Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic 'fingerprints'

Juan Carlos Jaume, Jin Guo, David L. Pauls, Margita Zakarija, J. Maxwell McKenzie, Janice A. Egeland, C. Lynne Burek, Noel R. Rose, William H. Hoffman, Basil Rapoport, Sandra M. McLachlan

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Autoimmune thyroid disease is characterized by the tendency to cluster in families and by IgG class autoantibodies to antigens such as thyroid peroxidase (TPO). The epitopes recognized by polyclonal serum autoantibodies can be quantitatively fingerprinted using four recombinant human TPO autoantibodies (expressed as Fab) that define A and B domain epitopes in an immunodominant region. To determine whether these fingerprints are genetically transmitted, we analyzed fingerprints of 63 members of 7 multiplex Old Order Amish families and 17 individuals from 4 Hashimoto thyroiditis families. Inhibition of serum autoantibody binding to [125I]TPO by the recombinant Fab was used to assess recognition of the TPO immunodominant region (4 Fab combined) and recognition of domain A or B (individual Fab). Complex segregation analysis was performed using a unified model (POINTER). For the 4 Fab combined inhibition phenotype, the no transmission model was rejected (x2((4)) = 20.67; P < 0.0032), and the most parsimonious model includes a major gene effect. More importantly, evidence for genetic transmission was obtained for the phenotype defined by the ratio of inhibition by subdomain Fab B1:B2. Thus, for this ratio (reflecting recognition of the B domain), the no transmission model was rejected X2((4)) = 63.59; P < 0.000008). Moreover, the polygenic hypothesis could be rejected, but not the major locus hypothesis, suggesting that major genes might be involved in familial transmission of this trait. In conclusion, our findings suggest that autoantibody recognition of the TPO immunodominant region and the TPO B domain is genetically transmitted. These data may open the way to the identification by candidate analysis or positional cloning of at least one gene responsible for the development of Hashimoto's thyroiditis.

Original languageEnglish (US)
Pages (from-to)1424-1431
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume84
Issue number4
StatePublished - Dec 1 1999

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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    Jaume, J. C., Guo, J., Pauls, D. L., Zakarija, M., McKenzie, J. M., Egeland, J. A., Burek, C. L., Rose, N. R., Hoffman, W. H., Rapoport, B., & McLachlan, S. M. (1999). Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic 'fingerprints'. Journal of Clinical Endocrinology and Metabolism, 84(4), 1424-1431.