The G Allele of the rs12050217 Polymorphism in the BDKRB1 Gene Is Associated with Protection for Diabetic Retinopathy

ABSTRACT

Purpose

The plasma kallikrein–kinin system is activated during vascular injury caused by diabetic retinopathy (DR), being involved in hyperpermeability and inflammation. Bradykinin B1 receptor (B1R) is expressed in human retina, and its levels are increased in murine models of diabetes. Experimental studies reveal that B1R antagonists ameliorate retinal injury caused by diabetes in rodents. Thus, the aim of this study was to investigate the association between the rs12050217A/G polymorphism in the BDKRB1 gene, the gene that codifies B1R, and DR in type 2 diabetes mellitus (T2DM) patients.

Methods

We analyzed 636 T2DM patients and 443 non-diabetic subjects. T2DM patients were categorized by the presence of non-proliferative DR (NPDR, n = 267), proliferative DR (PDR, n = 197), and absence of DR (n = 172). The BDKRB1 rs12050217A/G polymorphism was genotyped by real-time PCR using TaqMan MGB probes.

Results

The genotype frequencies of the BDKRB1 rs12050217A/G polymorphism are in Hardy–Weinberg equilibrium and did not differ between T2DM patients and non-diabetic subjects (P > 0.05). The presence of the genotypes containing the rs12050217 G allele was less frequent in patients with PDR when compared to patients with NPDR and without DR (32.0%, 41.9%, and 43.0%, P = 0.045, respectively). Interestingly, the presence of G allele was associated with ~40% protection for PDR, which was confirmed after correction for the presence of hypertension, ethnicity, age, HDL, and gender (odds ratio = 0.616, 95% confidence interval 0.385–0.986, P = 0.043).

Conclusion

For the first time, we showed that BDKRB1 rs12050217 G allele is associated with protection for the advanced stage of DR in T2DM patients; however, further studies are needed to confirm this finding.

KEYWORDS:

• Diabetic retinopathy
• B1 receptor
• BDKRB1
• type 2 diabetes mellitus
• DNA polymorphism

Acknowledgments

The authors are grateful to Cláudia de Aguiar Pisco for customizing the figure. This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – Chamada Universal MCTI/CNPq N° 01/2016), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes – Projetos Conjuntos de Pesquisa em Drug Discovery, Edital N° 41/2014), and Fundo de Incentivo à Pesquisa e Eventos (FIPE-HCPA, GPPG N° 16-0053) at Hospital de Clínicas de Porto Alegre. D.C. is a recipient from a scholarship from CNPq. The authors declare that they have no conflicts of interest with the contents of this article.