title: Variation in SLC19A3 and Protection From Microvascular Damage in Type 1 Diabetes.
abstract: The risk of long-term diabetes complications is not fully explained by diabetes duration or long-term glycemic exposure, suggesting the involvement of genetic factors. Because thiamine regulates intracellular glucose metabolism and corrects for multiple damaging effects of high glucose, we hypothesized that variants in specific thiamine transporters are associated with risk of severe retinopathy and/or severe nephropathy because they 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 an association with severe retinopathy or nephropathy or their combination in the FinnDiane cohort. Subsequently, the results were examined for replication in the DCCT/EDIC and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohorts. We found two SNPs in strong linkage disequilibrium in the SLC19A3 locus associated with a 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 that included the WESDR cohort. These findings suggest that genetic variations in SLC19A3 play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy and may explain why some individuals with type 1 diabetes are less prone than others to develop microvascular complications.
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Porta
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Iiro
authors.initials: I
authors.lastname: Toppila
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.affiliation: Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Canada.
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Kustaa
authors.initials: K
authors.lastname: Hietala
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Borio
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.affiliation: Department Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Klein
authors.affiliation: Department Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI.
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.affiliation: Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Baker IDI Heart and Diabetes Institute, Melbourne, Australia per-henrik.groop@helsinki.fi.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019610:Cytoprotection / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics; D003930:Diabetic Retinopathy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human