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The Juvenile Diabetes Research Foundation Center for Type 1 Diabetes Prevention in Finland (T.K., A.K., A.-M.H., M.Ku., P.Ku., K.S., T.S., P.Ke., J.I., O.S., M.Kn.), Department of Pediatrics, Medical School, University of Tampere (T.K., M.Ku., M.Kn.), and Tampere University Hospital, FIN-33014 Tampere; Department of Pediatrics (A.K., T.S., P.Ke., J.I., O.S.) and Department of Virology (J.I.), University of Turku, FIN-20520 Turku; University of Oulu (A.-M.H., P.Ku., K.S.), FIN-90220 Oulu; and Hospital for Children and Adolescents (M.Kn.), University of Helsinki, FIN-00029 Helsinki, Finland
Address all correspondence and requests for reprints to: Prof. Mikael Knip, Hospital for Children and Adolescents, University of Helsinki, P.O. Box 281, FIN-00029 HUCH, Finland. E-mail: mikael.knip{at}hus.fi
Abstract
Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of ß-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of ß-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of ß-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.
THE INCIDENCE OF type 1 diabetes has gradually increased in most Western countries since World War II (1, 2), and the highest annual incidence in the world has been reported in Finland, amounting to 50 new cases per 100,000 children under the age of 15 yr in 1998 (A. Reunanen, personal communication). The increase in incidence has been most obvious in the age group under 5 (3), even though the diagnosis of diabetes is still fairly rare among infants.
Type 1 diabetes is a multifactorial disease with a closely associated genetic predisposition. The most important genes contributing to disease susceptibility are located in the human leukocyte antigen (HLA) DQ locus on the short arm of chromosome 6 (4). Although more than 90% of the patients with type 1 diabetes carry the predisposing DQ8 (i.e. DQA1*0301/DQB1*0302) and/or DQ2 (i.e. DQA1*0501/DQB1*0201) alleles, only a minority of genetically susceptible individuals progress to clinical disease. Environmental factors are assumed to play an important role in the pathogenesis of type 1 diabetes. The autoimmune type of diabetes is characterized by the emergence of diabetes-associated autoantibodies in the preclinical period, likely reflecting ongoing ß-cell damage in the pancreatic islets. The latent preclinical phase may last for years; and by combining markers of genetic disease susceptibility and humoral markers, i.e. disease-associated autoantibodies, it is possible to identify most of the first-degree relatives of affected subjects who will develop clinical diabetes (5, 6). However, about 90% of the new cases occur in families with no affected first-degree relative (7).
Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life, and there are no reliable data on the emergence of the first signs of ß-cell autoimmunity in the general population. This prospective study describes the emergence of diabetes-associated autoantibodies during the first 2 yr of life in children who carry increased HLA-conferred genetic risk of type 1 diabetes in the general population.
Subjects and Methods
Subjects
The Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study was established to assess feasible strategies for predicting type 1 diabetes in the general population and to develop effective tools for preventing or delaying progression to clinical disease (8). Consecutive families with their baby born in 1 of the 3 participating university hospitals in Finland were invited to take part. The study was initiated at Turku University Hospital in November 1994, at Oulu University Hospital in September 1995, and at Tampere University Hospital in October 1997. These university hospitals serve primarily a population of 1.2 million (24% of the total population in Finland), and the number of annual births is about 11,500 (20% of the total number of births in Finland). No significant variation has been observed in the incidence of type 1 diabetes between various provinces of Finland (9). Excluded from the study were families where neither parent was Caucasian; where the parents had difficulties in understanding Finnish, Swedish, or English; or where the newborn infant had a severe congenital abnormality or disease. Umbilical cord blood samples were obtained from all the newborn infants, and the families were offered the possibility of screening for HLA-defined genetic risk of type 1 diabetes after the delivery. The parents were given both oral and written information on the study, and more than 94% of the families gave their written informed consent to genetic screening.
Families with an infant carrying increased genetic susceptibility to type 1 diabetes [high-risk: DQB1*02/*0302; moderate-risk: DQB1*0302/x (x = other than *02, *0301, or *0602)] were invited for the observational phase, after again giving their written informed consent, when the baby was approximately 3 months old. The first blood samples of the observation period were taken at the age of 3 months, the next at the age of 6 months, and subsequently at intervals of 3–6 months during the initial 2 yr. The older nondiabetic sibs of the genetically susceptible infants were also invited for genetic and autoantibody screening.
Islet cell antibodies (ICA) were used as the initial screening test for ß-cell autoimmunity. If an infant tested positive for ICA at the age of 3 months, ICA and insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase (GADA), and antibodies to the protein tyrosine phosphatase-related IA-2 molecule (IA-2A) were also analyzed in the cord blood sample. All ICA-positive 3-month-old infants had had ICA in their cord blood, suggesting that these antibodies had been transferred transplacentally from the mother. Such antibodies were excluded from the analysis, because they always disappeared by the age of 15 months at the latest. The children who tested positive for IAA and/or GADA at the age of 6 and 9 months had no detectable autoantibodies in their cord blood sample or in the sample taken at the age of 3 months. If an infant seroconverted to ICA positivity, he/she was observed at 3-month intervals, and all his/her blood samples, including those obtained previously, were analyzed for IAA, GADA, and IA-2A. All children were observed for the development of type 1 diabetes by November 1998.
By the end of September 1998, written informed parental consent for genetic screening had been obtained for 25,983 newborn infants, all of whom had been analyzed for HLA-DQB1 alleles. Out of these, 3,596 (13.8%) carried the high- or moderate-risk genotype. At the time of this analysis, at least 1 ICA measurement had been performed on 2,448 infants followed from birth. Their mean age at the end of the observation period was 1.2 yr. These children comprise the present study population, the oldest of these index children reaching the age of 2.5 yr during the follow-up. Altogether, 1,307 sibs of the index cases had also been genotyped and analyzed for ICA at least once. The samples taken at the time of diagnosis of type 1 diabetes in 6 index cases who progressed to clinical disease were included in the evaluation of the data. The DIPP study protocol had been approved by the ethical committees of the 3 participating hospitals.
Laboratory procedures
HLA-DQB1 alleles *02, *0301, *0302, *0602, *0603, and *0604 were analyzed as described (10).
Diabetes-associated autoantibodies were measured in the Research Laboratory of the Department of Pediatrics, University of Oulu. ICA were quantified by a standard indirect immunofluorescence method on sections of frozen human pancreas from a blood group O donor (11). The end-point dilution titer of ICA-positive samples were recorded, and the results were expressed in Juvenile Diabetes Foundation (JDF) units. The detection limit was 2.5 JDF units. All samples initially positive for ICA were retested to confirm antibody positivity. The sensitivity of the ICA assay in our laboratory was 100%, and the specificity was 98% in the fourth international standardization workshop (12).
Serum levels of IAA were quantified with a microassay modified from that described by Williams et al. (13). The IAA levels representing the specific binding were expressed in relative units (RU) based on a standard curve run on each plate using the MultiCalc software program (Perkin Elmer Life Sciences, Wallac, Inc., Turku, Finland). A subject was considered positive for IAA when the specific binding exceeded 1.55 RU (the 99th percentile in 371 nondiabetic Finnish subjects). The disease sensitivity of our microassay was 35%, and the specificity was 100%, based on 140 samples derived from the 1995 Multiple Autoantibody Workshop (14).
GADA were measured with a radiobinding assay as previously described (15). The results were expressed in RU, based on a standard curve constructed from a dilution of a pool of highly positive samples with a negative sample. The cutoff limit for antibody positivity (5.35 RU) was set at the 99th percentile of 373 nondiabetic Finnish children and adolescents. The disease sensitivity of the GADA assay was 69%, and its specificity was 100%, based on 140 samples included in the 1995 Multiple Autoantibody Workshop (14).
IA-2A were quantified with a radiobinding assay as described previously (16). Antibody levels were expressed in RU, based on a standard curve, as for GADA. The limit for IA-2A positivity was set at 0.43 RU, which represents the 99th percentile of 374 nondiabetic Finnish children and adolescents. The disease sensitivity of this assay was 62%, and the specificity was 97%, based on 140 samples included in the 1995 Multiple Autoantibody Workshop (14). All samples with IAA, GADA, or IA-2A levels between the 95th and 99.5th percentiles were reanalyzed to confirm the antibody status. In case of a discrepant result, such a sample was tested for a third time. Analyzing, blindly, three standards (low, medium, and high antibody levels), once a month in each assay, monitors possible assay drift over time.
Statistical analysis
The distributions of autoantibodies between genotypes and
seasons were evaluated by cross-tabulation and
2 statistics with Yates’ correction, unless
the expected value was less than five, when the Fisher exact test was
used (17). To compare the seasonal variation in the
appearance of the first autoantibodies, the time point for
seroconversion was approximated to be in the middle of the interval
between the last negative and first positive sample. The Wilcoxon
signed-rank test was used to compare the order of emergence of various
antibodies in those subjects who tested positive for at least two
disease-associated autoantibodies. The first antibody to appear was
given a score of 4; the second antibody, a score of 3; and subsequent
antibodies, scores continuing in like manner.
Results
The appearance of diabetes-associated antibodies in children with increased genetic disease risk
Out of the 25,983 infants genotyped, 780 (3.0%) had the high-risk
HLA-DQB1 genotype *02/*0302; and 2816 (10.9%), the moderate-risk DQB1
genotype *0302/x. About 10% of the older sibs genotyped (139 of 1307;
10.6%) carried the high-risk genotype; and more than one third (450;
34.4%), the moderate-risk genotype. Of the 2,448 infants analyzed for
ICA at least once, 548 had the high-risk genotype and 1,900 had the
moderate-risk genotype. The first 3 infants (3 of 1,856; 0.2%)
developed ICA between 3 and 6 months of age (ICA, 5–18 JDF units).
Thirty-eight children (38 of 2448; 1.6%), of whom 18 were boys, tested
positive for ICA at least once during the follow-up. The proportion of
infants who tested positive for ICA was significantly higher among
those with the high-risk genotype (15 of 548; 2.7%) than among those
with the moderate-risk genotype (23 of 1,900, 1.2%; P
= 0.019). In 30 children (79%), the first antibodies appeared in the
fall or winter, from September to February, whereas only 8 children
(21%; P < 0.001) presented with their first
antibodies in the spring or summer, from March to August (Fig. 1
).
|
). The prevalence of ICA was 6.5% (9 of
139) in the sibs carrying the high-risk genotype at a mean age of 6.0
yr (range, 1.3–17.1 yr) and 3.3% (15 of 450; P =
0.17) in those sibs with the moderate-risk genotype at a mean age of
6.0 yr (range, 1.2–22.8 yr).
|
The order of emergence of various autoantibodies among the 25
children who tested positive for at least 1 other antibody in addition
to ICA, during the follow-up, is shown in Table 1. IAA appeared as the first single
antibody specificity in 8 infants, whereas GADA were the first
detectable antibodies in 2 infants, and ICA in 1 individual. IAA were
among the first antibodies in all those 14 children who tested positive
for 2 or more antibodies already in their first antibody-positive
sample. Accordingly, IAA emerged as the first antibody, or among the
first antibodies, in 22 of the 25 children (88%) who were positive for
at least 2 antibodies during the follow-up, and they were, in general,
detected earlier than the other antibodies (IAA vs. ICA,
P = 0.002; IAA vs. GADA, P =
0.019; and IAA vs. IA-2A, P < 0.001),
whereas both ICA and GADA appeared earlier than IA-2A
(P = 0.007 and P = 0.049, respectively)
(Table 1).
|
All 8 of the 38 antibody-positive children who became completely antibody-negative during the follow-up (21%) had ICA only (maximum level, 18 JDF units). Four of them were positive for ICA only once, their highest ICA level being 10 JDF units. The cases of reversion to negativity for antibodies other than ICA comprised 3 children who, however, remained positive for at least 1 antibody specificity. One of these children tested weakly positive for IAA (IAA, 1.90 RU) once and reverted to IAA negativity later during the observation period. One infant who was initially positive for all 4 autoantibodies reverted to GADA negativity (highest level, 20.0 RU); and another child, positive for 3 autoantibodies, including IA-2A (0.432 RU), became subsequently transiently negative for IA-2A. Both of these subjects presented later with type 1 diabetes.
Autoantibodies in children who progressed to clinical diabetes
Six of the 38 ICA-positive children (16%) progressed to type 1
diabetes at a mean age of 1.7 yr (range, 1.1–2.5 yr) (Table 2). They all had had at least 2
autoantibodies, 0.1–1.5 yr (mean, 1.2 yr) before the diagnosis of
clinical diabetes. All 6 children who developed type 1 diabetes had, as
the first autoantibody, IAA; and 3 of them tested also positive for ICA
in that sample. The initial ICA levels were considerably higher among
those index cases who developed clinical diabetes (median, 31.0 JDF
units) than in the antibody-positive children who remained unaffected
(10.0 JDF units; P = 0.01). There was 1 boy (case 7,
Table 2) who carried the high-risk genotype, but had not participated
in the immunological surveillance, and presented with type 1 diabetes
at the age of 1.0 yr. Furthermore, there were 4 children who were not
included in the risk cohort because of their genotypes but developed
type 1 diabetes. Two of them carried the DQB1 *02/x genotype and the
other 2 carried neutral DQB1 alleles. They presented with clinical
disease at the ages of 1.6, 2.9, 0.8, and 1.8 yr.
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In this Finnish population-based prospective cohort study, the first diabetes-associated autoantibodies appeared before the age of 6 months, as described in the offspring of mothers with type 1 diabetes (18). The prevalence of ICA positivity increased with age in the children with HLA-defined genetic susceptibility to type 1 diabetes, from 0.2% at the age of 6 months to 2.2% at 2 yr. This prevalence of ICA is high, compared with 2.3% reported in the German BABY-DIAB Study observing offspring of affected parents from birth (19). The prevalence of ICA, most likely, will increase further in the present study when the age of the index children increases, because the ICA frequency was observed to be 4.1% at a mean age of 6 yr in the genetically susceptible older sibs. The absolute risk of type 1 diabetes by the age of 15 yr conferred by the HLA DQB1*02/*0302 genotype is approximately 6% in the Finnish population, whereas the risk associated with the moderate-risk genotype is close to 2% (4) and about 0.6% in the background population. So far, 7 of 25,983 genetically screened infants have progressed to clinical type 1 diabetes by the age of 2 yr, which is consistent with an expected number of 8 cases, based on Finnish incidence data (3). Genetic screening identified 7 of 11 children who developed type 1 diabetes. By combining this data with other data, our previous estimation that our genetic criteria would find 60–80% of those who will develop diabetes (4) seems to be correct. This approach of 2-phase screening strategy, aimed at identifying subjects, from the general population, at high risk of progression to type 1 diabetes, with genetic screening as the first phase, is feasible and cost-saving, as compared with a pure immunological screening strategy (20).
In the present study, we observed a 2.2-fold higher ICA frequency among the infants with the high-risk genotype than among those carrying the moderate-risk genotype. The sibs with the high-risk genotype tested also positive for ICA twice as often as those with the moderate-risk genotype, although this difference did not reach statistical significance at this point because of the lower number of sibs analyzed. These observations suggest that ß-cell autoimmunity appears more often and/or earlier in individuals with strong genetic susceptibility to type 1 diabetes than in those with weaker genetic risk. A recent twin study also suggests that genetic factors play an important role in the early development of islet cell autoimmunity (21).
Two thirds of the children who seroconverted to positivity for ICA also tested positive for 1 or more of the other diabetes-associated autoantibodies, suggesting that these infants had a destructive process going on in their pancreatic islets (22). The German BABYDIAB study, where autoantibodies are measured at birth and at 9 months, 2 yr, and 5 yr of age, reported that IAA were detected in the first antibody-positive sample in 87% of the 87 offspring analyzed (23). This is well in line with our finding of IAA to be the first or among the first antibodies in almost 90% of the cases with 2 or more antibodies detectable during the observation period. As a matter of fact, also the remaining 3 infants later tested positive for IAA, which appeared 3–6 months after the first antibodies. This observation implies that insulin may be the primary autoantigen in most cases of autoimmune type 1 diabetes. Insulin fits well into this role for several reasons. First, it is the only known true ß-cell specific autoantigen (24); second, IAA are very common in children with newly diagnosed type 1 diabetes under the age of 5 (25, 26); and third, it has been shown that autoimmune diabetes can be transferred experimentally by insulin-reactive T cells (27). Another prospective birth cohort study, where newborn babies from the general population are screened for genetic susceptibility to type 1 diabetes, is the American Diabetes Autoimmunity Study in the Young (28). Yu et al. (29) reported recently that detection of insulin antibodies was strongly associated with early development of diabetes in both children from the American Diabetes Autoimmunity Study in the Young and in nonobese diabetic (NOD) mice. On the other hand, the hypothesis on the role of insulin as the primary autoantigen in human type 1 diabetes has been challenged, based on the relatively low prevalence of IAA in adolescents and adults with newly diagnosed type 1 diabetes (30) and on the close association between IAA and the DR4/DQB1*0302 haplotype (31). In relation to the first argument, it has been reported that adults with recent-onset disease have a stronger T-cell response to insulin than newly diagnosed children, and that there is an inverse correlation between the T-cell response and IAA (32). Accordingly, adults with type 1 diabetes also seem relatively often to have an immune response to insulin. The possibility that IAA might be related to the early introduction of cow’s milk is also interesting, because cow’s milk feeding has recently been reported to be an environmental trigger of an immune response to insulin in infancy (33). In a recent study comprising DIPP children, we observed, however, that early exposure to cow’s milk was associated with an increased risk of seroconverting to positivity for IA-2A and all 4 autoantibodies but not for IAA alone (34). The development of IAA may be controlled by genes that predispose to early presentation of type 1 diabetes or are in linkage disequilibrium with such genes. Because all children in the present study carried the DQB1*0302 allele, it is not possible here to analyze how tightly early appearance of IAA is linked to this allele.
Our finding of an apparent seasonal variation in the emergence of the first autoantibodies could be attributable to infections involved in the induction of the first signs of ß-cell autoimmunity in some individuals. Enterovirus infections have been reported to be a candidate trigger for ß-cell autoimmunity (35, 36). Also, metabolic mechanisms might contribute to this obvious seasonal variation in the emergence of the first autoantibodies. In experimental autoimmune diabetes, the disease incidence was reduced at raised temperature in NOD mice (37). Seasonal variation has also been observed in insulin secretion and glucose tolerance (38), and cold environment may increase the need for insulin and, accordingly, ß-cell stress (39, 40).
The decision to use ICA for the primary screening of ß-cell autoimmunity in the present study was based on the observation that ICA were more sensitive in our hands than GADA or IAA, with more than 84% of children with newly diagnosed type 1 diabetes testing positive for ICA (15). In addition, we have shown that the predictive value of ICA is similar to that of the combination of GADA and IA-2A in initially nondiabetic siblings of affected children (6). Based on a preliminary analysis, our ICA screening identified 93% of genetically susceptible children (27 of 29) who developed persistently at least 1 autoantibody and 95% of those (21 of 22) who tested positive for multiple (2 or more) antibodies by the age of 2 yr. Persistent positivity was, in this context, defined as antibody positivity in the last available sample, with at least the preceding sample being positive as well. The unidentified child with multiple antibodies tested positive for IAA and IA-2A by the age of 2 yr, but this boy turned positive for ICA at the age of 2.5 yr (Kimpimäki et al., unpublished data). In the German BABYDIAB study on offspring of affected parents, about 30% of the subjects with multiple autoantibodies would have remained unrecognized if ICA had been used as the primary screening (23). In the present survey, all 6 progressors covered by the immunological surveillance were identified by primary screening for ICA, suggesting that the present screening strategy will identify most of those young children who eventually develop autoimmune diabetes.
In conclusion, ß-cell autoimmunity may appear before the age of 6 months in genetically susceptible individuals identified in the general population. The prevalence of autoantibody positivity increases with age, more rapidly so in children with a high HLA-defined genetic risk than in those with a moderate risk. IAA emerged as the first autoantibodies, or among the first, in the vast majority of those with two or more autoantibodies detectable during their first few years of life. This implies that insulin may be the primary autoantigen in the most common form of type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The conspicuous seasonal variation in the appearance of the first autoantibodies indicates that ß-cell autoimmunity may be triggered by infections. Accordingly, both genetic and environmental factors seem to contribute to the emergence of early signs of ß-cell autoimmunity in the general population.
Acknowledgments
We are indebted to Paula Arvilommi, Reija Hakala, Helena Savolainen, Sari Korhonen, Maija Törmä, Birgitta Nurmi, Hilkka Pohjola, Aino Stenius, Kaisu Riikonen, Ulla Markkanen, Paula Asunta, Aila Suutari, and Riikka Sihvo for their commitment to the study. We are also grateful to Sirpa Anttila, Susanna Heikkilä, Tuovi Mehtälä, Riitta Päkkilä, Sirpa Pohjola, Päivi Salmijärvi, Terttu Lauren, and Ritva Suominen for skillful technical assistance.
Footnotes
This work was supported by the Medical Research Funds; Tampere, Turku, and Oulu University Hospitals; the Medical Research Council, Academy of Finland; the Juvenile Diabetes Foundation International (Grants 197032 and 4-1998-274); the Novo Nordisk Foundation; and EU Biomed 2 (BMH4-CT98-3314).
Abbreviations: DIPP, Diabetes Prediction and Prevention; GADA, antibodies to the 65-kDa isoform of glutamic acid decarboxylase; HLA, human leukocyte antigen; IAA, insulin autoantibodies; IA-2A, antibodies to the protein tyrosine phosphatase related IA-2 molecule; ICA, islet cell antibodies; JDF, Juvenile Diabetes Foundation; NOD, nonobese diabetic; RU, relative units.
Received December 27, 2000.
Accepted May 31, 2001.
References
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) and those with the
moderate-risk genotype (HLA-DQB1*0302/x; x = other than *02, *03,
or *0602; - - - ) who had ICA, as a function of age. The two bars
on the right show ICA prevalence in the older sibs with high and
moderate genetic risk, at a mean age of 6.0 yr.