a Department of Internal Medicine, University of Turin, Italy.
b Department of Public Health, University of Turin, Italy.
c Unit of Cancer Epidemiology, Department of Human Oncology and Center for Oncologic Prevention, University of Turin, Italy.
Reprint requests to: Prof. Franco Merletti, Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Torino, via Santena 7, I-10126 Torino, Italy. E-mail: franco.merletti{at}unito.it
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Abstract |
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Methods In all, 202 cases with onset of type 1 diabetes aged 029 years during 19841991 and 1010 controls randomly selected from residents of the city of Turin, frequency-matched by sex and year of birth to cases, were included in this study. Name and place of birth of parents were ascertained by postal inquiry and linkage with city population and census files. Social class was based on the highest educational level of parents abstracted from 1991 and 1981 census files.
Results Differential effects on risk of type 1 diabetes of Sardinian heritage and social class in the age groups 014 and 1529 years were found. In children with one and both Sardinian parents the odds ratios (OR) were 2.09 (95% CI : 0.855.15) and 3.20 (95% CI : 0.7513.64); in young adults 0.81 (95% CI : 0.183.64) and 1.95 (95% CI : 0.517.40), respectively. In subjects with low social class the OR were 1.16 (95% CI : 0.681.97) in children and 0.66 (95% CI : 0.411.05) in young adults.
Conclusions This study shows higher risk of type 1 diabetes in subjects of Sardinian heritage; higher risk in children than in young adults and a protective effect of low social class in young adults. These findings are consistent with the hypothesis of heterogeneity of type 1 diabetes by age at onset, with prevailing genetic effect in childhood and environmental determinants in adulthood.
Keywords Migrants, insulin-dependent diabetes mellitus, Sardinia
Accepted 17 December 1999
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Introduction |
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Striking intra-country variation in the incidence of type 1 diabetes has been found in Italy, with a 34-fold higher risk in Sardinia relative to other Italian regions.3 On this island, the risk approaches that for Finland, the country with the highest incidence in the world4 (24.1/100 000, 95% CI : 21.726.6 in age 029), whereas in the Province of Turin, Northern Italy, it is 7.4/100 000 (95% CI : 6.88.1).5,6 Sardinians are genetically distinct from other populations including other Italians,79 and differences in frequencies of susceptibility or protective alleles could be involved in geographical risk variation of type 1 diabetes. Consistent with this hypothesis, two studies limited to childhood-onset diabetes showed a similar incidence in children living in the Lazio and in the Lombardia Regions with that found in Sardinia if both parents were Sardinians, and intermediate incidence if only one parent was Sardinian.10,11
Most registries have been limited to childhood-onset diabetes.2 However, a persisting high risk of the disease at least until age 30 has been found by the few surveys that expanded registration up to this age.5,6,12,13 Factors associated with variability in the age at onset of the disease are not known. With respect to childhood-onset, in adult-onset type 1 diabetes lower frequencies of HLA DQA1-DQB1 susceptibility alleles and diabetogenic heterodimers have been found,1417 together with better preservation of ß cells function.18 Therefore, the relative weight of genetic susceptibility and environmental determinants may have a bearing on age at clinical onset and rate of progression of the disease. A differential effect of Sardinian heritage by age at onset of type 1 diabetes could suggest that the importance of genetic susceptibility may vary by age at onset.
Whereas previous studies on type 1 diabetes among subjects of Sardinian heritage living in other Italian areas were limited to age 014 years, the population-based registry of the city of Turin, Northern Italy, allows for estimates of incidence up to age 29.5,6 Therefore, on the basis of the above hypothesis, we have analysed risks for type 1 diabetes among residents in the city of Turin separately for those aged 014 and 1529 years. Our analysis has been designed as a demographic case-control study, testing also the hypothesis of an aetiological role of social class, as suggested by others.1921
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Methods |
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Age-specific incidence rates in the period 19841991 were 8.4/100 000 (95% CI : 7.29.7) and 6.7/100 000 (95% CI : 6.07.6), respectively, in the age groups 014 and 1529.5
Cases in this report were 202 residents of the city of Turin with onset of type 1 diabetes from 1 January 1984 to 31 December 1991. Controls were 1010 subjects randomly selected from Turin residents frequency matched by sex and year of birth to cases in a 5 to 1 ratio. Information on exposures of interest (Sardinian heritage and social class) were obtained mainly by linkage with demographic files.
Name and place of birth of parents of cases were ascertained through clinical records (150 parents), the population file of the city of Turin residents (108) or postal inquiry to the place of birth of cases for parents no longer residents of Turin (146). One father was unidentified. Demographic data of 1878 parents of controls were ascertained through the files of the city of Turin, whereas 142 required a postal inquiry. Six fathers were unidentified.
Social class of cases and controls was based on the highest educational level of either parents abstracted from 1991 and 1981 census files. Eight cases and eight controls could not be classified. Social class was defined dichotomously as either <6 or 6+ years of schooling based on previous studies on social inequalities.22
Univariate analysis was carried out estimating odds ratios (OR) and their 95% CI using the exact method.23 Multivariate analysis applied unconditional logistic models (Sardinian heritage and social class as independent variables; diabetic status as dependent one).23 Since univariate results did not differ substantially from results of multivariate analysis, only the latter are presented.
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Results |
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As shown in Table 1, subjects with both Sardinian parents have more than a twofold higher risk of type 1 diabetes relative to those without Sardinian parents, with intermediate value in subjects with only one Sardinian parent. The effect of Sardinian heritage was higher in children than in young adults. Indeed, in the latter no effect was evident for those having only one Sardinian parent.
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Conclusions |
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An original feature of our findings is the suggestion that the association with Sardinian heritage is stronger for those with clinical onset of the disease early in life and relatively low for those with disease onset after age 15, leading to the hypothesis of a dependence of age at onset on the weight of genetic susceptibility. Given the low incidence of the disease, limited Sardinian migration and the low birth rate in Italy, numbers cannot be large, even if 46 subjects of Sardinian heritage in a population of one million over a period of 8 years is sound information from a sound study base. We are aware that results in the specific sub-analyses are based on very few cases, as shown by the large and overlapping confidence intervals, and that they should be interpreted as suggestive of a working hypothesis. Nevertheless, our finding is consistent with the few studies comparing childhood-onset with adult-onset type 1 diabetes,1416 including one of ours,17 which show higher frequencies of HLA-DQA1 and DQB1 susceptibility alleles and heterodimers in children than in adults in populations at medium risk. In addition, with respect to most geographical areas, where the peak of incidence is found at age 1014 years, in Sardinia the age group at highest risk is younger (59 years).24
At present, the complexity of gene-environment interaction in the pathogenesis of type 1 diabetes has not been adequately addressed. It is likely that the disease is caused by environmental determinants in genetically susceptible individuals. However, as pointed out in cancer epidemiological studies,25 an effect modification by weight of genetic susceptibility might also operate in type 1 diabetes. That is, children with high genetic susceptibility to type 1 diabetes, such as those with Sardinian heritage, might develop the disease early in life irrespective of environmental exposure, whereas the occurrence of diabetes in those who are less genetically susceptible could be the expression of a relatively long-lasting exposure to environmental agents. For the time being, we present this as a working hypothesis for the design of further epidemiological studies on type 1 diabetes.
The second finding of this study was the suggestion of a protective effect (with borderline statistical significance) of low social class (<6 years of schooling) with regard to onset of disease at age 1529 years. Results of population-based studies examining socioeconomic status in type 1 diabetes have been conflicting.1921,26 In Northern Ireland, children with higher social class had higher risk, whereas no effect was evident in Scotland.20 Higher rates have been reported in children living in areas with higher average income in Montreal19 and in Denmark,21 but not in Pittsburgh in the age group 019.26 However, no previous study examined the effect of social class on risk of type 1 diabetes separately in children and young adults.
In conclusion, this case-control study shows: (1) higher risk of type 1 diabetes in subjects of Sardinian heritage; (2) a greater effect of Sardinian heritage in children than in young adults; (3) a protective effect of low social class in young adults. These findings are consistent with the hypothesis of heterogeneity of type 1 diabetes by age at onset, with prevailing genetic effect in childhood and environmental determinants in adulthood.
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Acknowledgments |
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References |
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