No evidence for linkage between an insulin‐dependent diabetes mellitus‐susceptibility locus and immunoglobulin loci KM or GM

Abstract

We studied 52 families having more than one member affected with insulin-dependent diabetes mellitus (IDDM) for linkage of an IDDM-susceptibility locus to the immunoglobulin loci KM and GM. Linkage was analyzed by the LOD score method using single-locus recessive and dominant models of IDDM inheritance, with penetrances of the disease-susceptible genotypes being dependent on age and reaching a maximum of 20% by age 40. We found no evidence for linkage of IDDM to KM or GM. Close linkage (recombination fraction less than 5%) was rejected for KM under the recessive model and for GM under both models. These results suggest either that there are no IDDM-susceptibility loci closely linked to KM or GM or that use of a single-locus model of IDDM (which ignores the effects of the susceptibility locus in the HLA region) is inadequate for their detection.

Interactive effect of HLA and Gm tested in a study of 135 juvenile insulin‐dependent diabetic families

“…However, neither of these series were H L A typed. Field et al (1984) considering the presence or absence of only 3 allotypes: G l m (l), G l m (2) and G3m ( 5 ) , observed no association between any of these markers and IDD, but showed interaction of G l m (2) and DR3 in the absence of DR4 and interaction of G3m (5) and DR4 in the absence of DR3, in diabetic patients compared with sibling control subjects.…”

“…matched to the patients with respect to the geographical heterogeneity of the G m system. The selection of intrafamilial controls, also used by Field et al (1984) rules out this problem, but makes it less probable to detect significant differences between the groups because the patients are more likely to have markers in common with their siblings than with random controls. This difficulty is illustrated by the similarity, in our sample, between patients and sibling controls regarding DR3/X and DRWX allelic combinations which have otherwise been shown to differ significantly between patients and controls taken from the general population.…”

“…However, this was not possible because the Gm haplotype frequencies differ largely between geographical areas, even within one country and ethnic group. In order to rule out the geographical heterogeneity present in our patient sample, we decided, similar to Field et al (1984), to select a control group among the unaffected relatives of index cases, assigning the oldest non-affected sib of each family as a control subject. However, this way of constituting a control group has the disadvantage of exaggerating the similarities between patients and controls and thus blunting existing differences.…”

“…The search for association (Nakao et al 1981. Bertrams et al 1983, Field et al 1984, Schernthaner & Mayr 1984 or linkage (Field et al 1984, D e Jongh et al 1984 between Gm and IDD has so far given negative or contradictory results. There could be either no association at all or, alternatively, the complexity and geographical heterogeneity of the Gm system could make the interpretation for the purpose of a genetic analysis difficult.…”

Report of the committee on the genetic constitution of chromosomes 2, 3, 4, and 5

“…Field et al (1984) find no evidence in an extended series of families for such a locus being linked to IGK or G M . Dunsworth et al (1982) have also reported significantly negative lod scores for IDDM and Jk.…”