Genome-Wide Association Identifies [italic]SH3BP4, ADORA3[/italic] and 3 Other Loci with Diabetic Retinopathy in a Taiwanese Population

Genome-Wide Association Identifies [italic]SH3BP4, ADORA3[/italic] and 3 Other Loci with Diabetic Retinopathy in a Taiwanese Population Diabetic retinopathy (DR) is t Diabetic retinopathy (DR) is the leading cause of preventable blindness in adults; identifying genes contributing to DR should aid in elucidating the molecular pathogenesis. This study[apos]s goal is to identify genetic variation that contributes to DR using the genome-wide association study (GWAS) approach in a cohort of Chinese (Taiwanese) diabetics. We conducted a GWAS of 599 diabetics, comparing 378 with greater than 8 years duration without DR (controls) with 221 with proliferative diabetic retinopathy (PDR) (cases). Cases and controls were matched for HbA1c and diabetes duration. Genotyping utilized the whole-genome OmniExpress Infinium technology with 733,120 SNPs, analyzed with logistic regression. As covariates, systolic blood pressure (SBP) ([italic]p[/italic][lt]0.0001) and renal dysfunction ([italic]p[/italic][lt]0.0001) significantly associated with PDR. The average genotyping call rate among cases and controls was [gt]99.88% and the estimated genomic inflation factors ([italic][lambda][/italic][sub]GC[/sub]) was 1.008 without covariates and 1.000 using 4 significant covariates (age, gender, SBP, and renal dysfunction). Given the available sample size, we accepted as suggestive evidence for association a [italic]p[/italic]-value of 10[sup]-5[/sup]. Comparison between cases and controls identified 5 loci: [italic]SH3BP4[/italic] (rs2380261, OR=1.93, [italic]p[/italic]=4.09x10[sup]-7[/sup]),[italic] ARL4C[/italic] (rs2380261, OR=1.93, [italic]p[/italic]=4.09x10[sup]-7[/sup]; rs2380262, OR=2.85,[italic] p[/italic]=2.85x10[sup]-6[/sup]), [italic]DROSHA[/italic] (rs10068052, OR=1.98, [italic]p[/italic]=3.33x10[sup]-6[/sup]), [italic]ADORA3[/italic] (rs1361135, OR=0.55, [italic]p[/italic]=3.85x10[sup]-6[/sup]), [italic]SLC13A1[/italic] (rs3735438, OR=2.02, [italic]p[/italic]=5.41x10[sup]-6[/sup]), and [italic]HRH2[/italic] (rs4868527, OR=1.78, [italic]p[/italic]=6.04x10[sup]-6[/sup]) associated with PDR. [italic]SH3BP4[/italic] and [italic]ADORA3[/italic] are of particular interest because they are both expressed in the retina and may have important physiological significance for retinal pigment epithelial (RPE) cells and retinal ganglion cells ([italic]SH3BP4[/italic] in endocytosis and cell death pathways, ADORA3 neuroprotective). In conclusion, this study provides new evidence for novel DR susceptibility loci that are independent of the level of HbA1c and duration of diabetes. Identifying genetic risk factors for DR will provide new opportunities for risk stratification and potential therapeutic approaches for visual loss. WAYNE H.-H. SHEU, JANE Z. KUO, I.-TE LEE, XIAOWEN SU, YI-JEN HUNG, WEN-JANE LEE, HIN-YEUNG TSAI, J.-S. WANG, MARK O. GOODARZI, SHIN-YI LIN, XIUQING GUO, CHANG-HSUN HSIEH, KENT D. TAYLOR, CHIA-PO FU, JEROME I. ROTTER, YII-DER I. CHEN 1434-P Taichung, Taiwan, Los Angeles, CA, Taipei, Taiwan Genetics - Type 2 Diabetes