Journal of Autoimmunity (1996) 9, 415–421 IDDM2-VNTR-encoded Susceptibility to Type 1 Diabetes: Dominant Protection and Parental Transmission of Alleles of the Insulin Gene-linked Minisatellite Locus Simon T. Bennett 1 , Amanda J. Wilson 1 , Francesco Cucca 1 , Jørn Nerup 2 , Flemming Pociot 2 , Patricia A. McKinney 3 , Anthony H. Barnett 4 , Stephen C. Bain 4 , and John A. Todd 1 1 The Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, Windmill Road, Oxford OX3 7BN 2 Steno Diabetes Center, DK-2820 Gentofte, Denmark 3 Paediatric Epidemiology Group, Research School of Medicine, University of Leeds, Leeds LS2 9LN 4 Department of Medicine/Diabetes/Endocrinology, University of Birmingham, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS IDDM2-encoded predisposition to type 1 diabetes has recently been mapped to the minisatellite or variable number of tandem repeat (VNTR) locus upstream of the insulin and insulin-like growth factor II genes on human chromosome 11p15.5. In a UK case-control study (n =228 sporadic diabetics; n =441 healthy controls), we show here that the genotype homozygous for VNTR class I alleles is predisposing to disease (RR=2.68), and VNTR class III alleles are dominantly protective (RR=0.37). In 722 diabetic families from the UK (n =356), USA (n =173), Denmark (n =55) and Sardinia (n =138), we have analysed the transmission of class I alleles to diabetic offspring from class I/III heterozygous parents. We confirm that in families from the USA, class I alleles are transmitted preferentially from fathers. However, in family data sets from the UK, Denmark and Sardinia, the reverse is true and maternal transmission is stronger. Furthermore, in the UK family data set, the difference between maternal and paternal transmissions is significant (P<0.05). It is therefore unlikely that ‘maternal imprinting’ alone explains the parent-of-origin effects in IDDM2-encoded predisposition to type 1 diabetes, at least not in the UK. There is a relationship between VNTR class (allele length) and insulin gene expression, though some results from different studies are conflicting. In the human adult cadaveric pancreas, we confirm our preliminary results that class III alleles are associated with lower levels of insulin mRNA in vivo. Similar results have been obtained independently in human foetal pancreas samples. It is difficult to explain how these marginally lower levels of insulin expression could account for the observed VNTR class III-encoded protective effect. Perhaps the site of action of IDDM2, mediated by VNTR allelic variation, is not the pancreas but some other organ such as the thymus. © 1996 Academic Press Limited Key words: insulin gene expression, genomic imprinting, IDDM2 Introduction Type 1, or insulin dependent diabetes mellitus (IDDM), is one of the most common chronic diseases in children with an incidence ranging from about 5 to 35 per 100,000 caucasoids of European descent [2]. Characterized by the autoimmune destruction of the insulin-producing, pancreatic -cells of the islets of Langerhans, type 1 diabetes pathogenesis is multifac- torial, determined by both genetic and environmental agents. Unravelling the genetic component by identi- fying the predisposing aetiological mutations is an essential step for a comprehensive approach to pre- ventive therapy. A comparison of the risk to siblings of type 1 diabetic subjects (6%) with the population risk (0.4%), shows that there is appreciable clustering of type 1 diabetes in families ( s , or risk ratio=6/0.4=15; Ref. 3). A large proportion of the genetic component of this familial clustering is encoded for by genes (IDDM1) in the immune response HLA region on chromosome 6p21 [4–6], with smaller contributions from as many as ten other loci outside the HLA region [4, 7–12]. For example, in UK families, other than IDDM1, eight putative non-HLA-encoded chromo- some regions have now been mapped [12]. Assuming a multiplicative model of inheritance, in which loci interact epistatically, familial clustering of the disease can be explained almost entirely by susceptibility genes. Moreover, while the non-HLA-encoded suscep- tibility loci each account for only a small proportion of the familial clustering, the combined contribution of Correspondence to: Dr Simon Bennett; email: simon.bennett@well.ox.ac.uk 415 0896-8411/96/030415+07 $18.00/0 © 1996 Academic Press Limited