title: Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).
abstract: OBJECTIVE
  To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).
  
  
  METHODS
  Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.
  
  
  RESULTS
  Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.
  
  
  CONCLUSIONS
  Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA. lucia_sobrin@meei.harvard.edu
authors.forename: Lucia
authors.initials: L
authors.lastname: Sobrin
authors.forename: Todd
authors.initials: T
authors.lastname: Green
authors.forename: Xueling
authors.initials: X
authors.lastname: Sim
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jensen
authors.forename: E Shyong
authors.initials: ES
authors.lastname: Tai
authors.forename: Wan Ting
authors.initials: WT
authors.lastname: Tay
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Kustaa
authors.initials: K
authors.lastname: Hietala
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.forename: Matthew
authors.initials: M
authors.lastname: Brooks
authors.forename: Monika
authors.initials: M
authors.lastname: Buraczynska
authors.forename: Natalie
authors.initials: N
authors.lastname: Van Zuydam
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Alex S F
authors.initials: AS
authors.lastname: Doney
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Graham P
authors.initials: GP
authors.lastname: Leese
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Alan
authors.initials: A
authors.lastname: Penman
authors.forename: Ching J
authors.initials: CJ
authors.lastname: Chen
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Seang-Mei
authors.initials: SM
authors.lastname: Saw
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Klein
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: Cotch
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Tien Y
authors.initials: TY
authors.lastname: Wong
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics; D003930:Diabetic Retinopathy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007068:Iduronidase / Q000235:genetics; D016017:Odds Ratio; D019007:P-Selectin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D019007:P-Selectin; D007068:Iduronidase