While numerous genome-wide association studies (GWAS) have already identiﬁed common variants associated with age-related macular degeneration (AMD) in European-ancestry populations, there are only few reports published of such studies in Asians.
However, Asians seem to have a distinct clinical presentation of the disease (i.e. absence of drusen and minimal ﬁbrous scarring in polypoidal choroidal vasculopathy, a variant of AMD accounting for 20 to 55% of Asian patients with exudative AMD) and different responses to treatment.
“In Asians, there are 2 common sub-types of neovascular AMD: typical neovascular AMD (tAMD) and polypoidal choroidal vasculopathy (PCV),” reported Assoc. Prof. Cheng Ching-Yu, MD, MPH, PhD, Clinician Scientist, Glaucoma Department, Singapore National Eye Centre.
According to Dr. Cheng, while tAMD presents in older patients and more likely to have drusen, PCV on the other hand is more common in younger patients, has less drusen and has more subretinal hemorrhage.
To clarify if there are differences in underlying genetic characteristics of AMD between patients of Asian versus European ancestry, a genome-wide and exome-wide association study on 2,119 patients with exudative AMD (advanced AMD solely on the exudative or neovascular disease subtype) and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, was conducted as part of The Genetics of AMD in Asians (GAMA) Consortium.
The said study was conducted in 3 major hospitals (Singapore National Eye Centre, National University Hospital and Tan Tock Seng Hospital) in Singapore and in 25 hospitals and universities around East Asia.
Reporting ﬁndings of the GAMA Consortium at the recently held Asia-Paciﬁc Academy of Ophthalmology (APAO 2017) meeting in Singapore, Dr. Cheng highlighted that 2/3 of the global cases of AMD are in Asia by year 2040 (170 million projected cases of AMD worldwide versus 110 million in Asia).
Hence the study of genetics in AMD among Asians, noted Dr. Cheng, would answer questions such as whether there are novel Asian-speciﬁc AMD genetic variants, whether there is a difference between the disease genes and effective sizes between tAMD and PCV and whether there are novel PCV-speciﬁc genes or variants.
As Dr. Cheng and colleagues reported in the January 2015 issue of Nature Communications, they identiﬁed three novel loci (C6orf233, SLC44A4 and FGD6), two of which (SLC44A4 and FGD6) harbour coding, non-synonymous variants. These loci, noted Dr. Cheng, have not been identiﬁed in large samples of AMD patients of European descent.
“This validates the role of searching for coding variations in diverse ethnic groups to better understand the mechanistic basis of complex diseases such as AMD,” he explained.
But the more interesting ﬁndings in this study were the identiﬁcation of an uncommon East Asian-speciﬁc mutation at CETP (D442G) associated with exudative AMD. The mutant 442G allele (an AMD risk allele), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l-1 in East Asians.
“This allele is absent in European populations and appears to be present only in East Asians, rendering it independent from all other previously described common, noncoding CETP polymorphisms,” the investigators reported.
In summary, Dr. Cheng emphasized that ﬁndings from the GAMA Consortium provides new insights into the genetic mechanisms of AMD in East Asians.
“The identiﬁcation of signiﬁcant important differences in the ﬁne-scale genetic architecture of AMD, which appear speciﬁc to East Asians could underpin at least some of the inter-ethnic differences in clinical presentation and response to speciﬁc therapies,” the investigators concluded.