The dopamine receptor D₂ genotype is associated with hyperprolactinemia

Objective: To evaluate patients with hyperprolactinemia for the presence of dopamine receptor D₂ polymorphisms. Design: Case-control study. Setting: Academic research environment. Patient(s): Women and men with pathologic hyperprolactinemia and healthy controls. Intervention(s): DNA extraction of peripheral blood, polymerase chain reaction, single-strand conformation polymorphism, DNA sequencing, and restriction digest. Main Outcome Measure(s): Two polymorphisms in exon 7 of the dopamine receptor D₂ (DRD2) gene. Polymorphism 1 involves nucleotide 3420 (C to T, 313 His), and polymorphism 2 involves nucleotide 3438 (C to T, 319 Pro). Result(s): The frequency of DRD2 polymorphism 1 alleles was increased in subjects with hyperprolactinemia. Analysis of the DRD2 genotypes demonstrates an odds ratio of 6.77 (2.39, 19.14; 95% confidence interval) for the polymorphism 1 homozygous state in hyperprolactinemia. Conclusion(s): A genetic predisposition to hyperprolactinemia is suggested by an excess homozygosity for polymorphism 1 in exon 7 of the DRD2 gene. Previous studies of lactotrophs from prolactinomas have found normal DRD2 receptors but differing isoform density. Homozygosity of polymorphism 1 may influence the distribution of the DRD2 isoforms on the lactotroph. Other potential mechanisms include an association with a molecular defect in a postreceptor signaling mechanism, such as a somatic inactivating mutation in a G₁ protein, which could result in autonomous function of the lactotroph. Mutations could also result in different receptor-G protein interactions, such as a G_s instead of G_i, and result in autonomous lactotroph function.