Background
The incidence of type 1 diabetes is increasing across Europe (Bingley and Gale 1988). To take one example, the increase in Finland - with the highest incidence of type 1 diabetes in the world - is equivalent to a four-fold rise over 50 years. A predominantly linear increase has been observed over this period, with an annual increase of about 3% (Tuomilehto 1999). The same increasing has been seen in other European countries at high risk for Type 1 diabetes: Sweden, Norway, Denmark. (ref.)
Sardinia has the second highest incidence rate of type 1 diabetes in the world. Even there, the conscript study (Songini 1993) showed a progressive increase in successive birth cohorts of 20 year old male Sardinians, rising from nearly zero in cohorts from before 1945. Follow up of the cohort has shown a continued increase to nearly 5/1000 in more recent years (Songini, unpublished).
The rapid rise in genetically stable populations (such as in Finland and in Sardinia) has suggested environmental causation. The main effect of the environment may be to modulate the age at disease onset without influencing the lifetime risk of disease. This hypothesis was proposed by Kurtz in 1988 and termed by us the “spring harvest” hypothesis.). This phenomenon could be also due to “environmental anticipation”. For example, the incidence of childhood type 2 diabetes is rising rapidly in the Pima indians and other genetically predisposed ethnic groups. In the Pima Indians the increase can be attributed to the rising number of obese children and the increasing number of children born to mothers who were diabetic at the time of pregnancy (ref).We could propose an analogous role for environmental factors in the causation of childhood onset type 1 diabetes.
This phenomenon need not have only environmental causes, however. In fact, earlier presentation of genetic diseases in succeeding generations due to accumulation of trinucletide repeats is a familiar concept known as anticipation………….
For example, a variable number tandem repeat (VNTR) in the promoter of the insulin gene is also closely linked to disease. Class I alleles (26-63 repeats) predispose to disease while Class III alleles (140->200 repeats) are dominantly protective [Ref]. The recent observation that Class III alleles are associated with type 2 diabetes may contribute further to disease classification [Iref]. The existence of repeat sequences in the INS gene will allow us to establish whether accumulation of sequences occurs with transmission between generations, and whether this might play a role in increasing susceptibility to type 1 diabetes in later generations.
Notwithstanding, at present there is no satisfactory explanation, environmental or genetic, for the rapidity of the increase seen in Sardinia. Since the immunogenetic determinants of type 1 diabetes must have been present in previous generations, it is logical to look for evidence of autoimmune diabetes in previous generations. Clinical review of the records from a sample of patients with well characterized (C-peptide negative) type 1 diabetes attending Dr Songini’s clinic reveals a strikingly high rate of both type 1 and apparent type 2 diabetes (Table). The impression of a high frequency of type 2 diabetes may be misleading, since experience with non-insulin treated diabetic relatives in the Bart’s-Oxford population has shown that many of these have genetic and/or immune markers of autoimmune diabetes (Bingley, unpublished). The observation (Tarn 1985, Dahlquist 1994; Li 1998) that an excess of apparent type 2 diabetes is present in the parents of children with type 1 diabetes can probably be explained by the observation that older individuals in that study present with the features of LADA (latent autoimmune diabetes of adults). Supporting evidence comes from the study ofRich et al(1991) in whichtransmission of susceptibility to children with type 1 diabetes from parents with apparent type 2 diabetes was demonstrated; 11 families had both parents DR4 typed and DR4 in the diabetic offspring. In this small group 9/11 received the allele from the type 2 parent.
The same may be true of the Sardinian population. If this view is correct, the apparent epidemic of childhood onset diabetes in Sardinia might be seen to represent changing expression – modulated by the environment - of a genetically mediated condition.
The question could however only be answered in our own population by careful characterization of diabetes in the earlier generation.
This will involve re-examination of the familial basis of type 1 diabetes in Sardinia. The initial aim will be to test the hypothesis that autoimmune diabetes is present in the parents and grandparents of children with type 1 diabetes in Sardinia, but now manifests in an earlier and more acute form due to genetic or environmental changes.
The prevalence of type 1 diabetes in high risk populations (like Sardinians) is estimated to be near 0.4% among children. The risk of the disease is 6-7% among siblings and 14-25% among HLA-identical sibling. A recent survey on the monozigotic twins of type 1 patients shows a cumulative risk of 70% after a follow up of 35 years. Another study suggest that 2/3 of the MZ twins discordant for diabetes have islet related autoantibodies.
The contribution of genetic and environmental factors in the development of type 1 diabetes has also been studied in migrant: sons of Sardinian parents living in Lazio region (central Italy-with lower incidence than Sardinia) have the same risk of Sardinian children to develop diabetes (Muntoni et al. Lancet 1997). The same was seen in the Pavia province (Northern Italy) (Tenconi et al. 1998). These evidences suggest a high but uncompleted penetrance, and underline the importance of genetic factors in the pathogenesis of the disease.
Furthermore, Type 1 diabetes in Sardinia has distinctive HLA determinants, with different disease associations from those seen in other populations (Cucca 1993,1995). The high male/female ratio in this population may be due to linkage to chromosome Xp in HLA-DR3 positive patients (Cucca 1998). Transmission ratio distortion has also been observed in the Sardinian population (Cucca unpublished), and might provide a partial explanation for the rising incidence of the disease.
A further observation of considerable interest is that other forms of autoimmune disease including coeliac disease, thyroid autoimmunity and multiple sclerosis are also highly prevalent in the Sardinian population. The conditions have distinct but overlapping HLA determinants. A shared genetic basis for autoimmunity has been proposed (Becker 1999). The population of Sardinia therefore offers an unparalleled opportunity to study the genetic and environmental determinants of autoimmunity in general, and of type 1 diabetes in particular.
specific aims (max 8000)
The Study proposed has different main objective
- to establish a major family study cohort in Sardinia, in a population of outstanding interest with respect to type 1 diabetes and other forms of autoimmune disease. A well characterised population will prove invaluable for analysis of the genetic basis of autoimmunity, and for studying interactions between genetic susceptibility and environmental factors predisposing to immune-mediated disease. It will provide a valuable genetic collection and database linked to full phenotypic characterization of probands and relatives, which can provide a resource for many future studies;
- exploration of genetic links between diabetes and other autoimmunity, and more extensive pedigree analysis than is currently possible;
- first detailed analysis of inheritance of diabetes in Sardinia;
to test the hypothesis that unrecognised autoimmune diabetes is present in the parents and grandparents of children with type 1 diabetes in Sardinia. The hypothesis that autoimmune diabetes is present in parents and grandparents of children with type 1 diabetes in Sardinia – and that the genetic contribution to the rising incidence of the disease has been underestimated – will be tested by characterization of the clinical, genetic and immune characteristics of parents and grandparents in the study cohort.
- to examine the genetic and environmental determinants of type 1 diabetes in the light of the rising incidence of the disease, to test the hypothesis of genetic anticipation;
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