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Association between tissue inhibitor of metalloproteinase (TIMP) genetic polymorphisms and primary ovarian insufficiency (POI)

  • Author Footnotes
    1 These authors equally contributed to this work.
    Hui Jeong An
    Footnotes
    1 These authors equally contributed to this work.
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, South Korea

    Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Author Footnotes
    1 These authors equally contributed to this work.
    Eun Hee Ahn
    Footnotes
    1 These authors equally contributed to this work.
    Affiliations
    Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Jung Oh Kim
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, South Korea

    Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Han Sung Park
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, South Korea

    Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Chang Soo Ryu
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, South Korea

    Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Sung Hwan Cho
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, South Korea

    Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Ji Hyang Kim
    Affiliations
    Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
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  • Woo Sik Lee
    Affiliations
    Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul 06135, South Korea
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  • Nam Keun Kim
    Correspondence
    Corresponding author at: Department of Biomedical Science, School of Medicine, CHA University, CHA Bio Complex #627, 335 Pangyo-ro, Bundang-gu, Seongnam 13488, South Korea.
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, South Korea

    Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
    Search for articles by this author
  • Author Footnotes
    1 These authors equally contributed to this work.

      Highlights

      • We investigated the association between six tissue inhibitor of metalloproteinase (TIMP) polymorphisms and primary ovarian insufficiency in Korean females.
      • The TIMP2G > C (rs8179090) and TIMP2G > A (rs2277698) genotypes were strongly associated with primary ovarian insufficiency.
      • Our data suggest that the TIMP2 genotypes and TIMP1 haplotypes may increase the risk of primary ovarian insufficiency in Korean women.

      Abstract

      Background

      Until now, an association between tissue inhibitor of metalloproteinase (TIMP) polymorphisms and primary ovarian insufficiency (POI) has not been identified. The aim of our study was to investigate whether the TIMP polymorphisms TIMP1T > C (rs4898), TIMP1G > A (rs6609533), TIMP2G > C (rs8179090), TIMP2G > A (rs2277698), TIMP3G > A (rs135029), and TIMP4T > C (rs3755724), which regulate matrix metalloproteinases (MMPs), confer a risk for primary ovarian insufficiency (POI) in Korean women (further studies would be required to evaluate the associations between TIMP polymorphisms and POI in other populations).

      Methods

      We genotyped 137 POI patients and 236 controls for the single nucleotide polymorphism sites using PCR–RFLP analysis. Differences in the frequencies of the TIMP1T > C (rs4898), TIMP1G > A (rs6609533), TIMP2G > C (rs8179090), TIMP2G > A (rs2277698), TIMP3G > A (rs135029), and TIMP4T > C (rs3755724) genotypes between patients and controls were compared, and odds ratios and 95% confidence intervals were determined to measure of the strength of the association between the genotypes and POI.

      Results

      The TIMP1T > C (rs4898), TIMP1G > A (rs6609533), TIMP2G > C (rs8179090), TIMP2G > A (rs2277698), TIMP3G > A (rs135029), and TIMP4T > C (rs3755724) genotypes, but especially the TIMP2 genotypes, were found more frequently in POI patients than in control subjects. Among the four TIMP loci, the TIMP1T > C (rs4898), TIMP1G > A (rs6609533), TIMP2G > C (rs8179090), TIMP2G > A (rs2277698), TIMP3G > A (rs135029), and TIMP4T > C (rs3755724) haplotypes were identified more frequently in POI patients than in control subjects and conferred susceptibility to POI (P <0.0001).

      Conclusions

      The TIMP2G > C (rs8179090) and G > A (rs2277698) alleles were strongly associated with POI. Our data suggest that the minor TIMP2 alleles may increase POI risk in Korean women.

      Keywords

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