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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)

  • Genetics
  • Published:
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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.

Conclusion

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.

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Abbreviations

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

DR:

Diabetic retinopathy

PDR:

Proliferative diabetic retinopathy

SNPs:

Single nucleotide polymorphisms

OR:

Odds ratio

CI:

Confidence interval

BP:

Arterial blood pressure

GWAS:

Genome-wide association study

HWE:

Hardy-Weinberg equilibrium

EURODIAB:

European Diabetes Study Group

IDAA1c:

insulin dose-adjusted HbA1c

CHR:

Chromosome

MAF:

Minor allele frequency

MAF_A:

Minor allele frequency calculated for the affected individuals (cases)

MAF_U:

Minor allele frequency for the unaffected individuals (controls)

Circ. VEGF:

Circulating vascular endothelial growth factor

p adjust :

Adjusted p-value

ETDRS:

Early Treatment Diabetic Retinopathy Study

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Funding

The Beckett Foundation granted money for the genotyping.

Conflict of interest

Kristian Sandahl declare that he has received a research grant from Grosser Chr. Andersen og hustru Ingeborg Anders, f Schmidts legat. No other conflict of interest exists.

Statement of human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Statement of informed consent

Informed consent was obtained from all patients for being included in the study.

Author information

Author notes

    Authors and Affiliations

    1. Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark

      Steffen U. Thorsen, Kristian Sandahl, Lotte B. Nielsen, Marie L. M. Andersen, Henrik B. Mortensen, Flemming Pociot, Birthe S. Olsen & Caroline Brorsson

    2. Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

      Rebecca Broe, Malin L. Rasmussen & Jakob Grauslund

    3. The Clinical Research Institute, University of Southern Denmark, Odense, Denmark

      Rebecca Broe, Malin L. Rasmussen, Tunde Peto & Jakob Grauslund

    4. OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark

      Rebecca Broe

    5. NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK

      Tunde Peto

    6. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

      Henrik B. Mortensen

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    1. Steffen U. Thorsen
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    Correspondence to Kristian Sandahl.

    Additional information

    Steffen U. Thorsen and Kristian Sandahl contributed equally to this work.

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    Thorsen, S.U., Sandahl, K., Nielsen, L.B. et al. 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). Graefes Arch Clin Exp Ophthalmol 253, 1959–1965 (2015). https://doi.org/10.1007/s00417-015-3118-8

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