Genotypic and Phenotypic Markers of Pre-Eclampsia: A Folate Based Algorithm in Pregnancy

Abstract

Pre-eclampsia among pregnant women in Nigeria accounts for a high proportion of maternal and perinatal morbidity and mortality that has been reported. This study aimed to determine the pattern, sensitivity, and specificity of some genetic polymorphisms, epigenetic modification and phenotypic characteristics of some key enzymes in the folate cycle, in the pathogenesis and as potential markers of Pre-Eclampsia (PE) among pregnant women. Demographic and clinical histories were obtained from a group of 200 pregnant females clinically diagnosed with PE (Study Group) and 200 pregnant, normotensive females (Control Group) through questionnaires and hospital records. The biochemical parameters measured in the study were: red cell folate, plasma homocysteine (Hcy), plasma protein, methylene tetrahydrofolate reductase enzyme level (MTHFR) and malondialdehyde (MDA). The MTHFR C677T and MTR A2756G SNPs were amplified using PCR, and digested with Hinf I and Hae III restriction enzymes respectively. Methylation status of the MTHFR gene was assessed using the methylation specific PCR method. Homocysteine/MTHFR (Hcy/MTHFR) ratio at 81% sensitivity and homocysteine/protein ratio (Hcy/pro) at 77% sensitivity were better indicators of PE than Hcy (63% sensitivity) at a false positive rate of 10%. However, a combined nine parameter biomarker comprising of BMI, Hcy, MTHFR enzyme, MDA, Hcy/pro, Hcy/MTHFR, CpG island methylation status, MTHFR677 SNPs, and MTHFR/MTR Haplotypes, presented the highest sensitivity (83%) at 90% specificity for identifying PE at a cut-off value of 11 point (of 25). Folate metabolic derivatives, folate cycle gene polymorphisms and epigenetic modifications are significant factors in the pathogenesis of PE and may play significant role in the early identification of PE among pregnant women.