Three generations of autoimmune diabetes an exten

Authors: I F Douek K M Gillespie R J Dix P J Bingley E A M Gale

Publish Date: 2003/07/30

Volume: 46, Issue: 10, Pages: 1313-1318

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Abstract

One in four children with Type 1 diabetes in a populationbased family study has an affected grandparent We set out to study the clinical and immune features of diabetes in the grandparents generation and to examine sharing of HLA class II susceptibility haplotypes between grandparent and grandchildOf 5855 grandparents in the BartsOxford family study 428 73 were known to have diabetes Clinical data and samples were collected from 115 of 213 surviving affected grandparents and from 219 unaffected grandparents within the same families Samples were tested for ICA and autoantibodies to GAD and IA2 and typed for HLADRB1DQA1DQB1 Transmission of HLA class II haplotype from affected and unaffected grandparents to the diabetic proband was comparedOf 115 affected grandparents studied the median age at diagnosis was 61 years and at analysis was 73 years 70 were diet or tablet treated and 30 were on insulin One or more islet autoantibodies were found in 26 and 66 had one or both of the high risk HLA class II susceptibility haplotypes DRB103DQA10501DQB10201 or DRB104DQA10301DQB10302 In 79 informative families the HLA class II haplotype of the affected grandparent was transmitted to the proband more frequently than expected overall 59 p=002 and in the insulintreated subgroups 65 p=003A total of 73 of grandparents reported a clinical diagnosis of diabetes and 22 had features of Type 1 diabetes Genetic susceptibility was shared between grandparents with diabetes and their affected grandchildren Diabetes in the grandparents of children with Type 1 diabetes often has an autoimmune basis even when it presents late in life and does not require insulin treatmentImmunemediated diabetes is not exclusively or even typically a disease of childhood Presentation in later life ranges across a spectrum at one end are those who present acutely and require immediate insulin treatment and at the other are those who present as Type 2 diabetes yet carry islet autoantibodies Since the classification of immunemediated diabetes was previously based solely upon an early requirement for insulin 1 the frequency of the condition could have been underestimated in older relatives of children with classic Type 1 diabetes With this in mind we examined the parents of children with Type 1 diabetes in an earlier study and found that 31 had insulintreated diabetes and 21 did not require insulin When aetiological criteria were used however we found that 45 had immunemediated diabetes and only 09 had a nonimmune form of the disease the latter estimate did not differ from reported rates in the background population 2A prolonged prodromal period with onset in later life is characteristic of many other autoimmune conditions and it would not be surprising if a proportion of cases of Type 1 diabetes presented in this way this may even have been the characteristic mode of onset in earlier generations On this basis we have speculated that a more permissive environment might lead to earlier clinical presentation in genetically predisposed subjects and that earlier disease onset might partially explain the rising incidence of childhood onset Type 1 diabetes over the past 50 years 3 4 Another example of earlier disease onset in response to a more permissive environment would be the current epidemic of obesityrelated childhood onset Type 2 diabetes 5 We therefore aimed to establish whether examination of the grandparental generation would add biological support to this concept and set out to determine the prevalence of immunemediated diabetes in this generation and to look for evidence of shared genetic susceptibility between affected grandparent and grandchild

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