Objective: To investigate whether a polymorphism in the ESR2 gene (rs4986938, previously associated with endometriosis, ovulatory dysfunction and premature onset of coronary heart disease) increases the risk of Graves' disease (GD).
Subjects and design: A cohort of 375 GD patients (300 females and 75 males) and 1001 individuals representative of the background population of Poland (502 males and 499 females) were genotyped for rs4986938 using allele-specific polymerase chain reaction (PCR).
Results: We found an increased frequency of the ESR2 A allele among the patients vs. controls (38.0%vs. 32.7%, OR = 1.26, P = 0.009) that was caused by a co-dominant (OR = 1.25, P = 0.01, P(for model fit) = 0.127) or a recessive (OR = 1.67, P = 0.003, P(for model fit) = 0.554) effect. The association was found in both sexes (OR = 1.21, P = 0.046 and OR = 1.53, P = 0.029, respectively, for co-dominant and recessive models in females, and OR = 1.44, P = 0.034 and OR = 2.29, P = 0.01, respectively, for the two models in males) and was more pronounced among the DRB1*03-negative (OR = 1.63, P = 0.0002) than DRB1*03-positive patients (OR = 1.04, P = 0.822). No other statistically significant associations between the ESR2 genotype and GD subsets were found (age of onset, smoking, clinically evident ophthalmopathy, family history of GD, and PTPN22 and CTLA4 (CT60) genotypes were analysed).
Conclusions: In a Polish population the ESR2 A allele is associated with GD with a strength comparable to polymorphisms of PTPN22 and CTLA4 CT60 loci (OR approximately 1.7). The association with ESR2 is found in both sexes and may be particularly strong among the DRB1*03-negative individuals.