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Ching-Yu Cheng, Jiemin Liao, Xinyi Su, Peng Chen, Paul Mitchell, Tin Aung, Jie Jin Wang, Jost B Jonas, Yik-Ying Teo, Tien Y Wong; Meta-Analysis of Genome-Wide Association Studies in Multiethnic Asians Identifies Two Loci for Age-Related Nuclear Cataract. Invest. Ophthalmol. Vis. Sci. 2014;55(13):840. doi: https://doi.org/.
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Age-related cataract is the leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Although several mutations were identified as causative for congenital and juvenile cataracts, little is known about the risk genetic variants for age-related cataract.
We conducted a meta-analysis of genome-wide association studies (GWAS) on 2,369 Malays and 2,200 Indians aged 40 to 80 years enrolled in the Singaporean Epidemiology of Eye Diseases (SEED) Study. Participants underwent a comprehensive eye examination including slit-lamp lens photography and provided a blood sample for genotyping. Lens photographs were graded using the Wisconsin Cataract Grading System, with the grades ranging from 0.1 (the lowest grade) to 5.0 (the highest). Genotyping was performed with Illumina HumanHap610-Quad chips. We performed SNP imputation using the genotype data, together with the reference panels in the 1000 Genomes project (March 2012, GRCh37). The association between SNPs and the severity (i.e., grade) of nuclear cataract was assessed using linear regression analysis with adjustment for age, sex and genetic principal components. We replicated our analysis in 2,481 Chinese from two independent cohorts (1,768 Chinese in Singapore and 803 Chinese in Beijing).
In the meta-analysis of GWAS in the Malay and Indian subjects (n = 4,569), the strongest evidence was observed at chromosome 21q22.3 (β [the increase in nuclear cataract grade per risk allele] = 0.11, p = 5.2E-9), reaching genome-wide significance (p <5.0E-8). In the combined meta-analysis of four cohorts (n = 7,140), we confirmed the association at the 21q22.3 locus (β = 0.08, random-effect p = 2.0E-9). In addition, we identified one novel locus at 3q25.31 (β = 0.11, random-effect p = 1.1E-8). The results were similar after additional adjustment for smoking status. The findings were further supported by up-regulation and down-regulation of the gene in 3q25.31 and 21q22.3 in human lens capsule, respectively, as the severity of nuclear cataract increases.
To our knowledge, this is among the first GWAS to investigate age-related nuclear cataract. The results offer additional insights into the pathogenesis of nuclear cataract and may provide potential targets for future therapeutic strategies in the management of cataract.
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