Increased protein-coding mutations in the mitochondrial genome of African American women with preeclampsia

Abstract

Preeclampsia occurs more frequently in women of African ancestry. The cause of this hypertensive complication is unclear, but placental oxidative stress may play a role. Because mitochondria are the major sites of oxidative phosphorylation, we hypothesized that placentas of preeclamptic pregnancies harbor mitochondrial DNA (mtDNA) mutations. Next-generation sequencing of placental mtDNA in African American preeclamptics (N = 30) and controls (N = 38) from Chicago revealed significant excesses in preeclamptics of nonsynonymous substitutions in protein-coding genes and mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 5 gene and an increase in the substitution rate (P = .0001). Moreover, 88% of preeclamptics and 53% of controls carried at least one nonsynonymous substitution (P = .005; odds ratio [OR] = 6.36, 95% confidence interval [CI]: 1.5-39.1). These results were not replicated in a sample of African American preeclamptics (N = 162) and controls (N = 171) from Detroit. Differences in study design and heterogeneity may account for this lack of replication. Nonsynonymous substitutions in mtDNA may be risk factors for preeclampsia in some African American women, but additional studies are required to establish this relationship.

Figure 1.

Haplotypes of the MT-ND5 gene in the Chicago sample; only nonsynonymous substitutions are shown. The haplotype for each of the individuals is displayed as a single horizontal line. Nonsynonymous substitutions that differ from the Yoruban L haplotype are shown as filled colored squares. Filled triangles show insertions causing frameshift mutations. Preeclamptics are individuals 1 to 25 (red squares) and controls are individuals 26 to 61 (blue squares). The site of the Met314Val variant is shown by an arrow. Haplogroups are shown on the right y-axis. See Supplement Table 1 for additional details.