largest (25.6%) attributable risk, followed by ARMS2 (22.5%), then C3 (9.1%) and CST3 (5.8%). The derived allele of C2 has a protective effect with the highest value in the European population (6.2%). In all other populations the risk allele in the ARMS2 locus is the major contributor to risk, followed by CFH. In African and Asian populations CST3 takes precedence over C3 as the third strongest contributor to AMD risk.
This analysis provides evidence that the contribution of genetic risk factors towards AMD varies across African, American, Asian and European populations. For instance the PAR profile for Asian population is dominated by ARMS2. However the CST3 locus, encoding cystatin C, is a risk factor which contributes consistently throughout all four populations. The C2 locus is unique within this gene set in that the derived allele is protective against developing AMD; it is rare in all populations studied and may offer valuable therapeutic potential.
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