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Departments of Endocrinology-Diabetology (C.E.M.D.B., I.H.D.L.), Immunology (C.M.V.C.), and Hormonology (M.M.), University Hospital Antwerp, B-2650 Edegem, Belgium; and Diabetes Research Center, Vrije Universiteit Brussel (K.D., F.W., J.V.A., F.K.G.) and the Belgian Diabetes Registry, B-1090 Brussels, Belgium
Address all correspondence and requests for reprints to: Christophe De Block, M.D., Department of Endocrinology-Diabetology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: cdeblock{at}uia.ua.ac.be
Abstract
A quarter of type 1 diabetic patients have thyrogastric autoantibodies (thyroid peroxidase and gastric parietal cell antibodies). Clinical, immune, and genetic risk factors help predict antibody status. First degree relatives of these patients may also frequently exhibit these antibodies. We assessed the prevalence of thyrogastric antibodies and dysfunction in first degree relatives in relation to age, gender, human leukocyte antigen-DQ type, ß-cell antibody (islet cell, glutamic acid decarboxylase-65, and tyrosine phosphatase antibodies), and proband thyrogastric antibody status.
Sera from 272 type 1 diabetic patients (116 men and 156 women; mean age, 27 ± 18 yr; duration, 10 ± 9 y), 397 first degree relatives (192 men and 205 women; parents/siblings/offspring, 48/222/127; age, 22 ± 10 yr), and 100 healthy controls were tested for islet cell antibodies and gastric parietal cell antibodies by indirect immunofluorescence and for tyrosine phosphatase, glutamic acid decarboxylase-65, and thyroid peroxidase antibodies by radiobinding assays.
Glutamic acid decarboxylase-65 antibodies were present in 68% and 5%, islet cell antibodies were present in 36% and 2.5%, tyrosine phosphatase antibodies were present in 45% and 0.5%, thyroid peroxidase antibodies were present in 21% and 4.5%, and gastric parietal cell antibodies were present in 18% and 11% of diabetic patients and relatives, respectively. The presence of thyroid peroxidase antibodies in relatives was determined by age (ß = 0.22; P = 0.0001) and proband thyroid peroxidase antibodies status (ß = -2.6; P = 0.002; odds ratio = 11.1). Gastric parietal cell antibody positivity in relatives was associated with age (ß = 0.04; P = 0.026). Gastric parietal cell antibody-positive compared with gastric parietal cell antibody-negative relatives were more likely to have gastric parietal cell antibody-positive probands (P = 0.01; odds ratio = 3.0). ß-Cell antibody status and human leukocyte antigen-DQ type did not influence thyrogastric antibody status in relatives. (Sub)clinical dysthyroidism was found in 3%, iron deficiency anemia was present in 12% (26% gastric parietal cell antibody-positive and 9% gastric parietal cell antibody-negative subjects; P = 0.009), and pernicious anemia was found in 0.5% (5% gastric parietal cell antibody-positive and 0% gastric parietal cell antibody-negative subjects; P = 0.012) of relatives. They had less thyroid dysfunction (P < 0.0001) and pernicious anemia (P = 0.018) than diabetic probands.
In conclusion, thyrogastric antibodies and dysfunction are more prevalent in type 1 diabetic patients than in first degree relatives. The presence of these antibodies in relatives is associated with age and proband antibody status, but not with ß-cell antibodies or human leukocyte antigen-DQ type.
TYPE 1 DIABETES mellitus is an autoimmune disease arising through a complex interaction of immune, genetic, and environmental factors (1, 2). Human leukocyte antigen (HLA)-DQ genes constitute approximately 50% of the genetic risk of type 1 diabetes (3). Particularly, HLA DQA1*0301-DQB1*0302 (in linkage disequilibrium with DR4) and DQA1*0501-B1*0201 (in linkage disequilibrium with DR3) haplotypes confer a high diabetogenic risk (4, 5). ß-Cell antibodies, such as islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase-65 (GADA), and antibodies to tyrosine phosphatase (IA2A) document the autoimmune attack and may predict the onset of type 1 diabetes (6, 7, 8, 9, 10, 11, 12). Furthermore, we and others showed that 25–30% of type 1 diabetic patients have thyroid peroxidase (aTPO) and/or gastric parietal cell antibodies (PCA) (13, 14, 15, 16, 17, 18). aTPO status was influenced by age, gender, and PCA and GADA status (19), whereas PCA status was associated with age, aTPO, GADA, and HLA DQA1*0501-DQB1*0301 status (19, 20). PCA are a marker of iron deficiency anemia, pernicious anemia, and atrophic gastritis, and aTPO are associated with autoimmune thyroid disease (13, 21, 22, 23, 24, 25, 26).
First degree relatives of type 1 diabetic patients also have an increased frequency of organ-specific autoantibodies, but data are scarce (17, 18, 27, 28, 29). A good prediction of autoimmune disorders may be accomplished by determining immune and genetic risk markers. Although the relation among ICA, HLA-DR type, and thyrogastric autoimmunity in first degree relatives has been studied previously (28, 29, 30), no recent detailed data exist on the relationship with other ß-cell antibodies and HLA-DQ type. Therefore, we studied the prevalence of thyrogastric antibodies in first degree relatives of type 1 diabetic patients as a function of age, gender, HLA-DQ type, ß-cell antibodies (ICA, GADA, and IA2A), and proband thyrogastric antibody status. Furthermore, because not all patients with thyrogastric antibodies develop disease and because there could be differences in the frequency of thyrogastric disorders between type 1 diabetic patients and relatives, we assessed thyrogastric function.
Subjects and Methods
Subjects
A large group of 769 Caucasian individuals was studied, comprising 272 unselected type 1 diabetic patients (116 men and 156 women; mean age, 27 ± 18 yr; duration, 10 ± 9 yr), their 397 first degree relatives (192 men and 205 women; parents/siblings/offspring, 48/222/127; age, 22 ± 10 yr) recruited through a program of prediction and prevention of diabetes in families, FWO Levenslijn Diabetes Project, and 100 healthy controls (46 men and 54 women; age, 28 ± 14 yr). Diabetic patients attended the out-patient Antwerp diabetes clinic or were registered in the Belgian Diabetes Registry. They presented at onset of disease with hyperglycemia, polydipsia, polyuria and/or ketoacidosis, necessitating insulin treatment from the time of diagnosis. Fasting and 2 h postprandial C-peptide levels were very low at the time of this study (mean ± SD: 90 ± 70 pmol/liter and 110 ± 90 pmol/liter respectively; normal, 250-1000 pmol/liter). The study was approved by the Ethics Committee of the Belgian Diabetes Registry. In accordance with the Helsinki Declaration, each subject and/or parent gave informed consent.
Methods
ICA were determined by indirect immunofluorescence on cryosections of fresh frozen human donor pancreas (blood group O) (31). GADA and IA2A were determined by liquid phase radiobinding assay using respectively Centricon-purified recombinant human [35S]GAD65 and the 35S-labeled intracellular domain of IA2 as tracer (11). Cut-off values for antibody positivity were determined as the 99th percentile of antibody levels obtained in 783 nondiabetic control subjects and were 12 Juvenile Diabetes Foundation units or more for ICA, 2.6% tracer bound or more for GADA, and 0.5% tracer bound or more for IA2A (11). These assays were validated by repeated participation in Immunology of Diabetes Workshops and proficiency testing programs of the University of Florida (Gainesville, FL) and Louisiana State University (New Orleans, LA). In the latter program our assays achieved 100% diagnostic sensitivity, specificity, consistency, and validity. In the combinational islet autoantibody workshop, assay sensitivity adjusted for 99% specificity was 73% for ICA and 85% for GADA (32). In the first IA2A proficiency program of the University of Florida, our method received a 100% score for laboratory sensitivity, specificity, consistency, and validity (9).
aTPO were measured by radiobinding assay (Henningtest, Brahms, Germany; normal, <100 U/ml). Thyroid function was estimated by assay of TSH (normal, 0.47–4.7 mU/liter) and free T4 levels (normal, 10.8–21.9 pmol/liter; Vitros, Ortho Clinical Diagnostics, Amersham Pharmacia Biotech, Little Chalfont, UK). Subclinical hypothyroidism was defined as a combination of increased TSH and normal free T4 values, and subclinical hyperthyroidism was defined as decreased TSH and normal free T4 levels in the absence of hypothalamic or pituitary disease, nonthyroidal illness, or ingestion of drugs that inhibit TSH secretion (33). PCA were detected using indirect immunofluorescence (Medical Diagnostics, Carlsbad, CA; normal, <1:20 dilution) (13). The indirect immunofluorescence assay for PCA correlated well with the enzyme immunoassay to detect antibodies to H+/K+ATPase (Varelisa, Pharmacia & Upjohn, Inc., Freiburg, Germany; normal, <10 U/ml; n = 175; r = 0.85; P < 0.0001). Antibodies to intrinsic factor were measured by radiobinding assay (Diagnostic Products, Los Angeles, CA; normal, <1.1). Pernicious anemia was defined as a megaloblastic anemia with positive intrinsic factor antibodies and/or PCA. Iron deficiency anemia was defined as decreased hemoglobin concentration, microcytic and hypochromic indexes, and decreased ferritin concentration (men, <20; women, <12 µg/liter). Serum gastrin was measured using an RIA liquid technique (Euro-Diagnostics, Malmo, Sweden; normal, <110 ng/liter). HLA-DQ typing was performed as described previously (34). The second exons of the DQA1 and DQB1 genes were simultaneously amplified by PCR and reacted with a panel of allele-specific oligonucleotide probes (5). Genotypes were classified as susceptible, neutral, or protective according to the Ph.D. thesis of Dr. van der Auwera based on data from the Belgian Diabetes Registry (35).
Statistical analysis
Results were analyzed using SPSS (SPSS, Inc.,
Chicago, IL). Distributions of continuous data were tested for
normality by the Kolmogorov-Smirnov test. The unpaired t
test or Mann-Whitney U test was used to determine differences between
groups. Bonferroni adjustments for multiple comparisons were made when
appropriate. Differences in distributions of categorical data were
investigated by 
2 or Fisher’s exact test.
Stepwise forward logistic regression analysis was used to assess the
strength and independence of associations. A two-tailed
P < 0.05 was considered significant.
Results
In the group of 272 type 1 diabetic patients with a mean disease
duration of 10 ± 9 yr, 79% exhibited ß-cell antibodies, and
34% had thyrogastric antibodies. Sixteen patients (6%) had the
concurrent presence of aTPO and PCA, showing an association between
both antibodies [odds ratio (OR) = 2.2 (95% confidence interval
(CI), 1.2–10.2); P = 0.03]. Subclinical
thyroid dysfunction was found in 16% of all patients, overt
hypo/hyperthyroidism in 8%, iron deficiency anemia in 11%, pernicious
anemia in 3%, and hypergastrinemia (gastrin, >110 ng/liter) in 12%
(Table 1
). In the 397 first degree
relatives 6.5% had ß-cell antibodies, and 15% showed thyrogastric
antibodies, 3 of whom (1%) had the concurrent presence of aTPO and
PCA. The respective frequencies in male and female diabetic patients
and relatives are shown in Table 1. Six percent of healthy controls
exhibited aTPO, and 5% were PCA positive, but none simultaneously
exhibited both antibodies. In first degree relatives subclinical
dysthyroidism was found in 2.5%, overt hypothyroidism in 2 subjects
(0.5%), iron deficiency anemia in 12%, pernicious anemia in 0.5%,
and hypergastrinemia in 13% (Table 1). These numbers clearly show that
diabetic patients have a higher frequency of aTPO, PCA, subclinical and
overt thyroid dysfunction, and pernicious anemia than relatives.
Relatives of aTPO/PCA-positive probands were more prone to exhibit
thyrogastric antibodies (23%) than relatives of antibody-negative
probands [11%; OR = 2.4 (95% CI, 1.4–4.2);
P = 0.003] and than controls [11%; OR = 2.4
(95% CI, 1.2–5.1); P = 0.02].
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aTPO were present in 18 first degree relatives. Relatives with aTPO
were older than those without aTPO (Table 2). Parents (19%) were more prone to
exhibit aTPO than siblings (2%) [OR = 12.6 (95% CI, 3.7–42.9);
P < 0.0001] or offspring (4%) [OR = 5.6 (95%
CI, 1.8–17.8); P = 0.003]. aTPO showed a strong
female preponderance [OR = 2.5 (95% CI, 0.9–7.2);
P = 0.09]. When relatives had an aTPO-positive
proband, they were more likely to have aTPO themselves [OR = 11.1
(95% CI, 4.1–30.1); P < 0.0001]. No associations
were observed between the presence of aTPO and ß-cell antibodies. HLA
DQA*0301-DQB1*0302-positive relatives were more prone to have aTPO than
those without this haplotype [OR = 4.1 (95% CI, 1.5–11.1);
P = 0.005], but were less prone than HLA-matched
diabetic subjects [OR = 0.3 (95% CI, 0.1–0.6);
P = 0.0008]. Thyroid autoimmunity has also been linked
to HLA DQA1*0501-DQB1*0201. No such association was found in relatives,
but aTPO were more frequent in HLA DQA1*0501-DQB1*0201-positive
diabetic patients than in HLA-matched relatives [OR = 8.1 (95%
CI, 2.8–23.5); P < 0.0001]. However,
susceptibility/resistance is more likely to be determined by the
balance of specific gene combinations than by the presence of
individual alleles. aTPO were more prevalent in diabetic patients with
susceptibility genotypes [OR = 7.1 (95% CI, 2.1–24);
P = 0.0002] and surprisingly also in those with
protective genotypes [OR = 10.8 (95% CI, 3.1–36.9);
P = 0.0005] than in HLA-matched relatives. Independent
risk factors for aTPO positivity in relatives were age (ß =
0.22; P = 0.0001) and proband aTPO status (ß =
-2.58; P = 0.002), but not gender, ß-cell antibody
status, or HLA-DQ haplo- or genotype. TSH levels were similar in
euthyroid subjects with (1.79 ± 0.81 mU/liter) and without aTPO
(1.75 ± 0.86 mU/liter). Subclinical hypothyroidism (TSH,
5.37 ± 0.69 mU/liter) and subclinical hyperthyroidism (TSH,
0.30 ± 0.12 mU/liter) were diagnosed in 1% and 1%,
respectively, and overt hypothyroidism was found in 0.5% of relatives.
However, to our surprise, they were all aTPO negative. No link between
aTPO status and thyroid function was observed in relatives, in contrast
to the situation in diabetic subjects [OR = 7.4 (95% CI,
2.9–19.0); P < 0.0001].
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). Parents (23%) were more
likely to be PCA positive than siblings (7%); [OR = 3.8 (95%
CI, 1.7–8.9); P = 0.0026]. Furthermore, PCA were more
frequent in relatives of PCA-positive probands than in relatives of
PCA-negative probands [OR = 3.0 (95% CI, 1.4–6.3);
P = 0.01]. PCA have been linked to HLA
DQA1*0501-DQB1*0301 in diabetic subjects, but no such association was
found in relatives. However, the prevalence of PCA was higher in
diabetic patients with protective genotypes [OR = 3.9 (95% CI,
1.3–11.6); P = 0.024] than in HLA-matched relatives.
Logistic regression analysis showed that PCA positivity in relatives
was associated with age (ß = 0.04; P = 0.026),
but not with gender, ß-cell antibody status, or HLA DQ haplo- or
genotype. Similar to the situation in diabetic patients, PCA-positive
relatives had higher gastrin levels (P = 0.023) and
were more prone to iron deficiency anemia [OR = 3.1 (95% CI,
1.5–6.8); P = 0.009] and pernicious anemia
(P = 0.012) than PCA-negative relatives.
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In a large group of type 1 diabetic patients and first degree relatives we found a significant prevalence of organ-specific autoimmunity. One sixth of relatives exhibited thyrogastric antibodies, supporting previous data (1–7% in siblings and 7–17% in parents for aTPO, and 2–14% in siblings for PCA) (17, 18, 27, 28, 29). Three percent showed (sub)clinical dysthyroidism. Iron deficiency anemia was diagnosed in 12%, and pernicious anemia was found in 0.5%, particularly in PCA-positive relatives. We did not observe a higher frequency of aTPO in relatives than in healthy controls. However, more important, relatives of probands with aTPO and/or PCA had a higher frequency of thyrogastric antibodies than relatives of antibody-negative probands and controls. These and similar data (18, 29) suggest the importance of screening relatives of antibody-positive diabetic probands for thyrogastric autoimmunity. Determining immune and genetic risk markers may help to predict autoimmune disorders. The relation among HLA-DR, ICA, and thyrogastric antibodies in relatives has been studied previously (28, 29, 30), but this is the first report on the relationship with GADA, IA2A, and HLA-DQ type.
In first degree relatives of type 1 diabetic patients, more parents than siblings and offspring exhibited aTPO and PCA. The increased prevalence of thyrogastric antibodies with advancing age in diabetic patients and in relatives supports previous data (16, 17, 28) and the hypothesis of autoimmune disease being the final phase of a process starting with autorecognition, evolving toward immunity with appearance of antibodies, and finally cell damage and overt disease. Moreover, increased age has been related with deficient suppressor T cell function (36). This age-related increase occurs prematurely in patients with type 1 diabetes and their relatives compared with healthy controls (15, 17). Thus, the antibody frequencies we observed are particularly significant when considering the low mean age of the relatives studied.
Gender may modulate the prevalence of autoimmune diseases as well. Autoimmune thyroid disease shows a female preponderance (17, 18, 24, 25, 26). This was confirmed in diabetic subjects, and a strong tendency was observed in relatives, but statistical significance was not reached due to the small number of aTPO-positive relatives. Furthermore, we observed no differences in the prevalence of ß-cell antibodies or PCA between sexes. Of the few data available (17, 18, 27, 28, 29), three studies report a female preponderance for thyroid autoimmunity in relatives of diabetic patients (17, 18, 27), and only two mention a female preponderance for PCA (17, 27).
In contrast to type 1 diabetes, where persisting ICA positivity (18, 37) or GADA positivity (19, 38, 39, 40) has been associated with an increased risk for thyrogastric autoimmunity, we found no association between ß-cell and thyrogastric antibodies in relatives, confirming previous data (28) and data from healthy controls (15). Others did not report/investigate this in relatives (17, 18, 27, 29). The observation for diabetic subjects might be explained by the fact that glutamic acid decarboxylase-65 is not exclusively present in the pancreas and brain, but can also be found in the thyroid gland and stomach (37, 38, 40). Most likely because of the small number of ß-cell and/or thyrogastric antibody-positive relatives, this association could not be documented. Again, in contrast to type 1 diabetes, where thyroid and gastric autoimmunity have been linked (13, 17, 21), no such association was found in the relatives, probably due to the low number of antibody-positive subjects.
HLA molecules may also influence antibody status and can determine in part the tissue to which an autoimmune process develops. Gene polymorphisms are likely to determine antigen binding affinity and the nature of the T cell stimulation and the (auto)immune response. As reported by others (4, 5, 41), we saw that the high risk diabetogenic haplo- and genotypes were more frequent in diabetic patients. Moreover, 21 of 26 ß-cell antibody-positive relatives exhibited the high risk HLA-DQ haplotypes, and previously an association between HLA DQA1*0301-DQB1*0302 and ICA (42) and GADA and IA2A (11) was described for siblings. Susceptibility HLA-DQ molecules may preferentially bind and present triggering and/or ß-cell-derived peptides to T cells, causing ß-cell destruction or, intrathymically, may cause positive selection of potentially ß-cell-reactive CD4+ T cells (41). Because of convincing associations and linkage data and aberrant expression of HLA class II antigens on follicular cells and activated lymphocytes in patients with Graves’ disease, there is little doubt that the HLA region is involved in the development of Graves’ disease as well (43, 44, 45). However, HLA contributes only a small fraction of the total genetic predisposition to Hashimoto’s thyroiditis (46, 47, 48, 49). At risk haplotypes for Hashimoto’s thyroiditis are HLA DQA1*0301, DQB1*0301, and DQB1*0201 (46, 47, 48, 49), and that for Graves’ disease is DQA1*0501 (43, 44, 45). Our group previously reported an association between the HLA DQA1*0301-DQB1*0302 haplotype and the presence of aTPO in new-onset type 1 diabetic patients (14). Moreover, the present study shows that HLA DQA1*0301-DQB1*0302- positive relatives were more prone to have aTPO. No association between PCA and HLA-DQ type was found in the relatives, in contrast to diabetic patients, in whom we reported an association with the HLA DQA1*0501-DQB1*0301 haplotype (13, 20). Others reported that occurrence of thyrogastric antibodies in relatives was not associated with any particular HLA-DR molecule (30) or with the degree of HLA haplotype sharing with their diabetic probands (17). However, genetically controlled autoaggression is important because the provisional loci found in type 1 diabetes colocalize or overlap with loci found in different autoimmune diseases (50), which might also explain the association with thyrogastric autoimmunity. In addition, although controversial (15, 17, 18, 28, 51, 52, 53), subjects presenting thyrogastric antibodies might be at increased risk for type 1 diabetes. An important observation was that even after HLA matching, thyrogastric autoimmunity was still more frequent in diabetic subjects than in their relatives, suggesting that the diabetic state plays an important role. This might be explained by the fact that type 1 diabetic patients show multiple immunological abnormalities (54), including an imbalance in B and T lymphocytes, or that they have an increased tendency to react strongly against certain antigens or a poor ability to develop tolerance to autoantigens (15). Individuals with one autoimmune disease (in this case type 1 diabetes) are known to be at increased risk for other autoimmune processes.
In summary, aTPO status in first degree relatives was determined by age and proband aTPO status, whereas PCA status was determined by age. In addition, PCA-postive subjects were more likely to have a PCA-positive diabetic proband. Particularly in subjects with these risk profiles, screening for thyrogastric antibodies and, in case of positivity, additional functional tests or gastroscopy are advocated. In many cases early diagnosis of underlying disorders may be obtained and treated, or subjects at risk of developing overt autoimmune diseases may be followed periodically with subsequent reduction in morbidity (18, 55). The presence of aTPO may point to autoimmune dysthyroidism (24, 25, 26), as was documented in the diabetic group, but surprisingly not in relatives, for which we have no obvious explanation. PCA are a marker of iron deficiency anemia, pernicious anemia, and atrophic gastritis (13, 21, 22, 23), as supported by our data in diabetic subjects and relatives.
In conclusion, thyrogastric antibodies and dysfunction were more frequent in type 1 diabetic patients than in their first degree relatives. The presence of these antibodies in relatives is associated with age and their proband antibody status, but ß-cell antibody status or HLA-DQ haplo/genotype did not appear to be independent risk factors.
Acknowledgments
The Juvenile Diabetes Foundation standard for ICA determination and cDNA for preparation of [35S]GAD65 were donated by Prof. Dr. A. Lernmark (University of Washington, Seattle, WA) and by Dr. A. Falorni (when at the Karolinska Institute, Stockholm, Sweden). Human IA-2ic DNA was a gift from Dr. M. Christie (King’s College School of Medicine and Dentistry, London, UK). We are grateful to J. Vertommen, Dr. B. Manuel y Keenoy, P. Aerts, S. Schrans, and M. Vinckx (Laboratory of Endocrinology-Diabetology) of the University of Antwerp. We gratefully acknowledge Prof Dr. F. Schuit and Dr. B. Van der Auwera from the Department of Biochemistry, Diabetes Research Center, for the determination of genetic markers.
We thank the members of the Belgian Diabetes Registry: P. Arnouts (Turnhout), E. Balasse (Brussels), D. Beckers (Leuven), H. Becq (Wilrijk), J. Beirinckx (Izegem), A. Bocquet (Namur), A. Bodson (Jumet), R. Bouillon (Leuven), J. Bourguignon (Liège), M. Buysschaert (Brussels), A. Carlier (Gent), A. Chachati (Huy), L. Claeys (Zoersel), M. Coeckelberghs (Antwerp), I.M. Colin (Mons), J.L. Coolens (Hasselt), P. Coremans (Bornem), W. Coucke (Roeselare), E. Couturier (Brussels), R. Craen (Ghent), S. Daens (Brussel), C. Daubresse (Liege), J.C. Daubresse (Charleroi), P. Decraene (Bonheiden), I. De Feyter (Ghent), I. De Leeuw (Antwerp), C. Delvigne (Antwerp), B. Delgrange (Saint Mard), R. Demaeseneer (Aalst), L. Derdelinckx (Bouge-Namur), J. De Schepper (Brussels), H. Dorchy (Brussels), M. Du Caju (Antwerp), E. Duvivier (Montigny- sur-Sambre), L. Emsens (Knokke), C. Ernould (Liege), A. Eykens (Herentals), A. Fassotte (Verviers), F. Féry (Brussels), N. Gaham (Braine-l’Alleud), K. Garmijn (Lier), J. Gérard (Liege), C. Gillet (Brussels), F. Gorus (Brussels), J. Guiot (Seraing), F. Hay (Baudour), C. Herbaut (Mons), G. Heremans (Lier), P. Jopart (Haine-St. Paul), B. Keymeulen (Brussels), G. Krzentowski (Jumet), G. Lamberigts (Brugge), M.C. Lebrethon (Liege), P. Lefèbvre (Liege), M. Letiexhe (Liege), T.T. Lim (Poperinge), Litvine (Mons), K. Logghe (Roeselare), M. Maes (Brussels), C. Mathieu (Leuven), Y. Maus (Oupeye), J. Monballyu (Ekeren), G. Moorkens (Antwerp), D. Nicolaij (Kortrijk), F. Nobels (Aalst), M.C. Pelckmans (Lier), M. Pieron (Verviers), D. Pipeleers (Brussels), A. Purnode (Brussels), C. Righes (Verviers), D. Rocour-Brumioul (Liege), M.P. Roggemans (Brussels), R. Rooman (Antwerp), R. Rottiers (Ghent), D. Scarniere (Gilly), A. Scheen (Liege), I. Schoemaker (Lier), F. Schuit (Brussels), J. Schutyser (Kortrijk), O. Segers (Brussels), M.P. Stassen (Herstal), A. Stroobant (Brussels), P. Taelman (Ghent), L. Terriere (Hoboken), J. Teuwen (Kapellen), G. Thenaers (Hasselt), P. Thielemans (Tournai), G. Thiry-Counson (Liege), J. Tits (Genk), K. Van Acker (Antwerp), J.P. Van Biervliet (Brugge), P. Van Crombrugge (Aalst), L. Van de Mierop (Duffel), E. Vandenbussche (Herentals), B. Van der Auwera (Brussels), M. Vanderijst (Brussels), C. Vandewalle (Brussels), D. Van Doorn (Duffel), E. Van Fleteren (Izegem), L. Van Gaal (Antwerp), S. Van Imschoot (Brugge), S. Vanneste (Zoersel), C. Van Parijs (Peruwelz), P. Van Rooy (Antwerp), C. Vercammen (Bonheiden), A. Verhaegen (Merksem), G. Verhaert (Antwerp), J. Vertommen (Antwerp), E. Weber (Arlon), I. Weemaes (Turnhout), and G. Wyffels (Antwerp).
Footnotes
This work was presented in part at the 60th Scientific Sessions of the American Diabetes Association, San Antonio, Texas, 2000. This work was supported by a grant from the Fonds voor Wetenschappelijk onderzoek.
Abbreviations: aTPO, Thyroid peroxidase antibodies; CI, confidence interval; GADA, glutamic acid decarboxylase-65 antibodies; HLA, human leukocyte antigen; IA2A, tyrosine phosphatase antibodies; ICA, islet cell antibodies; OR, odds ratio; PCA, gastric parietal cell antibodies.
Received September 21, 2000.
Accepted May 11, 2001.
References
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