A retroviral long terminal repeat adjacent to the HLA DQB1 gene (DQ-LTR13) modifies Type I diabetes susceptibility on high risk DQ haplotypes |
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| Authors: | K. Bieda M. A. Pani B. van der Auwera C. Seidl R. R. Tönjes F. Gorus K. H. Usadel K. Badenhoop |
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| Affiliation: | (1) Department of Medicine I, Division of Endocrinology, University Hospital Frankfurt am Main, Frankfurt am Main, DE;(2) Department of Immunohematology, University Hospital Frankfurt am Main, Frankfurt am Main, Germany, DE;(3) Paul-Ehrlich-Institut Langen, Langen, Germany, DE;(4) The Diabetes Research Center, Vrije Universiteit Brussels, Brussels, Belgium, BE |
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| Abstract: | ![]()
Aims/hypothesis: 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; PTDT = 1.67 × 10–14) whereas no deviation from expected transmission frequencies was observed for DQ8/LTR13 – (20 transmitted vs 17 not transmitted; PTDT = 1.00). DQ8/LTR13 + alleles conferred a significantly higher risk for Type I diabetes than DQ8/LTR13 – alleles (pχ 2 = 2.58 × 10–14). This difference remained significant even after DRB1 subtyping (pχ 2 = 0.02). Also, there was a significant difference when comparing the transmission of DQ2/LTR13 + and DQ2/LTR13 – alleles (pχ 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 (pχ 2 = 0.01) and to female patients (pχ 2 = 0.04). Conclusion/interpretation: 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. [Diabetologia (2002) 45: 443–447] Received: 2 August 2001 and in revised form: 29 October 2001 |
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| Keywords: | Long-terminal repeat human leukocyte antigen DQB1 autoimmune Type I diabetes human endogenous retrovirus. |
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