<i>CACNB2</i> Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes.

Abstract

Diabetic retinopathy is a common diabetes complication that threatens the eyesight 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 <i>CACNB2</i> gene (logarithm of odds = 2.73). Evidence of association between variants in <i>CACNB2</i> and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and <i>P</i> value of 8.6 × 10^-4 for rs11014284. Sequencing of <i>CACNB2</i> revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. <i>CACNB2</i> 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 <i>CACNB2</i> via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.