title: Polymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).
abstract: BACKGROUND
  The incidence of type 1 diabetes mellitus (T1DM) is increasing globally, and as a consequence, more patients are affected by microvascular complications such as diabetic retinopathy (DR). The aim of this study was to elucidate possible associations between diabetes-related single-nucleotide polymorphisms (SNP) and the development of DR.
  
  
  METHODS
  Three hundred and thirty-nine patients with T1DM from the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987) went through an ophthalmic examination in 1995; 185 of these were reexamined in 2011. The development of DR was assessed by comparison of overall DR level between baseline and follow-up in the worst eye at baseline. Patients were graded on a modified version of the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and 20 SNPs were genotyped in 130 of the 185 patients.
  
  
  RESULTS
  We found the CTSH/rs3825932 variant (C > T) was associated with reduced risk of progression to proliferative diabetic retinopathy (PDR) (OR [95 % CI] = 0.20 [0.07-0.56], p = 2.4 × 10(-3), padjust = 0.048) and ERBB3/rs2292239 variant (G > T) associated with increased risk of two-step progression (OR [95 % CI] = 2.76 [1.31-5.80], p = 7.5 × 10(-3), padjust = 0.15). The associations were independent of other known risk factors, such as HbA1c, sex, and diastolic blood pressure.
  
  
  CONCLUSIONS
  In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to PDR and two-step progression of DR on the ETDRS scale accordingly. The variant CTSH remained statistically significant after adjusting for multiple testing. Our results suggest an overlap between genetic variants that confer risk of T1DM and progression of DR.
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Steffen U
authors.initials: SU
authors.lastname: Thorsen
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark. kristian.sandahl@regionh.dk.
authors.forename: Kristian
authors.identifier: http://orcid.org/0000-0002-0071-3575
authors.initials: K
authors.lastname: Sandahl
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.|The Clinical Research Institute, University of Southern Denmark, Odense, Denmark.|OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Broe
authors.affiliation: Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.|The Clinical Research Institute, University of Southern Denmark, Odense, Denmark.
authors.forename: Malin L
authors.initials: ML
authors.lastname: Rasmussen
authors.affiliation: The Clinical Research Institute, University of Southern Denmark, Odense, Denmark.|NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Tunde
authors.initials: T
authors.lastname: Peto
authors.affiliation: Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.|The Clinical Research Institute, University of Southern Denmark, Odense, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Grauslund
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Marie L M
authors.initials: ML
authors.lastname: Andersen
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Birthe S
authors.initials: BS
authors.lastname: Olsen
authors.affiliation: Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brorsson
mesh_terms: D056655:Cathepsin H / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003718:Denmark; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D060005:Genotyping Techniques; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D056655:Cathepsin H; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human; C534126:CTSH protein, human
keywords: CTSH/rs3825932; Diabetic retinopathy; ERBB3/rs2292239; Proliferative diabetic retinopathy; SNPs; Type 1 diabetes mellitus