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

Autoimmune thyroid disease is characterized by the tendency to cluster in f amilies and by IgG class autoantibodies to antigens such as thyroid peroxid ase (TPO). The epitopes recognized by polyclonal serum autoantibodies can b e quantitatively fingerprinted using four recombinant human TPO autoantibod ies (expressed as Fab) that define A and B domain epitopes in an immunodomi nant region. To determine whether these fingerprints are genetically transm itted, we analyzed fingerprints of 63 members of 7 multiplex Old Order Amis h families and 17 individuals from 4 Hashimoto thyroiditis families. Inhibi tion of serum autoantibody binding to [I-125]TPO by the recombinant Fab was used to assess recognition of the TPO immunodominant region (4 Fab combine d) and recognition of domain A or B (individual Fab). Complex segregation a nalysis was performed using a unified model (POINTER). For the 4 Fab combin ed inhibition phenotype, the no transmission model was rejected (chi((4)(2) ) = 20.67; P < 0.0032), and the most parsimonious model includes a major ge ne effect. More importantly, evidence for genetic transmission was obtained for the phenotype defined by the ratio of inhibition by subdomain Fab B1:B 2. Thus, for this ratio (reflecting recognition of the B domain), the no tr ansmission model was rejected chi((4)(2)) = 63.59; P < 0.000008). Moreover, the polygenic hypothesis could be rejected, but not the major locus hypoth esis, suggesting that major genes might he involved in familial transmissio n of this trait. In conclusion, our findings suggest that autoantibody recognition of the TP O immunodominant region and the TPO B domain is genetically transmitted. Th ese data may open the way to the identification by candidate analysis or po sitional cloning of at least one gene responsible for the development of Ha shimoto's thyroiditis.