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A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates.

ABSTRACT: Current evidence suggests that the acquisition of female reproductive capacity and the maintenance of mature reproductive function are related processes transcriptionally regulated by gene networks operating within the neuroendocrine brain. One of these genes, termed enhanced at puberty 1 (EAP1), encodes an upstream regulator of these processes. Selective inhibition of EAP1 expression in discrete regions of the rat and nonhuman primate (NHP) hypothalamus, via targeted delivery of RNA interference, either disrupts (rats) or abolishes (monkeys) reproductive cycles. The striking loss of menstrual cyclicity resulting from knocking down hypothalamic EAP1 expression suggests that diminished EAP1 function may contribute to disorders of the menstrual cycle of neuroendocrine origin. Here we show that a single-nucleotide polymorphism in the 5'-flanking region of EAP1 gene is associated with increased incidence of amenorrhea/oligomenorrhea in NHP. In the presence of the risk allele, binding of the transcription factor mothers against decapentaplegic homolog 3 (SMAD3) to its recognition site contained within the polymorphic sequence in the monkey EAP1 promoter is reduced. The risk allele also diminishes the increase in EAP1 promoter activity elicited by TGF?1, a peptide that activates a SMAD3/4-mediated signaling pathway to regulate gene transcription. These findings indicate that common genetic variation in the EAP1 locus increases the susceptibility of NHP to loss/disruption of menstrual cyclicity. They also raise the possibility that polymorphisms in EAP1 may increase the risk of functional hypothalamic amenorrhea in humans.

SUBMITTER: Lomniczi A

PROVIDER: S-EPMC3249686 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates.

Lomniczi Alejandro A Garcia-Rudaz Cecilia C Ramakrishnan Ranjani R Wilmot Beth B Khouangsathiene Samone S Ferguson Betsy B Dissen Gregory A GA Ojeda Sergio R SR

Endocrinology 20111129 1

Current evidence suggests that the acquisition of female reproductive capacity and the maintenance of mature reproductive function are related processes transcriptionally regulated by gene networks operating within the neuroendocrine brain. One of these genes, termed enhanced at puberty 1 (EAP1), encodes an upstream regulator of these processes. Selective inhibition of EAP1 expression in discrete regions of the rat and nonhuman primate (NHP) hypothalamus, via targeted delivery of RNA interferenc ...[more]

PMID: 22128021

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Project description:AbstractPain is one of the most prominent symptoms of osteoarthritis. However, there is often discordance between the pain experienced by individuals with osteoarthritis and the degree of articular pathology. This suggests that individual differences, including genetic variability in the central processing of nociceptive stimuli, may impact the presentation of osteoarthritis. Here, we show that the single nucleotide polymorphism rs16868943 in the collagen gene COL11A2 is significantly associated with lowered heat pain tolerance on the arm in participants with knee osteoarthritis (P = 1.21 × 10−6, P = 0.0053 after Bonferroni correction, beta = −3.42). A total of 161 knee osteoarthritis participants were included and evaluated for heat, punctate and pressure pain sensitivity of the affected knee and the ipsilateral arm. Each participant was genotyped for 4392 single nucleotide polymorphisms in genes implicated in pain perception, inflammation and mood and tested for association with pain sensitivity. The minor A allele of single nucleotide polymorphism rs16868943 was significantly associated with lower arm heat pain tolerance after correction for age, gender, race, and study site. This single nucleotide polymorphism was also nominally associated with other measures of heat pain sensitivity, including lowered knee heat pain tolerance (P = 1.14 × 10−5, P = 0.05 after Bonferroni correction), lowered arm heat pain threshold (P = 0.0039, uncorrected) and lowered knee heat pain threshold (P = 0.003, uncorrected). Addition of genotypes from 91 participants without knee pain produced a significant interaction between knee osteoarthritis status and the rs16868943 single nucleotide polymorphism in heat pain tolerance (P = 1.71 × 10−5), such that rs16868943 was not associated with heat pain tolerance in participants without knee pain (P = 0.12, beta = 1.3). This is the first study to show genetic association with heat pain tolerance in individuals with osteoarthritis. The association is specific to participants who have already developed knee osteoarthritis, suggesting that the COL11A2 gene, which has previously been associated with familial osteoarthritis, may play a role in pain sensitization after the development of osteoarthritis.

Dataset Information

A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates.

Publications

A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates.

Similar Datasets

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