Abstract
Premature ovarian failure (POF) is a complex disease of which the etiology is influenced by numerous genetic variations. Several POF candidate genes have been reported. However, no causal genes with high odds ratio (OR) have yet been discovered. This study included 564 females of Korean ethnicity, comprising 60 patients with POF and 182 controls in the discovery set and 105 patients with POF and 217 controls in the replication set. We conducted genome-wide association analysis to search for novel candidate genes predicted to influence POF development using Axiom Precision Medicine Research Arrays and additive model logistic regression analysis. One statistically significant single nucleotide polymorphism (SNP), rs55941146, which encodes a missense alteration (Val > Gly) in the APBA3 gene, was identified with OR values for association with POF of 13.33 and 4.628 in the discovery and replication sets, respectively. No rs55941146 minor allele homozygotes were present in either cases or controls. The APBA3 protein binds FIH-1 that inhibits hypoxia inducible factor-1α (HIF-1α). HIF-1α contributes to granulosa cell proliferation, which is crucial for ovarian follicle growth, by regulating cell proliferation factors and follicle stimulating hormone-mediated autophagy. Our data demonstrate that APBA3 is a candidate novel causal gene for POF.
Highlights
Premature ovarian failure (POF) is an idiopathic, complex disease in which menopause occurs before the age of 40 years [1]
FIH-1 is an asparaginyl hydroxylase enzyme that promotes asparaginyl hydroxylation of the COOH-terminal transactivation domain (CAD) of hypoxia inducible factor-1 (HIF-1), thereby reducing HIF-1 function [25,26]. Both APBA3 and hypoxia inducible factor-1α (HIF-1α) contain identical domains that compete for binding to FIH-1 [22]
If APBA3 is bound to FIH-1, the asparaginyl hydroxylase modification of the HIF-1 CAD region mediated by FIH-1 is inhibited [22]
Summary
Premature ovarian failure (POF) is an idiopathic, complex disease in which menopause occurs before the age of 40 years [1]. The diagnostic criteria for POF in premenopausal females include an increase of serum follicle stimulating hormone (FSH) levels (>40 mIU/mL), measured twice in the same month, alongside the presence of amenorrhea for 6 months before the normal age of menopause onset [5]. The ovarian follicle is important to oocyte growth and folliculogenesis is a crucial mechanism contributing to female fertility [8,9,10]. Small, dormant primordial follicles are enclosed by a single layer of granulosa cells (GCs) in the ovarian cortex [8,9]. GCs are important during follicle development under the influence of FSH and luteinizing hormone, which induce GC proliferation [13,15,16]. FSH promotes the development of preantral follicles and induces an anti-apoptotic process in antral follicles [15,16,17,18]
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