The Histocompatibility System in Juvenile, Insulin-Dependent Diabetic Multiplex Kindreds

Abstract

A B S T R A C T We have histocompatibility (HLA) genotyped 24 families with two or more juvenile, insulin-dependent, ketosis-prone diabetic siblings. This criterion for family selection was used to obtain a homogeneous form of diabetes within a sibship, because diabetes appears to be a genetically heterogeneous disease. 58 diabetic and 53 nondiabetic sibs and 40 parents were studied. 55% of the diabetic pairs were concordant for both HLA haplotypes (expected 25%), 40% were concordant for one haplotype (expected 50%), and 5% were discordant for both haplotypes (expected 25%). These values are significantly different from the expected values (P < 0.001). On the other hand, the inheritance of haplotypes among the nondiabetic sibs in these families was not significantly different from the expected mendelian segregation.When comparing 20 pairs of HLA identical (sharing two haplotvpes) with 15 pairs of haploidentical (sharing one haplotvpe) diabetic sibs for the intrapair difference in age of oniset of disease, we found that the HLA idenitical sibs were significantly more concordanit for age of onset (3.9 yr differenice) than the haploidentical (7.3 yr difference) (P < 0.05). The same type of analyrsis for the difference in seasonal incidence in months revealed that the HLA identical sibs were more concordant (1.8 mo difference) than the haploidentical sibs (3.2 mo difference) (P < 0.025). Furthermore, the HLA identical diabetic sibs were more likely to develop diabetes in the winter months (78%) than the haploidentical diabetic sibs (21%).No particular HLA haplotype or antigen seemed to be associated with any particular clinical feature.

Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans.

“…Whereas this conclusion may apply to the observations made in other groups of relatives of patients with type I diabetes, we do not believe it is relevant in our subjects, since they were selected based on variables that correlate with a lower risk for the development of type I diabetes (30) to insure that donors have normal pancreatic function before surgery. Consequently, they were older and more distant in age from the age of diabetes onset of the affected family member than were the family members included in other investigations of proinsulin in firstdegree relatives of patients with type I diabetes (4-7).…”

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

“…Subsequent studies in other countries 3 - 4 have confirmed these observations, but consid-erable argument has taken place concerning the mode of inheritance of the HLA susceptibility factor. For example, some investigators favor a dominant inheritance, 5 whereas others argue that the results from family studies are compatible with an autosomal recessive pattern.…”

Analysis of linkage between the major histocompatibility system and juvenile, insulin-dependent diabetes in multiplex families. Reanalysis of data.

“…The clinical material in 24 diabetic multiplex families and the immunological studies of the HLA have been published (1). Only the 21 families with affected members in the second generation are included in this work.…”

“…We performed this analysis only in the families without HLA recombinants, since the high frequency of recombinants in JIDD families has not been confirmed (1,8). Furthermore, we excluded another family with a homozygous parent.…”

“…We have recently reported a study ofhistocompatibility (HLA)' haplotypes (A and B alleles) on 24 diabetic multiplex families (1). These families were ascertained for the existence of two or more juvenile, insulindependent diabetic (JIDD) children in each sibship.…”