Type I (Insulin-dependent) Diabetic Multiplex Families: Mode of Genetic Transmission

Abstract

SUMMARYHLA genotypes have been analyzed in 120 classic type I (insulin-dependent) diabetic sib pairs with an age of onset below 16 yr reported to the British Diabetic Association register (1972-78). By this age, siblings of diabetic children are 26 times more likely to develop type I diabetes than other children. There is a highly significant disturbance in the zygotic assortment of HLA haplotypes in these sib pairs, providing conclusive evidence for the existence of major susceptibility genes in the HLA complex.The present data exclude a simple dominant or recessive mode of inheritance. It is likely that both parents contribute to the susceptibility, indicating the presence of two HLA-linked genes (or clusters of genes in linkage disequilibrium) that influence the predisposition to the disease. There is no evidence that type I diabetic multiplex families have an increased HLA risk or increased predisposition to autoimmunity compared with families with one affected child. DIABE-TES 29:1036-1039, December 1980.

Genetic Epidemiology

“…For example, for IDDM, data are compatible with a recessive but not with a dominant mode of inheritance for the HLA linked susceptibility gene (200,219). On the other hand, the data on multiple sclerosis are consistent with both dominant and recessive modes of inheritance.…”

A 212-kb Region on Chromosome 6q25 Containing the TAB2 Gene Is Associated With Susceptibility to Type 1 Diabetes

“…The inheritance of type 1 diabetes is genetically determined, although in a complex manner. In humans, two type 1 diabetes susceptibility genes have been studied in great detail: the HLA region on chromosome 6p21, IDDM1 (1)(2)(3), and the insulin gene region, IDDM2, on chromosome 11p15 (4 -9). IDDM1 and IDDM2 contribute 42 and 10%, respectively, to the familial inheritance of the disease, and it can be further extrapolated that while other type 1 diabetes susceptibility genes exist, none can have the relatively large contribution described for IDDM1 (9,10).…”

The Bf system in diabetes-gene interaction or linkage disequilibrium?

“…In contrast, B 18 without CW5 is not associated with BfF1. Furthermore, the frequency of the BfF1-B 18-CW5 haplotype in the probands was similar in families with one diabetic child and in families with two or more affected children, confirming that there is no difference in HLA susceptibility between 'sporadic' cases and those families with multiple affected siblings [13]. It is generally agreed that the Bf system is determined by one locus with four alleles, and that the Bf locus lies between HLA-B and -D. The HLA-C locus is also very close to HLA-B, but on the other side of it.…”

“…We have already shown that the HLA characteristics of these two family studies are very similar [13]. Because the Bf association is also similar in these two family studies, the data for the probands have therefore been combined (Table 1).…”

“…Twenty-three out of a total of 184 Caucasoid families with two or more Type 1 diabetic siblings ascertained from the British Diabetic Association Register 1972-78 [12] were also genotyped. These families were located throughout the UK and the majority had been HLA-A, B, C genotyped [13], including all those in the present study. The mean age at onset of diabetes in the probands was 8 years, and again there was a biased selection of families for Bf typing on the basis of informative HLA-haplotypes containing HLA-BIS.…”