Exp. Clin. Endocrino!. Vol. 97, No. 2/3, 1991, pp. 170-172
J. A. Barth, Leipzig
Endocrine Immunology Unit, Department of Medicine and Medical Genetics, University
of Wales, College of Medicine, Cardiff/Great Britain
D. I. W. PHILLIPS, L. PRENTICE, S. M. MCLACHLAN, M. UPADHYAYA, p. w. LUNT and B. REEs SMITH
Introduction The autoimmune response against the TSH receptor which is the cause of hyperthyroidism in Basedow's/Graves' disease is often associated also with thè presence of autoantibodies (Ab) to thyroid peroxidase (TPO) and in some cases to thyroglobulin (Tg) (reviewed by Rees Smith et al., 1988). The tendency for autoimmune disease to occur in families is well known (Hall et al., 1960, 1962), but the patterns of inheritance of disease have been difficult to clarify. In an alternative approach, we used highly sensitive assays based on the direct interaction between thyroid autoantibodies and 1251.. labelled TPO or Tg (Beever et al., 1989) to measure TPO Ab and Tg Ab in families with autoimmune thyroid disease. These studies demonstrated that the inheritance of TPO Ab and Tg Ab was consistent with Mendelian dominant inheritance in women but penetrance waS reduced in men (Phillips et al., 1990). However, the possibility existed that these results were biased as the families were ascertained through one or more probands with autoimmune thyroid disease. Thus we re-examined the inheritance of TPO/Tg Ab in a group of families being studied to map the gene for facioscapulohumeral disease (FSHD) among whom the prevalence of thyroid disease would be expec-
ted to approximate to that of the general population. Methods Sera were obtained from 24 families (145 men and 132 women) with FSHD and from a group of 700 female and 100 male blood donors without evidence of overt autoimmune thyroid disease. The presence of autoantibodies to TPO Ab and Tg Ab was detected using the highly sensitive direct assays involving '251-labelled TPO or Tg as previously described (Beever et al., 1989).
Results and Discussion In the families with FSHD, TPO Ab were detectable in of men and 22 of women and Tg Ab in 10% of men and 21 of women. These results were similar to the prevalence of TPO/Tg Ab in a group of 700 female and 100 male blood donors (20.2%
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Autosomal Dominant Interheritance of the Tendency to Develop Thyroid Autoantibodies
D. I. W. PHILLIPS et. al., Inheritance and Thyroid Autoantibodies
171
of women and 10% of men had TPO Ab; 20.1% of women and 12% of men had Tg Ab). The results of a segregation analysis for TPO Ab in the FSHD families is compared with the results previously obtained for AITD families in Table 1. Of the 42 meioses in the
FSHD families where either the father or mother had TPO Ab, three sons were TPO Ab + ve and 19 TPO Ab-ve, five daughters were TPO Ab + ve and 15 TPO Abve, results which were inconsistent with autosomal dominant inheritance. However, the studies in female blood donors showed that the prevalence of TPO Ab increased markedly with age from 16% at age 15-24 rising progressively to 27% in the 45 + age group. Re-examination of the FSDH data, in families where only one or other parent was Ab + ve, indicated that among the 10 daughters aged less than 25, only one was TPO Ab + ve (significantly daughters aged 25 or over, four were TPO Ab + ve and five TPO Ab-ve which was not significantly different from the 50% expectation) and similar observations were made for Tg Ab (data not shown). These data indicate that our hypothesis concerning autosomal dominant inheritance of TPO Ab and/or Tg Ab is fundamentally correct but also suggest that gene expression may be reduced in young women.
Segregation analysis of the tendency to develop TPO antibody in 16 families with autoimmune thyroid disease and in 24 families with FSHD where either the mother or father has TPO antibody. läble 1
TPO Ab +ve
ve
Autoimmune thyroid disease: Sons
5
Daughters
25
21**
25 ns
Facioscapulohuxperal disease: Sons
3
Daughters
5
19** 15*
Daughters 25 years
1
10**
4
5 ns
Significantly different from Mendelian expectation: * p < 0.05, ** p < 0.01, ns nonsignificant.
Acknowledgements. This study was supported in part by RSR Ltd, Cardiff, UK.
References BEEVER, K.; BRADBURY, J.; PHILLIPS, D. et al.: Highly sensitive assays of autoantibodies to thyroglo-
bulin and to thyroid peroxidase. Clin. Chem. 35 (1989) 1949-1954. HL, R.; OWEN, S. G.; G. A.: Evidence for a genetic predisposition to the formation of thyroid autoantibodies. Lancet ii (1960) 187-188. HxiL, R.; SAXENA, K. M.; OWEN, S. G.: A study of the parents of patients with Hashimoto's disease.
Lancet ii (1962) 1291-1292.
Downloaded by: University of Connecticut. Copyrighted material.
different from the Mendelian expectation of 50%, x2 = 7.4, p < 0.01) whereas of the
172
Exp. Clin. Endocrinol. 97 (1991) 2/3
[4) PHILLIPS, D. I. W.; MCLACHLAN, S. M.; STEPHENSON, A. et al.: Autosomal dominant transmission of
autoantibodies to thyroglobulin and thyroid peroxidse. J. Clin. Endcrinol. Metab. 70 (1990) 742-746. [5] REES SMrrH, B.; MCLACHLAN, S. M.; F UIANIAK, J.: Autoantibodies to the thyrotrophin receptor.
Endocrine reviews 9 (1988) 106-121.
Downloaded by: University of Connecticut. Copyrighted material.
Author's address: D. J. W. PHILLIPS, Endocrine Immunology Unit, College of Medicine, 7th Floor, Heath Park, University of Wales, Cardiff CF4 4XN, U.K.
J. A. Barth, Leipzig
Endocrine Immunology Unit, Department of Medicine and Medical Genetics, University
of Wales, College of Medicine, Cardiff/Great Britain
D. I. W. PHILLIPS, L. PRENTICE, S. M. MCLACHLAN, M. UPADHYAYA, p. w. LUNT and B. REEs SMITH
Introduction The autoimmune response against the TSH receptor which is the cause of hyperthyroidism in Basedow's/Graves' disease is often associated also with thè presence of autoantibodies (Ab) to thyroid peroxidase (TPO) and in some cases to thyroglobulin (Tg) (reviewed by Rees Smith et al., 1988). The tendency for autoimmune disease to occur in families is well known (Hall et al., 1960, 1962), but the patterns of inheritance of disease have been difficult to clarify. In an alternative approach, we used highly sensitive assays based on the direct interaction between thyroid autoantibodies and 1251.. labelled TPO or Tg (Beever et al., 1989) to measure TPO Ab and Tg Ab in families with autoimmune thyroid disease. These studies demonstrated that the inheritance of TPO Ab and Tg Ab was consistent with Mendelian dominant inheritance in women but penetrance waS reduced in men (Phillips et al., 1990). However, the possibility existed that these results were biased as the families were ascertained through one or more probands with autoimmune thyroid disease. Thus we re-examined the inheritance of TPO/Tg Ab in a group of families being studied to map the gene for facioscapulohumeral disease (FSHD) among whom the prevalence of thyroid disease would be expec-
ted to approximate to that of the general population. Methods Sera were obtained from 24 families (145 men and 132 women) with FSHD and from a group of 700 female and 100 male blood donors without evidence of overt autoimmune thyroid disease. The presence of autoantibodies to TPO Ab and Tg Ab was detected using the highly sensitive direct assays involving '251-labelled TPO or Tg as previously described (Beever et al., 1989).
Results and Discussion In the families with FSHD, TPO Ab were detectable in of men and 22 of women and Tg Ab in 10% of men and 21 of women. These results were similar to the prevalence of TPO/Tg Ab in a group of 700 female and 100 male blood donors (20.2%
Downloaded by: University of Connecticut. Copyrighted material.
Autosomal Dominant Interheritance of the Tendency to Develop Thyroid Autoantibodies
D. I. W. PHILLIPS et. al., Inheritance and Thyroid Autoantibodies
171
of women and 10% of men had TPO Ab; 20.1% of women and 12% of men had Tg Ab). The results of a segregation analysis for TPO Ab in the FSHD families is compared with the results previously obtained for AITD families in Table 1. Of the 42 meioses in the
FSHD families where either the father or mother had TPO Ab, three sons were TPO Ab + ve and 19 TPO Ab-ve, five daughters were TPO Ab + ve and 15 TPO Abve, results which were inconsistent with autosomal dominant inheritance. However, the studies in female blood donors showed that the prevalence of TPO Ab increased markedly with age from 16% at age 15-24 rising progressively to 27% in the 45 + age group. Re-examination of the FSDH data, in families where only one or other parent was Ab + ve, indicated that among the 10 daughters aged less than 25, only one was TPO Ab + ve (significantly daughters aged 25 or over, four were TPO Ab + ve and five TPO Ab-ve which was not significantly different from the 50% expectation) and similar observations were made for Tg Ab (data not shown). These data indicate that our hypothesis concerning autosomal dominant inheritance of TPO Ab and/or Tg Ab is fundamentally correct but also suggest that gene expression may be reduced in young women.
Segregation analysis of the tendency to develop TPO antibody in 16 families with autoimmune thyroid disease and in 24 families with FSHD where either the mother or father has TPO antibody. läble 1
TPO Ab +ve
ve
Autoimmune thyroid disease: Sons
5
Daughters
25
21**
25 ns
Facioscapulohuxperal disease: Sons
3
Daughters
5
19** 15*
Daughters 25 years
1
10**
4
5 ns
Significantly different from Mendelian expectation: * p < 0.05, ** p < 0.01, ns nonsignificant.
Acknowledgements. This study was supported in part by RSR Ltd, Cardiff, UK.
References BEEVER, K.; BRADBURY, J.; PHILLIPS, D. et al.: Highly sensitive assays of autoantibodies to thyroglo-
bulin and to thyroid peroxidase. Clin. Chem. 35 (1989) 1949-1954. HL, R.; OWEN, S. G.; G. A.: Evidence for a genetic predisposition to the formation of thyroid autoantibodies. Lancet ii (1960) 187-188. HxiL, R.; SAXENA, K. M.; OWEN, S. G.: A study of the parents of patients with Hashimoto's disease.
Lancet ii (1962) 1291-1292.
Downloaded by: University of Connecticut. Copyrighted material.
different from the Mendelian expectation of 50%, x2 = 7.4, p < 0.01) whereas of the
172
Exp. Clin. Endocrinol. 97 (1991) 2/3
[4) PHILLIPS, D. I. W.; MCLACHLAN, S. M.; STEPHENSON, A. et al.: Autosomal dominant transmission of
autoantibodies to thyroglobulin and thyroid peroxidse. J. Clin. Endcrinol. Metab. 70 (1990) 742-746. [5] REES SMrrH, B.; MCLACHLAN, S. M.; F UIANIAK, J.: Autoantibodies to the thyrotrophin receptor.
Endocrine reviews 9 (1988) 106-121.
Downloaded by: University of Connecticut. Copyrighted material.
Author's address: D. J. W. PHILLIPS, Endocrine Immunology Unit, College of Medicine, 7th Floor, Heath Park, University of Wales, Cardiff CF4 4XN, U.K.
