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m.4216 T > C polymorphism in JT cluster determines a lower pregnancy rate in response to controlled ovarian stimulation treatment

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To analyze the influence of Caucasian mitochondrial haplogroups on controlled ovarian stimulation outcome (COS), embryo (E), and pregnancy success.

Methods

In a Caucasian population (n = 517) undergoing COS, mitochondrial haplogroups and physiological parameters were determined. Patients were classified, according to Bologna criteria, as good (>3)/poor ≤3) responder, on dependence of recruited oocytes (RO), and in pregnancy/non-pregnancy groups. Haplogroups were determined by sequencing mitochondrial hypervariable sequence I and confirmed by polymerase chain reaction (PCR), followed by restriction fragment length polymorphisms (RFLP).

Results

The rank of total dose of FSH (TD FSH) was similar in all clusters/haplogroups, except in JT, which is narrower (950–3,650 IU), particularly in T (1,350–3,650 IU). The statistical analysis showed higher RO and E in JT when compared to U, although it was only Uk which accumulated significantly in pregnancy respect to JT. Pearson’s correlations between TD FSH and RO showed negative statistical significance in all population (P = 0.001), H (P = 0.03), JT (P = 0.01), and T (P = 0.03). The percentage of contribution of TD FSH on RO was almost nine times in the JT cluster as compared to all population one.

Conclusions

JT cluster shows a different influence of TD FSH on RO. JT cluster shows higher RO and E than U, but it is Uk which exhibits a significant higher pregnancy rate than JT. The negative influence of the JT cluster on pregnancy success strongly suggests that the m.4216 T > C polymorphism could be responsible.

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Data Availability

All data are available upon request.

Web resources:

MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org, 2019. Statistical power of the study was determined by Epidat 3.1. http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1135-57272004000200013&lng=es&nrm=iso>. ISSN 2173-9110.

Abbreviations

ATP:

Adenosine triphosphate

COS:

Controlled ovarian stimulation

FSH:

Follicle stimulating hormone

ICSI:

Intracytoplasmatic sperm injection

IVF:

In vitro fertilization

mtDNA:

Mitochondrial DNA

OXPHOS:

Mitochondrial oxidative phosphorylation system

PD:

Parkinson disease

PCR:

Polymerase chain reaction

RFLP:

Restriction fragment length polymorphism

ROS:

Reactive oxygen species

tRNA:

Transfer ribonucleic acid

VO2max:

Maximal oxygen uptake

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Acknowledgements

The authors would like to express their gratitude to all patients and to their partners, who contributed genetic material for this study.

Funding

BM-O was supported by a grant of the Foundation for Biomedical Research of the Hospital Universitario Príncipe de Asturias of Alcalá de Henares, Madrid (Spain). The study was supported by a grant from the Government of Aragon (Spain) (Applied Research Group B33 of 2009. Main Researcher Dr. Julio Montoya). The funding sources had no involvement in study design, collection, analysis, interpretation of data, writing the report or decision to submit the article for publication.

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain

    Belén Monge-Ochoa, Julio Montoya, Eduardo Ruiz-Pesini, Manuel J. López-Pérez & Carmen Díez-Sánchez

  2. Unidad de Reproducción Asistida, Hospital Universitario Príncipe de Asturias, Universidad Complutense de Madrid, Alcalá de Henares, Madrid, Spain

    Luis Montoro & Francisco de Castro

  3. Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Julio Montoya & Eduardo Ruiz-Pesini

  4. Instituto de Investigación Sanitaria (IIS) de Aragón, Zaragoza, Spain

    Julio Montoya & Eduardo Ruiz-Pesini

Authors
  1. Belén Monge-Ochoa
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  7. Carmen Díez-Sánchez
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Contributions

BM-O performed the laboratory work of the study and contributed to writing the manuscript information. FC and LM collected data and provided subjects’ treatment. ML-P, JM, and ER-P did the laboratory studies for the mitochondrial DNA haplogroups determination. ML-P and FC designed the study. BM-O and CD-S performed statistical analysis of data. ML-P and CD-S supervised quality control of molecular biology studies and designed RFLP studies. CD-S contributed to study design and wrote the manuscript information.

Corresponding author

Correspondence to Carmen Díez-Sánchez.

Ethics declarations

Ethics approval and consent to participate

The subjects were fully informed of the aims of the work before signing the informed consent form. The study conforms to the code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved (January 22, 2003) by the Committee of Clinical Trials of the Hospital Universitario Príncipe de Asturias of Alcalá de Henares, Madrid (Spain).

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All authors agree in publishing the data contained in this article.

Conflict of interest

The authors declare no competing interests.

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Manuel J. López-Pérez and Francisco de Castro are deceased.

Supplementary information

Supplementary Figure 1

Phylogenetic tree of mtDNA clusters and haplogroups. Changes respect the Revised Cambridge Reference Sequence (rCRS) of the Human Mitochondrial DNA. The corresponding polymorphism is indicated in some haplogroups and subhaplogroups with the restriction enzyme and the Restriction Fragment Length Polymorphisms (RFLP) used for their identification. In this figure, the most important Caucasian variants can be observed. From left to right: cluster U and, in particular, U1811 (framed), cluster JT (framed) characterized by the polymorphism m.4216 T > C and cluster H/HV (framed). The set of these mitochondrial variants adds up more than 90% of the Caucasian population. The rest would correspond to IWX and those who cannot be ascribed to any of these variants. Figure modified from [18]. (PNG 462 kb)

High resolution image (TIF 8023 kb)

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Monge-Ochoa, B., Montoro, L., Montoya, J. et al. m.4216 T > C polymorphism in JT cluster determines a lower pregnancy rate in response to controlled ovarian stimulation treatment. J Assist Reprod Genet 40, 671–682 (2023). https://doi.org/10.1007/s10815-023-02721-2

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