Mitochondrial DNA Copy Number in Peripheral Blood in the First Trimester of Pregnancy and Different Preeclampsia Clinical Phenotypes Development: A Pilot Study

Abstract

Inflammation and oxidative stress are intrinsically linked to early poor placentation, typical of pregnancies complicated by preeclampsia associated with intrauterine growth restriction (PE-IUGR). Low mitochondrial DNA copy number (mtDNAcn) in peripheral blood constitutes a good peripheral surrogate marker of inflammation and oxidative stress. On these basis, we explored a possible correlation between mtDNAcn in peripheral blood in the first trimester of pregnancy and the PE-IUGR onset. To shed light on this issue, we setup a nested case–control study from a prospective cohort of pregnant women undergoing first-trimester aneuploidies screening. Two groups of patients affected by PE classified according to the clinical phenotype were identified: (1) patients who developed PE-IUGR and (2) patients who developed PE associated with appropriate for gestational age intrauterine fetal growth (PE-AGAf). Controls were women with a physiologic pregnancy matched to cases on the basis of age (±6 months, ratio 2:1). Mitochondrial DNA copy number was quantified using real-time polymerase chain reaction and normalized to nuclear DNA. The median (interquartile range) mtDNAcn in peripheral blood in patients with PE-IUGR (n = 12) and in patients with PE-AGAf (n = 16) was 70 (44-97) and 108 (95-145), respectively ( P = .004). Both these values were significantly lower than that detected in the control group (161[133-183], P < .001). The area under the receiver–operator curve for PE-IUGR and PE-AGAf were 0.94 (95% confidence interval [CI]: 0.88-1.00, P < .001) and 0.81 (95%CI: 0.70-0.91, P < .001), respectively. In conclusion, MtDNAcn in peripheral blood resulted significantly lower both in patients affected by PE-IUGR and in those affected by PE-AGAf when compared to controls. The accuracy of this biomarker resulted particularly good in predicting PE-IUGR.

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

“…Our data demonstrate increases in the immunostimulatory potential of CFCmtDNA and upregulation of DNA degradation mechanisms in women with preeclampsia during the third trimester. Additionally, this study sets the foundation for future investigations in the exact role of CFCmtDNA in the pathogenesis of preeclampsia, as previous studies have suggested that CFCmtDNA may be a potential pathogenic trigger or a contributor to the maintenance of the maternal syndrome in preeclampsia 13, 15, 16 .…”

“…Cross-sectional and case-control studies have reported increased CFCmtDNA copy number in serum and whole blood from women with preeclampsia in the third trimester 13, 14 or at time of delivery 15 . On the other hand, CFCmtDNA was suppressed in the first trimester in women who later developed preeclampsia 16 . These previous studies suggest that CFCmtDNA may be a potential pathogenic trigger or a contributor to the maintenance of the maternal syndrome in preeclampsia.…”

“…The copyright holder for this preprint this version posted February 5, 2021. ; https://doi.org/10.1101/2021.02.02.21250841 doi: medRxiv preprint 5 in women who later developed preeclampsia 16 . These previous studies suggest that CFCmtDNA may be a potential pathogenic trigger or a contributor to the maintenance of the maternal syndrome in preeclampsia.…”

Pilot Screening of Cell-Free mtDNA in NIPT: Quality Control, Variant Calling, and Haplogroup Determination

“…Due to continuous apoptosis of placental trophoblasts, pregnancy can be viewed as a pseudoinflammatory state [ 22 ]. As a result, mtDNA is detectable in maternal plasma in normal pregnancy and increased in cases of many pregnancy complications [ 23 , 24 , 25 , 26 ]. This increases the interest of clinicians in cf-mtDNA fraction due to its potential application in diagnostics of pregnancy pathologies such as preterm birth that is known to be tightly connected with inflammation [ 27 ].…”

Evaluation of D-loop hypervariable region I variations, haplogroups and copy number of mitochondrial DNA in Bangladeshi population with type 2 diabetes

“…Reduced mtDNA copy number in patients with type 2 diabetes is now well evident ( Al-Kafaji et al, 2018 ; Fazzini et al, 2021 ; Latini et al, 2020 ; Xu et al, 2012 ). Busnelli et al (2019) ) demonstrated indirect relation between reduced mtDNA copy number and oxidative stress along with inflammation. Variants within mtDNA are population specific and are clustered in lineages that in turn define haplogroups.…”