Human Molecular Genetics, 2000, Vol. 9, No. 20 2929-2935
© 2000 Oxford University Press
Influence of allele lineage on the role of the insulin minisatellite in susceptibility to type 1 diabetes
Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK and 1Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK
The insulin minisatellite or variable number of tandem repeats locus (INS VNTR) is the best candidate for the type 1 diabetes mellitus (T1DM) susceptibility locus IDDM2. Small class I alleles associate with predisposition to T1DM, whereas large class III alleles associate with dominant protection. We have analysed variant repeat distribution within the minisatellite and combined this with flanking haplotypes to define five new ancestral allele lineages. Class III alleles divide into two highly diverged lineages, IIIA and IIIB, which correspond perfectly to the previously defined Protective (PH) and Very Protective (VPH) haplotypes, respectively. Class I alleles are divided into three newly defined lineages, IC+, ID+ and ID–, by a combination of variant repeat distributions and flanking haplotypes. All class I alleles are equally predisposing to T1DM except for ID– alleles which are protective when transmitted from ID–/III heterozygous fathers. Similar results have been previously reported for alleles of 42 repeats in length (allele 814) which represent a subset of the ID– lineage. Division of class ID– alleles into those of 42 repeats and those of other sizes suggested that this protective effect was a feature of all ID– alleles, irrespective of size. ID– alleles are only clearly distinguished from all other alleles by an MspI– variant within IGF2 downstream of the minisatellite, suggesting that the apparent role of the minisatellite in susceptibility to T1DM may be modified by neighbouring haplotype and therefore that IDDM2 could have a multi-locus aetiology.
+ To whom correspondence should be addressed. Tel: +44 116 252 3413; Fax: +44 116 252 3378; Email: jdhs1@le.ac.uk
§ Present address: Institut de Biologie, CNRS UPR 1142, 4 Boulevard Henri IV, 34060 Montpellier, France
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