title: A retroviral long terminal repeat adjacent to the HLA DQB1 gene (DQ-LTR13) modifies Type I diabetes susceptibility on high risk DQ haplotypes.
abstract: OBJECTIVE
  HLA-DQ genes, located in the human leukocyte antigen region on chromosome 6 p, are the main inherited factors predisposing to Type I (insulin-dependent) diabetes mellitus. Endogenous retroviral long-terminal repeats are integrated at several sites within this region, one of which is known to enhance susceptibility for Type I diabetes. We examined another LTR within the HLA-region as an additional genetic risk marker.
  
  
  METHODS
  We investigated the segregation of one long-terminal repeat (DQ-LTR13), located 1.3 kb upstream of HLA DQB1 with different HLA-DQ haplotypes, and its transmission to patients. A total of 284 Caucasian families (203 German and 81 Belgian) with at least one diabetic offspring were genotyped for DQA1, DQB1 and DQ-LTR13.
  
  
  RESULTS
  DQ8/LTR13(+) was preferentially transmitted (139 transmitted vs 28 not transmitted; P(TDT) = 1.67 x 10(-14)) whereas no deviation from expected transmission frequencies was observed for DQ8/LTR13(-) (20 transmitted vs 17 not transmitted; P(TDT) = 1.00). DQ8/LTR13(+) alleles conferred a significantly higher risk for Type I diabetes than DQ8/LTR13(-) alleles (p chi(2) = 2.58 x 10(-14)). This difference remained significant even after DRB1 subtyping (p chi(2) = 0.02). Also, there was a significant difference when comparing the transmission of DQ2/LTR13(+) and DQ2/LTR13(-) alleles (p chi(2) = 0.01), the latter conferring an increased risk. The transmission of DQ-LTR13(+) haplotypes did not show any differences regarding paternal, maternal or gender-related stratification. However, DQ8/LTR13(-) was significantly more often transmitted from mothers (p chi(2) = 0.01) and to female patients (p chi(2) = 0.04).
  
  
  CONCLUSIONS
  We conclude that DQ-LTR13 marks additional genetic risk for Type I diabetes on predisposing DRB1(*)0401- DQ8 and DQ2 haplotypes and will help to further define susceptibility in this gene region.
authors.affiliation: Department of Medicine I, Division of Endocrinology, University Hospital Frankfurt am Main, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Bieda
authors.forename: M A
authors.initials: MA
authors.lastname: Pani
authors.forename: B
authors.initials: B
authors.lastname: van der Auwera
authors.forename: C
authors.initials: C
authors.lastname: Seidl
authors.forename: R R
authors.initials: RR
authors.lastname: Tönjes
authors.forename: F
authors.initials: F
authors.lastname: Gorus
authors.forename: K H
authors.initials: KH
authors.lastname: Usadel
authors.forename: K
authors.initials: K
authors.lastname: Badenhoop
mesh_terms: D001483:Base Sequence; D001530:Belgium; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018392:Genomic Imprinting; D005858:Germany; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006239:Haplotypes; D006801:Humans; D008297:Male; D009679:Nuclear Family; D016133:Polymerase Chain Reaction; D020079:Terminal Repeat Sequences / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D017931:DNA Primers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen