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
Autoimmune Disease Unit, Cedars-Sinai Research Institute and University of California School of Medicine, Los Angeles 90048, USA.
J Clin Endocrinol Metab. 1999 Apr;84(4):1424-31. doi: 10.1210/jcem.84.4.5639.
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 (chi2(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 chi2(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.
自身免疫性甲状腺疾病的特点是在家族中具有聚集倾向，以及存在针对甲状腺过氧化物酶（TPO）等抗原的IgG类自身抗体。多克隆血清自身抗体识别的表位可用四种重组人TPO自身抗体（以Fab形式表达）进行定量指纹分析，这四种抗体可确定免疫显性区域中的A和B结构域表位。为了确定这些指纹是否可遗传传递，我们分析了7个阿米什大家族中63名成员以及4个桥本甲状腺炎家族中17名个体的指纹。用重组Fab抑制血清自身抗体与[125I]TPO的结合，以评估对TPO免疫显性区域（4种Fab组合）以及A或B结构域（单个Fab）的识别。使用统一模型（POINTER）进行复杂分离分析。对于4种Fab组合抑制表型，无传递模型被拒绝（χ2(4)=20.67；P<0.0032），最简约的模型包括一个主基因效应。更重要的是，对于由亚结构域Fab B1:B2抑制率定义的表型，获得了遗传传递的证据。因此，对于该比率（反映对B结构域的识别），无传递模型被拒绝（χ2(4)=63.59；P<0.000008）。此外，多基因假说可被拒绝，但主基因座假说不能被拒绝，这表明主基因可能参与了该性状的家族传递。总之，我们的研究结果表明，TPO免疫显性区域和TPO B结构域的自身抗体识别是可遗传传递的。这些数据可能为通过候选分析或定位克隆来鉴定至少一个导致桥本甲状腺炎发生的基因开辟道路。
