title: The association of previously reported polymorphisms for microvascular complications in a meta-analysis of diabetic retinopathy.
abstract: We investigated the association of signals from previous GWAS and candidate gene meta-analyses for diabetic retinopathy (DR) or nephropathy (DN), as well as an EPO variant in meta-analyses of severe (SDR) and mild diabetic retinopathy (MDR). Meta-analyses of SDR (≥severe non-proliferative diabetic retinopathy (NPDR) or history of panretinal photocoagulation) and MDR (≥mild NPDR), defined based on seven-field stereoscopic fundus photographs, were performed in two well-characterized type 1 diabetes (T1D) cohorts: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC, n = 1,304) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR, n = 603). Among 34 previous signals for DR, after controlling for multiple testing, no association was replicated in our meta-analyses. rs1571942 and rs12219125 at PLXDC2 locus showed nominally significant (<0.05) association with SDR in the same direction as previous report, as did rs1801282 in PPARG gene with MDR. Among 55 loci previously associated with DN, three showed suggestive associations with SDR in our study without maintaining significance after correction for multiple testing. Of particular interest, rs1617640 (EPO) was not significantly associated with DR status, combined SDR-DN phenotype, time to SDR or time to DN (all P > 0.05). Lack of replication of previous DR hits and EPO despite reasonable statistical power implies that many of these may be false positives. Consistent with pleiotropy, we provide suggestive collective evidence for association between DR and variants previously associated with DN without reaching statistical significance at any single locus.
authors.affiliation: Genetics and Genome Biology Program, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Rm 12.9835, 686 Bay Street, Toronto, ON, M5G 0A4, Canada, mohsen.hosseini@utoronto.ca.
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Boright
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Canty
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Bull
authors.forename: Barbara E K
authors.initials: BE
authors.lastname: Klein
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
mesh_terms: D002986:Clinical Trials as Topic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C554270:EPO protein, human; C558538:PLXDC2 protein, human; D011956:Receptors, Cell Surface; D004921:Erythropoietin