Variation in SLC19A3 and Protection from Microvascular Damage in Type 1 Diabetes
The risk of long-term diabetes complications is not fully explained by diabetes duration or long-term glycemic exposure, suggesting the involvement of genetic factor(s). Since thiamine regulates intracellular glucose metabolism and corrects for multiple damaging effects of high glucose, we hypothesised that variants in specific thiamine transporters are associated with risk of severe retinopathy and/or severe nephropathy, as they might modify an individual’s ability to achieve sufficiently high intracellular thiamine levels. We tested 134 single-nucleotide polymorphisms (SNPs) in two thiamine transporters (SLC19A2/3) and their transcription factors (SP1/2) for association with severe retinopathy, nephropathy or their combination in the FinnDiane cohort. Subsequently, the results were examined for replication in the DCCT/EDIC and WESDR cohorts. We found two SNPs in strong linkage disequilibrium in the SLC19A3 locus associated with reduced rate of severe retinopathy and the combined phenotype of severe retinopathy and end-stage renal disease. The association for the combined phenotype reached genome-wide significance in a meta-analysis including the WESDR cohort. These findings suggest that genetic variations in SLC19A3 may play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy. This may help explain why some persons with type 1 diabetes are less prone than others to develop microvascular complications.
- Received September 4, 2015.
- Accepted December 14, 2015.
- © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.