© International Epidemiological Association 2000 Printed in Great Britain International Journal of Epidemiology 2000;29:532–535

Effect of Sardinian heritage on risk and age

at onset of type 1 diabetes: a demographic
case-control study of Sardinian migrants
Graziella Bruno,a Gianfranco Pagano,a Fabrizio Faggiano,b Alberto De Salviaa and Franco Merlettic

Background Children of Sardinian heritage are at high risk of type 1 diabetes, whereas no data
are available in young adults. Age at onset of type 1 diabetes could be associated
with different relative weight of genetic susceptibility and environmental
determinants in the pathogenesis of the disease. We test this hypothesis in
subjects with Sardinian heritage 0–29 years of age living in the city of Turin, a
highly industrialized area in Northern Italy.
Methods In all, 202 cases with onset of type 1 diabetes aged 0–29 years during 1984–1991
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 0–14 and 15–29 years were found. In children with one
and both Sardinian parents the odds ratios (OR) were 2.09 (95% CI : 0.85–5.15)
and 3.20 (95% CI : 0.75–13.64); in young adults 0.81 (95% CI : 0.18–3.64) and
1.95 (95% CI : 0.51–7.40), respectively. In subjects with low social class the OR
were 1.16 (95% CI : 0.68–1.97) in children and 0.66 (95% CI : 0.41–1.05) 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

Type 1 (insulin-dependent) diabetes mellitus is an autoimmune
disease characterized by the selective destruction of insulin-
producing b cells in the pancreatic Islet of Langerhans. Despite
decades of intensive investigation, the trigger for this self-attack
is still unknown.1 Geographical and temporal variation in
incidence suggest that environmental factors, such as infections,
dietary components or toxins, could precipitate the disease in
susceptible individuals.2
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@unito.it
Striking intra-country variation in the incidence of type 1
diabetes has been found in Italy, with a 3–4-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 world 4 (24.1/100 000, 95% CI : 21.7–26.6 in
age 0–29), whereas in the Province of Turin, Northern Italy,
it is 7.4/100 000 (95% CI : 6.8–8.1).5,6 Sardinians are gen-
etically distinct from other populations including other
Italians,7–9 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

532

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,14–17 together with
better preservation of b cells function.18 Therefore, the relative
weight of genetic susceptibility and environmental determin-
ants 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 0–14 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 0–14 and 15–29 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.19–21
Methods
The population base of the case-control study was the
inhabitants 0–29 years of age (325 882 at 1991 general census)
of the city of Turin, a highly industrialized area in the northwest
part of Italy. In 1984, a population-based registry was
established in the Province of Turin (789 882 inhabitants 0–29
years of age) which has collected all incident cases of type 1
diabetes in the age group 0–29 years. Three independent
sources of ascertainment have been employed to ensure that
case ascertainment was as complete as possible. The primary
data source was the list of all patients with type 1 diabetes who
attended one of the diabetes clinics where most diabetic patients
are referred after the diagnosis. The secondary data sources
were: (1) the file of hospital discharges from public and private
hospitals in the city of Turin in the period 1984–1988; (2) the
computerized file of all subjects who obtained, in the study
period, exemption from payment for medicine, syringes, and
glucose monitoring strips because of a diagnosis of diabetes
mellitus.5 The estimated completeness of ascertainment,
according to the capture-recapture method was high (99% in
the age group 0–14 years and 95% in the age group 15–29
years).
Age-specific incidence rates in the period 1984–1991 were
8.4/100 000 (95% CI : 7.2–9.7) and 6.7/100 000 (95%
CI : 6.0–7.6), respectively, in the age groups 0–14 and 15–29.5
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
CASE-CONTROL STUDY OF SARDINIAN MIGRANTS 533
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.
Results
Mean age (standard deviation) of cases and controls was 15.4
(7.0) and 15.4 (7.05), respectively. Sixty per cent were male. No
sex differences were found in the frequency of subjects with
either one or both Sardinian parents. Parents of controls of low
versus high social class were 7/1010 (0.69%) and 7/1010
(0.69%) versus 25/1010 (2.38%) and 7/1010 (0.69%) (one or
both Sardinian parents). Corresponding figures for parents of
cases were 3/102 (1.49%) and 2/202 (0.99%) versus 6/202
(2.97%) and 4/202 (1.98%).
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.
An effect of social class by age at onset of type 1 diabetes was
evident, with a slightly higher risk in the low social class in
children and a marked increase in the higher social class in
young adults.
Conclusions
This population-based case-control study, based on demo-
graphic data, shows that children of Sardinian heritage living in
Northern Italy remain, for at least one generation, at increased
risk of the disease, particularly when both parents are
Sardinians. This finding, which is consistent with results of
previous studies conducted in Lazio and in Lombardia10,11
provides further evidence of a strong genetic effect on the
pathogenesis of the disease in this population. In both pre-
vious studies, census data on children with Sardinian heritage
allowed the estimation of incidence rates based on a reasonably
large number of cases limited to this subgroup of patients. In the
present study we assessed the effect of being of Sardinian
heritage on the risk of type 1 diabetes not only in children but
also in young adults. To test the hypothesis that this effect may
vary with the age at onset, we employed data provided by the
534 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

Table 1 Effect of Sardinian heritage and social class on risk of type 1 diabetes in the city of Turin, Northern Italy

Age at onset
0–14 years 15–29 years 0–29 years
Cases Controls ORa Cases Controls OR Cases Controls OR
(No.) (No.) (95% CI) (No.) (No.) (95% CI) (No.) (No.) (95% CI)
Sardinian parentb
None 88 467 1.00 99 497 1.00 187 964 1.00
One 7 18 2.09 2 14 0.81 9 32 1.54
(0.85–5.15) (0.18–3.64) (0.72–3.30)
Both 3 5 3.20 3 9 1.95 6 14 2.37
(0.75–13.64) (0.51–7.40) (0.89–6.26)
Social classc
High 76 396 1.00 68 312 1.00 144 708 1.00
Low 21 94 1.16 29 200 0.66 50 294 0.83
(0.68–1.97) (0.41–1.05) (0.58–1.17)
Missing 1 0 7 8 8 8
a Odds ratio.
b Odds ratios were adjusted for social class.
c Odds ratios were adjusted for Sardinian heritage; social class was defined by educational level (6+ versus ,6 years of schooling).

registry of Turin, which is among the few extending the
registration up to 29 years of age. A case-control study was
designed, since census data on Sardinian heritage are not
available after childhood.
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,14–16 including one of ours,17 which show higher fre-
quencies 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 10–14 years, in Sardinia
the age group at highest risk is younger (5–9 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 environ-
mental 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 environ-
mental 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 15–29 years. Results of population-based studies
examining socioeconomic status in type 1 diabetes have been
conflicting.19–21,26 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 0–19.26
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.
Acknowledgement
The authors are grateful to Lucia Nonnato and to Lucia Marsilio
for their contribution to data collection and analysis. This study
was partially supported by a grant from the Association for
Cancer Research (AIRC).
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