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Original Article |
Department of Pediatrics (M.S., A.M.P.), Endocrinology Unit, University "La Sapienza," I-00161 Rome, Italy; and Department of Medicine I (M.A.P., K.B.), Division of Endocrinology, University Hospital, D-60596 Frankfurt am Main, Germany
Address all correspondence and requests for reprints to: Klaus Badenhoop, Department of Internal Medicine I, University Hospital Frankfurt am Main, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail: . badenhoop{at}em.uni-frankfurt.de
Abstract
Thyroid autoimmunity is one of the most common immune disorders in females, and its polygenic background remains to be elucidated. The human leukocyte antigen (HLA) DQ region of chromosome 6 has been shown to confer susceptibility to thyroid autoimmune disease. The aim of our present investigation was to determine whether the transmission of high risk HLA DQ to patients with thyroid autoimmunity differs when transmission is from fathers as opposed to when transmission is from mothers. We studied 91 juvenile patients with chronic lymphocytic thyroiditis (68 females and 23 males; mean age, 10.5 ± 3.9 yr), 12 patients with Graves’ disease (all females; mean age, 8.8 ± 4.0 yr), 53 healthy siblings, and their parents for thyroid function, antibodies, ultrasound, and DNA typing for HLA DQ susceptibility alleles. We observed an increased rate of transmission for the DQA1*0501-DQB1*0201 (DQ2) haplotype [35 of 53 transmitted (66%); P = 0.02]. This allele was preferentially transmitted by fathers [21 of 27 (78%); P < 0.004], whereas the maternal DQ2 haplotypes were not transmitted more often than expected. Subsequently, families were stratified as follows according to the parental thyroid peroxidase antibody (TPOAb) status: no parent, only mothers, only fathers, and both parents positive. There was no significant maternal transmission disequilibrium in any subset, but the paternal HLA DQ2 was preferentially transmitted [11 of 14 cases (79%); P = 0.03] in the group of TPOAb-positive mothers, and we observed a similar trend in the group of TPOAb- positive fathers (P = 0.08). Also, the portion of offspring affected by Graves’ disease was significantly higher in TPOAb-positive than in TPOAb-negative fathers (P < 0.02). In conclusion, our findings demonstrate a significant effect of paternal HLA DQ alleles as well as antibody status on susceptibility to thyroid autoimmune disease in juvenile patients.
AUTOIMMUNE THYROID DISEASES (AITDs) are defined by the lymphocytic infiltration of the thyroid (1), accompanied by the detection of autoantibodies to thyroid antigens in the serum [i.e. thyroid peroxidase antibody (TPOAb), antithyroglobulin (TgAb), and anti-TSH-receptor (TRAb); reviewed in Ref.2 ]. The most common AITDs in humans are chronic lymphocytic thyroiditis (CLT) and Graves’ disease (GD; reviewed by Weetman in Ref.3).
Both genetic and environmental factors are thought to be involved in the pathogenesis of AITD, and family studies have shown a high prevalence of thyroid antibodies (ThyAb) in relatives of both adults and children affected with AITD (4).
An early report from 1962 indicated that fathers can transmit the predisposition to produce thyroid autoantibodies (5). A later family study showed this phenotype to be inherited in an autosomal fashion to female affected but not to male affected offspring (6). The recent work on gender-specific susceptibility has demonstrated that parental imprinting may modulate the genetic risk of an individual to contract AITD. We earlier showed that human leukocyte antigen (HLA) DQ genes confer susceptibility to thyroid and other endocrine autoimmune diseases (7). The association of HLA DR-DQ is not specific for thyroid autoimmunity; certain alleles also affect the risk for other autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, celiac disease, and Addison's disease. We wondered whether a combination of the immunogenetic profile and the thyroid antibody status in parents of children with thyroid autoimmunity has an influence on the risk for thyroid autoimmune disease in their offspring.
Patients and Methods
We studied 91 patients with CLT (68 females and 23 males; mean age at diagnosis ± SD, 10.5 ± 3.9 yr) and 12 patients with GD (all females; mean age at diagnosis ± SD, 8.5 ± 4.0 yr) belonging to 81 families. Fifteen families were one-child families; the remaining 66 had two or more children. We also analyzed 53 healthy siblings (27 females and 26 males; mean age ± SD, 10.8 ± 5.6 yr). All 81 mothers and fathers were studied. All of the patients were from the Pediatric Endocrine Clinic at the University "La Sapienza" (Rome, Italy). Informed consent was obtained from parents and children. Patients with chromosomal abnormalities such as Turner’s or Down’s syndromes were not included.
CLT was defined on the basis of the presence of ThyAb [antiperoxidase (TPOAb) and/or antithyroglobulin antibodies (TgAb)] more than two times the upper normal value (nv) (TPOAb nv <20 IU/ml; TgAb nv <50 IU/ml), and thyroid ultrasound with reduced echogenicity compatible with thyroiditis (8), regardless of the thyroid function (9).
GD was defined by clinical and biochemical hyperthyroidism and positivity for TRAb. Thyroid hormones and thyroid autoantibodies in serum were determined in all children and parents by commercial kits: free T3, free T4 by RIA, TSH (upper nv, 3.5 µU/ml) by immunoradiometric assay (all by Byk-Sangtec Diagnostica, Dietzenbach, Germany), TRAb by radio-receptor assay (Radim, Angleur, Belgium), TPOAb by RIA, and TgAb by immunoradiometric assay (both by ICN Pharmaceuticals, Inc., Costa Mesa, CA). A careful clinical history about thyroid disorders and other autoimmune diseases was recorded from each family. Thyroid ultrasound was performed with a high frequency 7.5-MHz linear array transducer (Esaote, Genoa, Italy). HLA DQA1 and DQB1 typing was performed as described previously (10) from DNA that had been prepared by standard methods (salting out procedure or by Blood Maxi DNA preparation kit, QIAGEN, Hilden, Germany).
Antibody titers were compared using a two-tailed t test. Transmission disequilibrium testing (TDT) was performed for HLA DQ haplotypes (11). Differences regarding the proportion of affected offspring and genotypes were analyzed by 
2 or Fisher's exact testing, where appropriate.
Results
Prevalence of antibodies in the parents
We found 47 of 81 (58%) mothers positive for TPOAb and/or TgAb, of whom 30 were previously undiagnosed. Of the 30 new cases, 36% presented with subclinical or clinical hypothyroidism (TSH range, 4.1–11 µU/ml).
We found 21 of 81 (26%) fathers with elevated TPOAb and/or TgAb; only 2 of them reported AITD at the clinical history and were already treated with L-T4 substitution therapy. Of the 19 new cases, 5 (26%) fathers were diagnosed with subclinical or clinical hypothyroidism (TSH range, 4.2–62 µU/ml).
Correlation of parental ThyAb status and children's AITD
We defined four groups of families on the basis of the ThyAb status in the parents (Tables 1–3
). These four groups were comparable for mean age of the parents, mean age of the children, and families with two or more children.
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). In families with only one ThyAb-positive parent, the mean TPOAb titers were significantly higher in fathers (mean, 760 ± 774 U) than in mothers (mean, 328 ± 465 U; P = 0.0274), whereas the TPOAb titers in mothers from group 4 (both parents Ab-positive) were significantly higher than in group 2 (only mothers were positive; 743 ± 820 U vs. 328 ± 465 U; P = 0.0229). We found very similar titers of TPOAb in children from group 1 (no parents with ThyAb) and group 2 (only mothers with ThyAb), 594 ± 796 U vs. 690 ± 880 U, respectively. In contrast, TPOAb titers in children from group 3 (only fathers were ThyAb-positive; 1284 ± 1200 U) and from group 4 (mothers and fathers ThyAb-positive; 1100 ± 1280 U) were significantly increased (groups 1 and 2 vs. 3 and 4; P = 0.024).
Considering only families with two or more children, the percentage of children who were affected ranged from 59% of children affected in group 1 to 60% in group 2, 67% in group 3, and 72% in group 4. The percentage of hypothyroid children was 39% in group 1, 53% in group 2, 66% in group 3, and 42% in group 4. However, none of these differences were significant using 2 or Fisher’s exact testing as appropriate.
Altogether, we examined 91 patients with CLT (68 females and 23 males) and 12 with GD (all females). The difference between the proportion of children affected with GD in relation to all affected children in group 3 (4 of 10) vs. the proportion of affected children in groups 1, 2, and 4 (8 of 93) is significant (Fisher’s exact test, P = 0.016), implying a higher risk for GD in children of fathers with TPOAb, compared with children born to parents with all other possible TPOAb constellations.
Birth order and the risk of AITD
The birth order could be reconstructed in all children with AITD. There was no difference in the order of birth between male and female patients nor with regards to the HLA DQ type or the ThyAb status (data not shown).
Parental origin of HLA DQ risk alleles and AITD in offspring
We observed an increased rate of transmission for the DQA1*0501/DQB1*0201 (DQ2) haplotype [35 of 53 (66%); P = 0.02] to patients with AITD. DQ2 was significantly more often transmitted by fathers [21 of 27 (78%); P < 0.004], whereas the maternal DQ2 haplotypes were not more often transmitted than expected [14 of 26 (54%); P = 0.69]. When the families were analyzed according to the TPOAb status of the parents, there was no significant excess of maternal transmission, however the fathers transmitted the HLA DQ2 to 11 of 14 cases (79%; P = 0.03) in the group of TPOAb-positive mothers (group 2). There was a similar trend in the group of TPOAb-positive fathers (group 3; P = 0.08; Table 4).
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We demonstrated a higher risk for juvenile CLT or GD in offspring of fathers that either are TPOAb-positive or transmit a HLA DR3-DQ2 risk haplotype to offspring with AITD. This observation implies a different immune and genetic predisposition inherited from fathers, in comparison to children in which neither or both parents or only the mother is TPOAb-positive. In families with ThyAb-positive fathers, there was also a slight increase of affected male children, but the absolute number of all children in groups 3 and 4 was small. The difference of parental autoimmunity has also been found in patients with Turner's syndrome who had a higher prevalence of thyroid autoimmunity if their fathers had thyroid autoantibodies (12). The presence of thyroid autoantibodies was associated in that study with DR7-DQ2 and DR7-DQ9. Thus, a combination of the immunogenetic profile (the DQB1 gene in DR3-DQ2 and DR7-DQ2 is shared) and ThyAb status in fathers appears to enhance the risk for AITD in the offspring in both children with normal chromosomes and those with chromosomal aberrations leading to Turner's syndrome. A higher risk for AITD in offspring of affected fathers compared with affected mothers had earlier been proposed in an extended study of 18 kindreds with autoimmunity comprising 370 individuals (13). A similar difference was also observed in families with type 1 diabetes (14, 15). A possible explanation for this difference would be that secondary genes for autoimmunity can have a higher penetrance if transmitted by fathers, pointing to an imprinting mechanism. Such secondary genes may predispose to autoimmunity in general.
AITD is a trait that occurs often in families either by itself or associated with other autoimmune disorders such as type 1 diabetes, vitiligo, alopecia areata, celiac, or Addison's disease and may form the autoimmune pluriglandular syndrome type 2. We had earlier shown that HLA DQA1*05 is a shared immunogenetic marker common to type 1 diabetes, Graves’ and Addison’s disease, Hashimoto’s and postpartum thyroiditis (7). Apart from HLA, other immunogenes also confer susceptibility such as CTLA4 on chromosome 2q33, where we observed an interaction with HLA in type 1 diabetes (10). In contrast, the autoimmune regulator gene harboring mutations causing the pluriglandular syndrome I (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) appears not to contribute to sporadic forms of autoimmune endocrinopathies such as thyroiditis or Addison’s disease (16, 17).
In conclusion, our findings demonstrate a significant effect of paternal HLA DQ haplotypes on genetic susceptibility to thyroid autoimmunity in juvenile patients. Because females are predominantly affected by AITD, the preferential transmission of HLA DQ-mediated susceptibility from fathers may imply a chromosome X-linked gene interacting with the HLA DQ haplotype-derived factor. Alternatively, hormonal regulation of the susceptibility gene or linked products by estrogens could explain why the main sex difference on thyroid autoimmunity occurs at the postpubertal stage (18). Chromosome X has been implicated to modify DR3-linked susceptibility to type 1 diabetes in Sardinia (15), and a recent analysis of Graves’ disease from the United Kingdom has shown a significant linkage of microsatellite DXS8083 with a peak unweighted nonparametric linkage (NPL = 2.21) at Xp11 (19). Further work extending these studies is warranted to clarify the parental origin and interaction of inherited susceptibility factors as well as ThyAb status to AITD.
Acknowledgments
We are indebted to Vincenzo Toscano for measurement of thyroid function and antibody testing and to Rafaela di Nardo for performing thyroid ultrasound.
Footnotes
This work was supported by a grant from Deutsche Forschungsgemeinschaft (Ba 976/8-1, 8-2; to K.B.).
Abbreviations: AITD, Autoimmune thyroid disease; CLT, chronic lymphocytic thyroiditis; DQ2, DQA1*0501-DQB1*0201; GD, Grave’s disease; HLA, human leukocyte antigen; nv, normal value; TDT, transmission disequilibrium testing; TgAb, thyroglobulin antibodies; ThyAb, thyroid antibodies; TPOAb, thyroid peroxidase antibodies; TRAb, TSH-receptor antibodies.
Received December 27, 2001.
Accepted May 1, 2002.
References
This article has been cited by other articles:
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  Y. Tomer and T. F. Davies Searching for the Autoimmune Thyroid Disease Susceptibility Genes: From Gene Mapping to Gene Function Endocr. Rev., October 1, 2003; 24(5): 694 - 717. [Abstract] [Full Text] [PDF]
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