• PMID: 25740880
• Gene Name: miR-146a
• Condition: Male subfertility
• Association: miR-155 was associated with male subfertility independent of LGSI or androgens while miR-146a was only weakly associated with subfertility and LGSI.
• Population size: 179
• Population details: 179 (60 subjects each (exploratory and confirmatory cohort), 40 hypogonadal, 40 eugonadal, 39 controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: miR-155, miR-146a
• Other associated phenotypes: Male subfertility

Serum miR-155 as a potential biomarker of male fertility

Tsatsanis C, Bobjer J, Rastkhani H, Dermitzaki E, Katrinaki M, Margioris AN, Giwercman YL, Giwercman A.

STUDY QUESTION: Are serum levels of micro-RNAs miR-155 and miR-146a associated with male fertility, low-grade systemic inflammation (LGSI) and androgens? SUMMARY ANSWER: miR-155 was associated with male subfertility independent of LGSI or androgens while miR-146a was only weakly associated with subfertility and LGSI. WHAT IS KNOWN ALREADY: Male subfertility has been associated with LGSI as well as with androgen deficiency. miR-155 and miR-146a are central regulators of inflammation and their level in cells and in the serum has been associated with several inflammatory conditions. STUDY DESIGN, SIZE, DURATION: In this case-control study, two independent groups of 60 subjects each (exploratory and confirmatory cohort) were randomly selected from an ongoing study on subfertile men (in total: hypogonadal; n = 40, eugonadal; n = 40 and control group n = 39) at a University Hospital Reproductive Medicine Centre. Individuals were matched for age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total RNA was isolated from cell-free serum. As internal control a synthetic miRNA, UniSp6, was added to each sample prior to extraction. miRNA expression levels were measured by real-time RT-PCR and presented as fold difference (arbitrary units, U) from control. Sera from these individuals had been previously analyzed for hormone and cytokine levels. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of miR-155 were associated with levels of miR-146a (P < 0.0001), but only miR-146a was associated with inflammatory markers. miR-155 was strongly associated with subfertility (for subfertile group 1.88 U, 95% confidence interval (CI) 1.6-2.1 U versus 1.15, 95% CI 1.0-1.2 U in controls; P = 0.001). Receiver operating characteristic curve analysis indicated that miR-155 but not miR-146a can be used as a marker of subfertility. MiR-155 with a cutoff value of 1.77 had 47% sensitivity and 95% specificity for identifying subfertility and a positive predictive value (PPV) and negative predictive value (NPV) of 95 and 47%, respectively. When used in combination with FSH, sensitivity and specificity were 80 and 100%, respectively, while PPV and NPV were 100 and 71%, respectively, those values being higher than for the FSH alone. Repeating the results obtained in the exploratory cohort in an independent confirmatory cohort reduced the risk of a chance finding. LIMITATIONS, REASONS FOR CAUTION: Although the results from the exploratory cohort were confirmed in the confirmatory cohort, studies from other centers are needed to establish the role of miR-155 as a new biomarker of male fertility. Furthermore, the role of this marker in distinguishing between different groups of male subfertility is to be elucidated. WIDER IMPLICATIONS OF THE FINDINGS: Association of the inflammatory miRNA miR-155 with male fertility contributes to our understanding of the pathophysiology of subfertility and suggests a novel biomarker. Serum miR-155 in combination with FSH has higher diagnostic specificity and sensitivity compared with FSH alone. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from Swedish Governmental Grant (ALF), Skane county council research and development foundation, Skane University Hospital Fonds and by the EU and Greek funds under the action 'Education and lifelong learning' program THALIS-FAT-VESSEL (No 379527). The authors have no competing interests to disclose. CI - © The Author 2015. 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@oup.com. FAU - Tsatsanis, Christos AU - Tsatsanis C AD - Molecular Reproductive Research Group, Department of Translational Medicine, Lund University, Malmö, Sweden Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Crete, Greece tsatsani@med.uoc.gr. FAU - Bobjer, Johannes AU - Bobjer J AD - Molecular Reproductive Research Group, Department of Translational Medicine, Lund University, Malmö, Sweden Reproductive Medicine Centre, Skåne University Hospital Malmö, Malmö, Sweden. FAU - Rastkhani, Hamideh AU - Rastkhani H AD - Molecular Genetic Reproductive Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden. FAU - Dermitzaki, Erini AU - Dermitzaki E AD - Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Crete, Greece. FAU - Katrinaki, Marianna AU - Katrinaki M AD - Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Crete, Greece. FAU - Margioris, Andrew N AU - Margioris AN AD - Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Crete, Greece. FAU - Giwercman, Yvonne Lundberg AU - Giwercman YL AD - Molecular Genetic Reproductive Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden.