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Evidence for Genetic Transmission of Thyroid Peroxidase Autoantibody Epitopic "Fingerprints"¹

Autoimmune Disease Unit, Cedars-Sinai Research Institute and University of California School of Medicine (J.C.J., J.G., B.R., S.M.M.), Los Angeles, California 90048; the Child Study Center and Departments of Genetics and Psychology, Yale University School of Medicine (D.L.P.), New Haven, Connecticut 06520; the Departments of Medicine (M.Z., J.M.M.) and Psychiatry (J.A.E.), University of Miami School of Medicine, Miami, Florida 33101; the Departments of Pathology and Molecular Microbiology and Immunology, The Johns Hopkins University (C.L.B., N.R.R.), Baltimore, Maryland 21205; and the Department of Pediatrics, Medical College of Georgia (W.H.H.), Augusta Georgia 30912

Address all correspondence and requests for reprints to: Dr. Sandra M. McLachlan, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048.

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 (²₍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 ²₍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.

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