title: Linkage Analysis of Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications and Interaction with HLA.
abstract: We conducted linkage analysis to follow up earlier work on microvascular complications of type 1 diabetes (T1D). We analyzed 415 families (2,008 individuals) previously genotyped for 402 SNP markers spanning chromosome 6. We did linkage analysis for the phenotypes of retinopathy and nephropathy. For retinopathy, two linkage peaks were mapped: one located at the HLA region and another novel locus telomeric to HLA. For nephropathy, a linkage peak centromeric to HLA was mapped, but the linkage peak telomeric to HLA seen in retinopathy was absent. Because of the strong association of T1D with DRB1*03:01 and DRB1*04:01, we stratified our analyses based on families whose probands were positive for DRB1*03:01 or DRB1*04:01. When analyzing the DRB1*03:01-positive retinopathy families, in addition to the novel telomeric locus, one centromeric to HLA was identified at the same location as the nephropathy peak. When we stratified on DRB1*04:01-positive families, the HLA telomeric peak strengthened but the centromeric peak disappeared. Our findings showed that HLA and non-HLA loci on chromosome 6 are involved in T1D complications' expression. While the HLA region is a major contributor to the expression of T1D, our results suggest an interaction between specific HLA alleles and other loci that influence complications' expression.
authors.affiliation: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA ; Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Ettie M
authors.initials: EM
authors.lastname: Lipner
authors.affiliation: Department of Medicine, Mount Sinai Medical Center, New York, NY 10013, USA.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94702, USA.
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Noble
authors.affiliation: National Research Council, Neuroscience Institute, 35128 Padova, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Monti
authors.affiliation: National Disease Research Interchange, Philadelphia, PA 19103, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Lonsdale
authors.affiliation: National Research Council, Neuroscience Institute, 35128 Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Corso
authors.affiliation: Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, Columbus, OH 43215, USA ; Department of Pediatrics, Wexner Medical Center, Ohio State University, Columbus, OH 43205, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
mesh_terms: D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide
chemical_list: D006680:HLA Antigens