Although association of insulin-dependent diabetes mellitus with a haplotype at a locus encompassing the genes for insulin and the insulin-like growth factor II has been well established, two major studies disagree as to whether linkage to this locus is confined to paternally inherited alleles, or is present in alleles transmitted from either parental sex. Towards resolving this discrepancy, we examined parent-of-origin specific association rather than linkage, using the haplotype relative risk method in a mixed Caucasian population. We find that the haplotype relative risk (HRR) conferred by paternal chromosomes was much higher (5.1, p < 0.01) than the corre-sponding maternal value (2.3, p = 0.07), which narrowly failed to reach statistical significance. Thus, although we cannot exclude an effect of the maternal allele, such an effect appears to be considerably weaker. We review evidence that parental imprinting is genotype-dependent, which may explain the different degrees to which the paternal effect is seen in different populations. [Diabetologia (1995) 38: 715-719] Key words Genetic association, imprinting, insulin, insulin-like growth factor II.
Susceptibility to insulin-dependent diabetes mellitus (IDDM) appears to depend on more than one genetic locus [1]. In addition to the major role of the HLA complex, substantial contribution from a second locus, at or near the insulin gene (INS), is known to exist: in a French population, both linkage to and association with IDDM was demonstrated over a 4.1 kb area, from the INS 5' flanking region to within 1 kb of the first promoter of the insulin-like growth factor II gene IGF2 [2-3]. Alleles in non-coding sequence polymorphisms in that region form a highly conserv-