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Diabetes. 2019 Aug 22. pii: db190130. doi: 10.2337/db19-0130. [Epub ahead of print]

CACNB2 is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes.

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Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.
Faculty of Medicine and Health Technology, Tampere University, Finland.
Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Okinawa, Japan.
Ophthalmology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.


Diabetic retinopathy is a common diabetic complication that threatens the eye sight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib-pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds (LOD) = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an OR of 0.83 and p-value of 8.6×10-4 for rs11014284. Sequencing of CACNB2 revealed two coding variants R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the β2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19), and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.


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