Mitochondrial DNA copy number in peripheral blood: a potential non invasive biomarker for female subfertility
Abstract
Publication Date:
2018
abstract:
Study question: Does the mitochondrial DNA copy number (mtDNAcn) in
peripheral blood have the potential to serve as a non invasive biomarker for
female subfertility?
Summary answer: A mtDNA peripheral blood level below 105 mtDNAcn
resulted associated with a five-folds increased risk of subfertility, providing a
possible way of predicting this condition.
What is known already: Low mtDNA content in oocytes and in cumulus
cells is a significant indicator of poor oocyte quality and may prevent the oocyte
from completing the process of fertilization and embryo development.
Furthermore, and of utmost relevance, is the recent evidence showing a correlation
between mtDNA content in cumulus cells and mtDNAcn in peripheral
blood cells.
Study design, size, duration: This is a nested case-control study drawn
from a prospective cohort of pregnant women referred for routine first trimester
screening for aneuploidies (from 11+0 to 12+6 weeks of gestation)
between January 2012 and March 2013 at the “Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico” of Milan, Italy.
Participants/materials, setting, methods: Cases were subfertile women
who attempted to become pregnant for 12–24 months. Controls were the two
subsequently age-matched women who became pregnant in less than one year.
Blood samples were obtained from all participating women. MtDNA was quantified
using real time PCR and normalized to nuclear DNA.
Main results and the role of chance: One hundred and four subfertile
women and 208 matched fertile controls were selected. The median (interquartile
range) mtDNAcn was 95 (73-124) and 145 (106-198), respectively
(p<0.001). The area under the receiver operating characteristic (ROC) curve
was 0.73 (95% Confidence Interval-CI: 0.67-0.79) (p<0.001). The Youden
index was 105 mtDNAcn. The crude odds ratio for subfertility in women with
mtDNAcn below this threshold was 5.72 (95%CI: 3.43-9.55). We repeated
these analyses in different age groups: the accuracy of mtDNAcn assessment in
peripheral blood resulted higher in younger women and progressively
decreased with increasing age.
Limitations, reasons for caution: We did not perform an infertility diagnostic
work-up of the couples and we are thus unable to rule out other potential
causes of subfertility. However, severe concomitant causes of infertility can be
confidently ruled out since all women conceived within two years.
Wider implications of the findings: MtDNAcn assessment in peripheral
blood appears to have all the features of the much sought non-invasive biomarker
of female fertility. Noteworthy its performance resulted very good in
young women. Our results may thus have future clinical applications. However,
further independent studies including non-pregnant women undergoing high
throughput screening are warranted.
Trial registration number: Not applicable.
peripheral blood have the potential to serve as a non invasive biomarker for
female subfertility?
Summary answer: A mtDNA peripheral blood level below 105 mtDNAcn
resulted associated with a five-folds increased risk of subfertility, providing a
possible way of predicting this condition.
What is known already: Low mtDNA content in oocytes and in cumulus
cells is a significant indicator of poor oocyte quality and may prevent the oocyte
from completing the process of fertilization and embryo development.
Furthermore, and of utmost relevance, is the recent evidence showing a correlation
between mtDNA content in cumulus cells and mtDNAcn in peripheral
blood cells.
Study design, size, duration: This is a nested case-control study drawn
from a prospective cohort of pregnant women referred for routine first trimester
screening for aneuploidies (from 11+0 to 12+6 weeks of gestation)
between January 2012 and March 2013 at the “Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico” of Milan, Italy.
Participants/materials, setting, methods: Cases were subfertile women
who attempted to become pregnant for 12–24 months. Controls were the two
subsequently age-matched women who became pregnant in less than one year.
Blood samples were obtained from all participating women. MtDNA was quantified
using real time PCR and normalized to nuclear DNA.
Main results and the role of chance: One hundred and four subfertile
women and 208 matched fertile controls were selected. The median (interquartile
range) mtDNAcn was 95 (73-124) and 145 (106-198), respectively
(p<0.001). The area under the receiver operating characteristic (ROC) curve
was 0.73 (95% Confidence Interval-CI: 0.67-0.79) (p<0.001). The Youden
index was 105 mtDNAcn. The crude odds ratio for subfertility in women with
mtDNAcn below this threshold was 5.72 (95%CI: 3.43-9.55). We repeated
these analyses in different age groups: the accuracy of mtDNAcn assessment in
peripheral blood resulted higher in younger women and progressively
decreased with increasing age.
Limitations, reasons for caution: We did not perform an infertility diagnostic
work-up of the couples and we are thus unable to rule out other potential
causes of subfertility. However, severe concomitant causes of infertility can be
confidently ruled out since all women conceived within two years.
Wider implications of the findings: MtDNAcn assessment in peripheral
blood appears to have all the features of the much sought non-invasive biomarker
of female fertility. Noteworthy its performance resulted very good in
young women. Our results may thus have future clinical applications. However,
further independent studies including non-pregnant women undergoing high
throughput screening are warranted.
Trial registration number: Not applicable.
Iris type:
1.5 Abstract in rivista
List of contributors:
Busnelli, A; Lattuada, D; Paffoni, A; Somigliana, E
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