Epistasis between polymorphisms in ACVR2B and ADAMTS19 is associated with premature ovarian failure

OBJECTIVE: This study investigated whether epistasis between single nucleotide polymorphisms (SNPs) within ACVR2B (activin A receptor, type IIB) and ADAMTS19 (ADAM metallopeptidase with thrombospondin type 1 motif, 19) genes is associated with premature ovarian failure (POF). METHODS: One hundred twenty women with POF and 152 controls were recruited for stage I, and 1,641 additional female controls participated in stage II. GoldenGate assay with VeraCode technology was used for genotyping ACVR2B and ADAMTS19 SNPs in stage I. In stage II, we obtained genotype data for SNPs using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data using IMPUTE program from the Korean Genome Epidemiology Study. RESULTS: In stage I, five combinations showed significant synergistic interactions after Bonferroni correction. One SNP (rs1468077 within 5' flanking region) and two intronic SNPs (rs2268753 and rs2268757) in ACVR2B and three intronic SNPs within ADAMTS19 (rs13158524, rs1476083, and rs1972624) were involved in synergistic interactions in a recessive manner. In stage II and combined analyses, we could not find any significant interactions between the SNPs. However, diplotypes within ACVR2B and ADAMTS19 that consist of risk genotypes or alleles in the results of significant synergistic interactions between SNPs showed significant interactions after Bonferroni correction. Thirteen and nine significant synergistic interactions were found in a dominant model in stage II and combined analyses, respectively (strongest association in combined analysis: odds ratio, 5.93; 95% CI, 2.47-14.20; P = 6.65 × 10(-5)). CONCLUSIONS: Epistasis between polymorphisms within ACVR2B and ADAMTS19 is significantly associated with susceptibility to POF.