Epistasis between polymorphisms in TSHB and ADAMTS16 is associated with premature ovarian failure

Objective: This study investigated whether epistasis between single nucleotide polymorphisms (SNPs) within the TSHB (thyroid-stimulating hormone A) and ADAMTS16 (ADAM metallopeptidase with thrombospondin type 1 motif, 16) genes is associated with an increased risk of premature ovarian failure (POF) in Korean women. Methods: In stage I, 120 women with POF and 222 controls participated. A GoldenGate assay with VeraCode technology was used to genotype SNPs within the TSHB and ADAMTS16 genes. For stage II, we obtained genotype data merged with imputed data for 1,641 female controls from the Korean Genome Epidemiology Study. Results: In stage I, two SNPs (rs7530810 and rs1321108) in the 5' flanking region of the TSHB gene demonstrated significant synergistic interactions with one tagging intronic SNP (rs13172105) in the ADAMTS16 gene (odds ratios, 6.63 and 5.57; 95% CIs, 2.30-19.18 and 2.05-15.12; P = 0.00048 and 0.00074, respectively) although the SNPs were not significantly associated with POF in a single SNP model. When at least one G allele at rs7530810 or one A allele at rs1321108 was present in combination with a C allele at rs13172105, significant synergistic effects were observed in a recessive model. In stage II and combined analyses, the same combinations repeatedly showed significant synergistic interactions. Conclusions: Epistasis between SNPs within the TSHB and ADAMTS16 genes may increase the risk of POF in Korean women.