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Placenta mitochondrial DNA mutation burden and the risk of preterm birth in pregnant women living with HIV Dunn, Rachel


Background: Preterm birth (PTB) (<37 weeks of gestation), the leading cause of mortality among children <5 years old, is up to three times more common among women living with HIV (WLWH) compared to the general population. The etiology of PTB remains poorly understood, but oxidative stress, and impaired placenta mitochondrial function are believed to play a role. Both HIV and antiretroviral therapy (ART) can affect mitochondrial DNA (mtDNA), which may contribute to high rates of PTB in WLWH. Maternal smoking and older age, both risk factors inPTB, have been associated with increased mtDNA mutation burden in blood. I herein exploredrare placenta mtDNA mutations and their association with PTB, maternal HIV, smoking, and age. Methods: Placenta mtDNA was sequenced using a molecular barcoding approach to detect rare substitutions within a 264bp region of the mitochondrial D-loop. MtDNA was sequenced from multiple locations within the same placenta, taken at multiple times post-delivery, and extracted by two different methods (silica column and salting-out). A subset of pregnant women (37 HIV+ and 27 HIV-negative), enrolled in two studies, 23 of whom had a PTB, was selected. Mutations were quantified within the 264bp region, within subregions known to be resistant to polymorphisms, and within a region outside hypervariable segments. Results: MtDNA sequencing showed low intra-placenta variability, no significant bias associated with time post-delivery up to 48h, but low correlation between two DNA extraction methods (rho=0.34, p=0.15). Increased placenta mtDNA mutations were associated with maternal smoking (p=0.006), and older age (rho=0.21, p=0.02). WLWH showed increased mtDNA mutations outside of hypervariable regions (p<0.001) and at positions typically resistant to polymorphisms (p=0.03). These associations persisted in multivariable models. Conclusions: My results suggest that a single placenta sampling collected within 48h of delivery would be suitable for future studies, but that the method of DNA extraction must be consistent within a study as it influences results. Rare placenta mtDNA mutations increase with maternal HIV, smoking, and age, three factors associated with PTB. However, PTB showed no independent association with placenta mtDNA mutations. The type of mutations differs between HIV and other factors, suggesting different mechanisms.

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