A simple estimate of the general population frequency of the MHC susceptibility gene for autoimmune polygenic disease

We wished to determine the frequencies of the MHC and non-MHC susceptibilit y genes for polygenic autoimmune diseases like type 1 diabetes (IDDM). We u sed Mendelian inheritance and the Hardy-Weinberg equilibrium to calculate t he frequencies of mating pairs and susceptible offspring under classical re cessive and dominant inheritance of the MHC susceptibility gene. We then an alyzed the distribution of haplotype sharing by affected sib pairs of the 4 MHC haplotypes in each of the kinds of mating pairs in terms of the freque ncy of the disease susceptibility gene. For IDDM, the analysis was consiste nt with a recessive, but not a dominant, MHC susceptibility gene of frequen cy 0.525 at a distribution of 55, 38 and 7% of affected sib pairs who share 2, 1 and 0 MHC haplotypes, respectively. A simple relationship was obtaine d: if inheritance is recessive, the MHC susceptibility gene frequency is th e square root of the fraction of affected sib pairs who share no MHC haplot ypes multiplied by 4. For recessive inheritance, affected sib pairs who sha re no haplotypes are solely in families where both parents are homozygous M HC-susceptible. Although homozygous MHC susceptibles represent over 25% of the population, only 2-3% of them are IDDM-susceptible at non-MHC susceptib ility loci, also required for disease expression. Predictions from our anal ysis fit all published observations of the familial occurrence of disease. The analysis is general, simple and provides a single estimate (not a range ) of the MHC susceptibility gene frequency. This approach should be applica ble to other MHC-determined polygenic diseases. Copyright (C) 2000 S. Karge r AG,Basel.