Linkage Analysis between the Major Histocompatibility System and Insulin-dependent Diabetes in Families with Patients in Two Consecutive Generations

Abstract

A B S T R A C T INTRODUCTIONOne of the few seemingly well-established facts about the etiology of insulin-dependent diabetes mellitus (IDDM)l is that extensive heterogeneity is present (1-8). Thus, several genetic mechanisms are likely to be involved. These may possibly range from multigenic (with each locus contributing only a small effect) to the major genetic effect of Mendelian modes of inheritance. The recent reports of association between the histocompatibility system (HLA) and IDDM (5,6) indicate a direct and important effect of the HLA antigens on the risk of the disease. One possible explanation of this association is linkage between the two traits; we have conducted a series of linkage analysis studies to examine these possibilities. Genetic studies of IDDM must be designed to answer a specific research question under circumstances that minimize the "noise" of heterogeneity. We have, therefore, sampled multiplex families (i.e., those families with

Genetic Analysis of Multiply-Affected Families of Insulin-Dependent Diabetes Mellitus (IDDM) Probands

“…Since examination of the likeli hoods in the families with only a parent and child affected revealed that they ac count for almost all of the difference in likelihoods between incomplete dominant and incomplete recessive modes of inheri tance. Barbosa et al [1] also found similar results with their two-generation-affected families that the likelihood of the incom plete dominant model is ten times more likely than the incomplete recessive. How ever, one cannot rule out the possibility, as pointed out by Suarez and Van Eerdewegh [25], that this difference may be due to sampling and/or incorrect specification of the true genetic mode of inheritance.…”

“…It is not possible to compare this find ing with previous studies, since except Barbosa et al [1], who looked at an incom plete dominant mode only when analyz ing their two-generation IDDM families, previous investigators have assumed an incomplete recessive mode of inheritance in their linkage analyses. In our study evi dence for linkage between susceptibility to IDDM and HLA is stronger for a domi nant rather than a recessive model with the same population prevalence.…”

“…Barbosa et al [1] selected families with IDDM individuals in two consecutive generations for the purpose of testing the hypothesis of incomplete dominant inher itance. In this set of families, they find weak evidence for linkage under the in complete dominant or incomplete reces sive mode.…”

“…Barbosa et al [1] also analyzed families with two generations af fected, examining both recessive and dom inant inheritance with incomplete pene trance. These authors found that the lod scores were not much different between the two modes of inheritance, and in fact, were very low for both.…”

Erratum

“…Similarly, many groups, including our own [10], have shown that the frequency of HLA recombinants in Type I diabetes is normal. Further, it is true that HLA typing does identify siblings of probands at considerably higher risk of diabetes.…”