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Hum. Reprod. Advance Access published online on March 18, 2008
Human Reproduction, doi:10.1093/humrep/den086
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure

HyunJun Kang1, Seung Ku Lee1, Min-Ho Kim1, JiHyun Song1, Su Jin Bae2, Nam Keun Kim2, Sook-Hwan Lee3 and KyuBum Kwack1,4

1 Medical Genomics Laboratory, Pochon CHA University, Gyeonggi-do, Korea 2 Institute for Clinical Research, Pochon CHA University, Gyeonggi-do, Korea 3 Genome Research Center for Reproductive Medicine and Infertility of Korea Ministry of Health and Welfare, Seoul, Korea

4 Correspondence address. Tel: +82-31-725-8376; Fax: +82-31-725-8350; E-mail: kbkwack{at}cha.ac.kr/ kbkwack{at}gmail.com

BACKGROUND: Premature ovarian failure (POF) is a complex and heterogeneous disorder that is influenced by multiple genetic components. Here, we performed a two-stage association study to identify POF-associated genes.

METHODS: A first stage linkage disequilibrium (LD)-based genome-wide association study was performed using 24 pairs of patients with POF and matched controls and a high-throughput BeadChip assay with 109365 single-nucleotide polymorphisms (SNPs) that are scattered throughout the genome in an exon-centric and evenly spaced manner. A region that was shown to be strongly associated with POF was then tested again for POF association in the second stage by using a larger sample size (101 cases and 87 controls) and additional putative causal SNPs.

RESULTS: The first stage analysis revealed that many regions were associated with POF, with part of chromosome 7p14 that contains the parathyroid hormone responsive-B1 (PTHB1) gene showing the strongest association. A POF-susceptible haplotype of PTHB1 (ht1, ‘GAAAG’, P = 0.00034) and a POF-resistant haplotype (ht2, ‘TGTGC’) were also identified. The association between POF and two PTHB1 SNPs (rs3884597 and rs6944723) and part of ht1 was confirmed in the second stage analysis. The additional SNP, rs11773504, was considered as a putative causal variant causing an amino acid change, Ala to Thr.

CONCLUSIONS: We showed for the first time that PTHB1 is strongly associated with POF, and ht1 confers susceptibility to POF. While causative SNPs were not identified, the polymorphism of the non-synonymous SNP rs11773504 and the repeated association of ht1 with POF suggest that PTHB1 may contribute to POF pathogenesis.

Key words: POF/PTHB1 gene/LD mapping/SNP/haplotype

Submitted on August 17, 2007; resubmitted on February 12, 2008; accepted on February 26, 2008.


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