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Jane Z. Kuo, Xiaoyi Gao, Xiuqing Guo, Kent D Taylor, Ronald Klein, Barbara E K Klein, Eli Ipp, Yii-Der Ida Chen, Rohit Varma, Jerome I Rotter; A Candidate-Wide Association Study of Diabetic Retinopathy in Latinos Implicates TNF Receptor Pathophysiology: Genetics of Latino Diabetic Retinopathy (GOLDR) and Los Angeles Latino Eye (LALES) studies. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4509.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the associations of candidate genes from cardiovascular and metabolic trait loci to diabetic retinopathy (DR) in Latinos with type 2 diabetes using a fine-mapping approach.
A prospective, multicenter cohort of 1599 Latinos with type 2 diabetes with and without retinopathy were included in this study. Retinopathy status was assessed using the Early Treatment Diabetic Retinopathy Study scale, defined as any DR (cases; level ≥ 14) and no DR (controls; level < 14). We conducted a candidate-wide association study including 565 Latinos from the GOLDR study (discovery), who were genotyped with the Illumina Cardio-Metabochip, a custom array to enhance fine-mapping of cardiovascular and metabolic trait loci. In silico replications of the top signals (selected by multiple hits per locus) were performed in 1034 Latinos from the LALES cohort (replication), who were genotyped with the Illumina OmniExpress and imputed with 1000 Genome. Analysis was conducted in R using the GWAF package and in METAL for meta-analysis, Bonferroni correction for 20 loci.
Association analysis of in silico replication of the top findings and meta-analysis confirmed 4 potential DR susceptibility loci. They are RBKS-BRE (rs72854438, P.meta=1.03x10-3), DNAH1 (rs28481563, P.meta=3.81x10-4), RGS21-RGS1 (rs1323295; P.meta=3.32x10-5) and SMAD3 (rs12324036; P.meta=1.24x10-5), the latter two loci were associated independent of the level of HbA1c and diabetes duration. In addition, quantitative trait analysis of levels of tumor necrosis factor (TNF) receptors 1 (P<10-3) and 2 (P<10-4) to BRE, a TNF-receptor super family 1A modulator, supports the involvement of TNF-receptors in DR.
We identified 4 novel potential loci to DR in Latinos with type 2 diabetes. Furthermore, our findings support our prior reported quantitative role of TNF receptors in DR, which may provide critical insights into the pathophysiology of DR in Latinos.
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