IDDM2-VNTR-ENCODED SUSCEPTIBILITY TO TYPE-1 DIABETES - DOMINANT PROTECTION AND PARENTAL TRANSMISSION OF ALLELES OF THE INSULIN GENE-LINKED MINISATELLITE LOCUS

IDDM2-encoded predisposition to type 1 diabetes has recently been mapp ed to the minisatellite or variable number of tandem repeat (VNTR) loc us 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 d iabetics; n=441 healthy controls), we show here that the genotype homo zygous 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) an d Sardinia (n=138), we have analysed the transmission of class I allel es to diabetic offspring from class I/III heterozygous parents. We con firm that in families from the USA, class I alleles are transmitted pr eferentially from fathers. However, in family data sets from the UK, D enmark and Sardinia, the reverse is true and maternal transmission is stronger. Furthermore, in the UK family data set, the difference betwe en maternal and paternal transmissions is significant (P<0.05). It is therefore unlikely that 'maternal imprinting' alone explains the paren t-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 d ifferent studies are conflicting. In the human adult cadaveric pancrea s, we confirm our preliminary results that class III alleles are assoc iated with lower levels of insulin mRNA in vivo. Similar results have been obtained independently in human foetal pancreas samples. It is di fficult to explain how these marginally lower levels of insulin expres sion 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 . (C) 1996 Academic Press Limited