The role of genetics in pre-eclampsia and potential pharmacogenomic interventions

Figures & data

Table 1 Risk factors for pre-eclampsia

Risk factors for pre-eclampsia
Immunological	Nulliparity
	Primipaternity
	Donor sperm/oocyte
Obstetric	In vitro fertilization treatment
	Multiple pregnancy
	Previous adverse obstetric history – gestational hypertension, pre-eclampsia, fetal growth restriction, abruption placentae, perinatal death
Pre-existing conditions	Chronic hypertension
	Renal disease
	Type 2 diabetes
	Thrombophilia syndromes
	Autoimmune disorder
Abnormal uterine Doppler	Resistance index 0.58
	Presence of diastolic notch
Maternal factors	Extremes of maternal age
	Black ethnicity
	Obesity

Table 2 Candidate genes and predominant polymorphisms implicated in the pathogenesis of pre-eclampsia

Proposed mechanism	Gene name	Gene symbol	Polymorphism
Vasoactive proteins	Angiotensinogen	AGT	235Met > Thr
	Angiotensin converting enzyme	ACE	I/D intron 16
Thrombophilia and hypofibrinolysis	Factor V Leiden	F5	506Gln > Arg
	Methylenetetrahydrofolate reductase	MTHFR	C667T
	Prothrombin	F2	G20210A
	Plasminogen activator factor-1	SERPINE1	Promoter insertion/deletion
	Integrin glycoprotein IIIa	GPIIIA	C98T
Oxidative stress and lipid metabolism	Apolipoprotein E	APOE	C886T
	Microsomal epoxide hydrolase	EPHX	113Tyr > His
	Glutathione-S-transferase	GST	A313G
Endothelial function	Endothelial nitric oxide synthase 3	eNOS3	298Glu > Asp
	Vascular endothelial growth factor receptor 1	VEGFR1	TG repeat
	Vascular endothelial growth factor	VEGF	C936T
Immunogenetics	Tumour necrosis factor α	TNF	G-308A
	Interleukin 10	IL10	G1082A

Figure 1 The importance of nitric oxide (NO) in the regulation of endothelial function.

Abbreviations: eNOS, endothelial nitric oxide synthase; BH4, tetrahydrobiopterin; GC, guanylate cyclase; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; ONOO⁻, peroxynitrite; OH, hydroxide.

Table 3 Summary of pharmacogenomic studies on antiplatelet agents

Protein	Polymorphism	Patient numbers studied	Functional effects	Clinical effects
GP IIb/IIIa	PI^A(Pro33Leu)	>5000	Individuals with PI^A2 allele require higher dose of aspirin to achieve comparable anti-aggregant effect as wild-type homozygotes	Increased risk of thrombosis
GPIa	C807T	1170	Associated with collagen-receptor density on the platelet membrane surface and greater platelet reactivity	Conflicting data
COX-1	C50T	563	Associated with higher levels of thromboxane B2	No clinical data
COX-2	G-765C	24	Associated with a higher reduction of thromboxane B2levels after aspirin treatment	No clinical data
ADP subtype receptor	P2Y12	980	Associated with reduced platelet aggregation after aspirin intake	No clinical data

Abbreviations: ADP, adenosine diphosphate; COX, cyclooxygenase; GP, glycoprotein.