Genetic variation of SLC19A3 is associated to diabetic retinopathy and nephropathy in type 1 diabetes

Background and aims: Diabetes duration, glycaemic control and blood pressure control are the strongest known risk factors for the development of diabetic microangiopathy. Thiamine (Vitamin B1) regulates intracellular glucose management at different levels and has been shown to correct high glucose-induced abnormalities by reducing reactive oxygen species production. Thiamine and its derivative benfotiamin have also been shown to reduce progression of retinopathy and nephropathy in animals with experimental diabetes. According to our hypothesis, patients who are prone to develop diabetic retinopathy and/or nephropathy may have impaired ability to achieve sufficiently high intracellular thiamine levels. This might be particularly damaging in insulin independent tissues that are more exposed to hyperglycaemia because they cannot regulate glucose inflow, such as retinal capillary endothelium and pericytes, the neuroretina, renal podocytes and mesangium. The aim of this study was to test if mutations in thiamine transporters hTHTR1 and hTHTR2 (coded by SLC19A2 and SLC19A3, respectively), and/or their transcription factors Sp1 and Sp2 (coded by SP1 and SP2), are associated with proliferative diabetic retinopathy (PDR) and/or diabetic nephropathy (DN). Materials and methods: The patient population consisted of 1568 cases with PDR, and 217 controls with no/mild retinopathy from the Finnish Diabetic Nephropathy (FinnDiane) Study. PDR was defined as ETDRS-score of 53 or worse or scattered laser treatment. Controls were required to have minimal diabetes duration of 20 years, maximal ETDRS-score of 30 on altered ETDRS-scale (corresponding to mild retinopathy) and no laser treatment. We chose HapMapII imputed SNPs from all four candidate genes and 10kb up and downstream of them (n=134). Logistic regression adjusted for sex, age, diabetes duration, and first ten genetic principal components were used for statistical calculations. In addition, association was tested between patient groups with different states of DN, and intersection of classes with both severe PDR and end-stage renal disease (ESRD) (n=369) vs. normo/microalbuminuric controls with no/mild retinopathy (n=190). Results: Two SNPs, rs12694743 and rs6713116, showed association with PDR (rs12694743: OR = 1.91, CI95% = 1.62-2.19, P = 1.02×10-5; rs6713116: OR = 2.34, CI95% = 1.97-2.72, P = 9.10×10-6). Both SNPs are located in intronic regions of SLC19A3. The signal was also noticeable in DN phenotypes, but was not significant after correcting for multiple testing. In analysis of intersection of extreme phenotypes the signal was amplified (rs12694743: OR = 3.18, CI95% = 2.76-3.60, P = 7.51×10-8; rs6713116: OR = 3.87, CI95% = 3.33-4.40, P = 7.49×10-7) providing proof of association not only with retinopathy, but both retinopathy and nephropathy. Replications in DCCT/EDIC and WESRD cohorts are ongoing. Conclusion: The results of this study suggest that mutations in SLC19A3 may increase susceptibility to PDR and especially to the combined phenotype of PDR and ESRD.