Autoimmune thyroid disease (AITD), including Graves' disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, is caused by multiple genetic and environmental factors. Genes involved in immune response and/or thyroid physiology appear to influence susceptibility to disease. The PDS gene (7q31), responsible for Pendred syndrome (congenital sensorineural hearing loss and goiter), encodes a transmembrane protein known as pendrin. Pendrin is an apical porter of iodide in the thyroid. To evaluate the contribution of PDS gene in the genetic susceptibility of AITD, we examined four microsatellite markers in the gene region. Two hundred thirty-three unrelated patients (GD,141; HT, 54; primary idiopathic myxedema, 38), 15 multiplex AITD families (104 individuals/46 patients) and 154 normal controls were genotyped. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with GD (P = 10(-3)) and HT (P = 1.07 10(-24)), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test are in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). Multipoint nonparametric linkage analysis using MERLIN showed intriguing evidence for linkage with marker D7S496 in families with only GD patients [Z = 2.12, LOD = 0.81, P = 0.026]. Single-point and multipoint parametric LOD score linkage analysis was also performed. Again, the highest multipoint parametric LOD score was found for marker D7S496 (LOD = 1.23; P = 0.0086) in families segregating for GD under a dominant model. This work suggests that the PDS gene should be considered a new susceptibility gene to AITDs with varying contributions in each pathology.