Although extensive studies have suggested that an individual's predisposition to develop autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) has a genetic component, a recent report has suggested that growth restriction during fetal life may also contribute. We have therefore measured TPOAb and TgAb in a population-based study of twins (44 monozygous and 91 dizygous) born between 1950 and 1955 who were identified through a registry of birth records in Birmingham, United Kingdom. TPOAb and TgAb were measured by a highly sensitive immunoprecipitation assay in which 0.01 U/mL and 0.1 U/mL, respectively, were detectable. TPOAb were found in 49 of 156 (31%) of women and 7 of 116 (6%) of men with similar values for TgAb (31% and 9%, respectively). Of 28 monozygous pairs, 10 were concordant for TgAb and 7 discordant giving a probandwise concordance rate of 74%. Concordance rates for TPOAb were similar (64%) and were higher than concordance rates in dizygous twins. Monozygous twins had a higher prevalence of TgAb than dizygous twins (30% vs. 17%, p = 0.01). In addition, we found that where there was discordance in birth size within monozygous twin pairs, the smaller twin had a higher prevalence of TPOAb (p = 0.01). Our results suggest that both heritable and early environmental components contribute to the susceptibility to thyroid autoimmunity.

Intervention with GAD-alum in LADA patients had no effect on GADA affinity. Our data suggest that patients with low GADA affinity have a prolonged preservation of residual β-cell function.

The inheritance of autoantibodies to thyroglobulin and thyroid peroxidase (thyroid microsomal antigen) has been reevaluated with newly developed ultrasensitive assays that depend on the direct interaction between antibody and radiolabeled antigen. In a study of 16 families with autoimmune thyroid disease, autoantibodies to thyroid peroxidase (TPO) were found to be inherited as a dominant Mendelian trait in females with reduced penetrance in males. Similar results were obtained with thyroglobulin (Tg) autoantibodies. Genetic linkage analysis of the loci for TPO and Tg autoantibodies with 28 polymorphic serological markers (including HLA and Gm allotypes) was carried out in 9 families. LOD scores for some serological markers (such as Gm) were uninformative, but linkage with other markers, notably the HLA antigens -A, B, -DR, -DQ, and BF on chromosome 6, could be excluded. Further studies using a comprehensive panel of gene probes to analyze DNA from families with autoimmune thyroid disease should permit the localization of the gene cluster responsible for regulating the ability to produce autoantibodies to TPO and Tg in man.