The effect of association of genetic factors on relative risk

We have examined the numerical properties of relative risk (RR) estimates under the conditions of gene frequency and genetic association (delta) that generally obtain for the different HLA loci. It is found that significant RR may be created solely by the existence of positive delta between the disease susceptibility gene and a specific allele at the marker (e.g. HLA) locus. It is shown further, that the value of RR is strongly affected by the gene frequencies and not only by the corresponding delta. If positive delta exists between one disease susceptibility gene and two HLA haplotypes, the RR estimates will usually be highest for the corresponding heterozygote, intermediate for the two homozygotes and lowest for the other carrier phenotypes. This model was found to be perfectly compatible with the situation encountered in the case of juvenile diabetes mellitus and shows that 'overdominance' is not required to account for the excessive RR found in some populations for certain HLA heterozygous classes.