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sFLT-1 gene polymorphisms and risk of severe-spectrum hypertensive disorders of pregnancy

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sFLT-1 gene polymorphisms and risk of severe-spectrum hypertensive disorders of pregnancy

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Content SFLT-1 GENE POLYMORPHISMS AND RISK OF SEVERE-SPECTRUM
HYPERTENSIVE DISORDERS OF PREGNANCY:
A PILOT CASE-CONTROL STUDY
by
Tracy Chen
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)
May 2024
Copyright 2024 Tracy Chen

ii
ACKNOWLEDGEMENTS
I would like to give special thanks to my thesis chair, Dr. Melissa Wilson, for her expert
guidance and support throughout the entirety of this project, as well as allowing me to join
several of her ongoing research studies. I would also like to thank my committee members, Dr.
Trevor Pickering and Dr. Claire Baldauf, for their many helpful insights and assistance with the
culmination of my Master’s thesis.

iii
TABLE OF CONTENTS
ACKNOWLEDGMENTS………………………………………………………………………...ii
LIST OF TABLES………………………………………………………………………………..iv
LIST OF FIGURES……………………………………………………………………………….v
ABSTRACT……………………………………………………………………………………...vi
CHAPTER ONE: INTRODUCTION……………………………………………………………..1
CHAPTER TWO: METHODS……………………………………………………………………3
CHAPTER THREE: RESULTS…………………………………………………………………..8
CHAPTER FOUR: DISCUSSION………………………………………………………………17
CHAPTER FIVE: CONCLUSION……………………………………………………………...21
REFERENCES…………………………………………………………………………………..22

iv
LIST OF TABLES
Table 1a: sFLT-1 single nucleotide polymorphisms……………………………………………...5
Table 1b: Pairwise linkage disequilibrium in sFLT-1 single nucleotide
polymorphisms…………………………………………………………………………………….5
Table 2: Maternal demographics and clinical characteristics stratified
by case-control status…………………………………………………………………………….10
Table 3a: Maternal and child carriage of sFLT-1 polymorphisms and
risk of HDP………………………………………………………………………………………12
Table 3b: Maternal and child carriage of sFLT-1 polymorphisms and
risk of severe PE/HELLP syndrome……………………………………………………………..12
Table 3c: Combined analysis of maternal and child carriage of sFLT-1
polymorphisms and risk of HDP and severe PE/HELLP syndrome……………………………..13
Table 4a: Maternal and child sFLT-1 haplotypes and risk of HDP……………………………...14
Table 4b: Maternal and child sFLT-1 haplotypes and risk of severe
PE/HELLP syndrome…………………………………………………………………………….15
Table 4c: Combined analysis of maternal and child sFLT-1 haplotypes
and risk of HDP and severe PE/HELLP syndrome……………………………………………...15

v
LIST OF FIGURES
Figure 1. Participant flow in HDP population…………………………………………………….8
Figure 2. Participant flow in Severe PE/HELLP syndrome population…………………………..9

vi
ABSTRACT
Objective: Soluble fms-like tyrosine kinase-1 (sFLT-1) is a splice variant of VEGF receptor-1
(Flt-1) implicated in the pathogenesis of hypertensive disorders of pregnancy (HDP) such as
preeclampsia (PE). Our study seeks to examine the role of sFLT-1 gene polymorphisms and its
association with HDP and severe PE or hemolysis, elevated liver enzymes, low platelet count
(HELLP) syndrome in parent-case dyads and triads.
Methods: Two patient cohorts (HDP and Severe PE/HELLP) were examined in this study. In the
HDP population, cases (n = 143) and controls (n = 169) of mother-baby dyads were recruited
from their postpartum hospital stay at the Los Angeles County Women’s and Children’s Hospital
(WCH). Cases (n = 99) and controls (n = 31) of mother-father-baby triads in the severe
PE/HELLP syndrome population were recruited through online HELLP syndrome research
websites. Case diagnosis was verified by medical chart abstraction. Four sFLT-1 SNPs
(rs7993594, rs3751395, rs7983774, and rs664393) were genotyped from buccal swab or saliva
samples. Genetic association analyses were performed using a log-linear regression model in the
Haplin package in R.
Results: In the HDP population, significant associations were found with double-dose maternal A
allele in the SNP rs7993594 [RR = 3.52 (95% CI 1.08, 11.20), p = 0.04]. The severe PE/HELLP
syndrome population revealed a significant protective effect in infants with single-dose carriage
of the A allele in SNP rs7983774 [RR = 0.59 (95% CI 0.36, 0.98), p = 0.05]. Mothers with
double-dose carriage of the G-t-G-G haplotype were also found to have significantly increased

vii
risk of severe PE/HELLP syndrome [RR = 4.13 (95% CI 1.22, 13.80), p = 0.02]. No parent-oforigin effects were observed.
Conclusion: rs7993594 polymorphism within the sFLT-1 gene is associated with increased risk
of HDP in a primarily Hispanic population. The G-t-G-G haplotype is associated with risk of
severe PE/HELLP syndrome in a Caucasian population.

1
CHAPTER ONE: INTRODUCTION
Hypertensive disorders of pregnancy (HDP) can complicate up to 10% of pregnancies in
the United States1 and encompass a range of severities, including preeclampsia, eclampsia,
chronic hypertension with superimposed preeclampsia, and gestational hypertension, as defined
by the American College of Obstetricians and Gynecologists (ACOG).2 Maternal complications
at time of delivery include placental abruption, heart failure, intravascular coagulopathy, acute
renal failure, and pleural effusions.3,4 Long term outcomes of maternal HDP consist of increased
risks of cardiovascular disease (CVD),22 diabetes mellitus, chronic kidney disease, and stroke.5,6
Neonatal complications include fetal growth restriction, intrapartum death, and stillbirth with
long-term associations seen in childhood asthma, early-onset CVD, and diabetes mellitus within
the first decade of life.7-9
HDP comprises a variety of clinical manifestations, and the molecular etiology remains
largely unclear. Studies have implicated an imbalance in the circulating plasma concentration of
angiogenic and anti-angiogenic factors to be integral in the pathophysiology of PE.10,11 The
upregulation of the anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1), and the
reduction of angiogenic factors, placental growth factor (PlGF) and vascular endothelial growth
factor (VEGF), have been associated with the development of PE.12-14
Located on Chromosome 13, sFLT-1 is a splice variant of the VEGF receptor-1 (Flt-1)
that inhibits angiogenesis by binding the pro-angiogenic factors PlGF and VEGF. Studies have
revealed excess sFLT-1 levels and reduced circulating free PlGF and VEGF in women before the
onset of PE13,14 and in preeclamptic placentas, with elevated levels usually subsiding after
placenta delivery.15 An imbalance in angiogenic factors is believed to lead to adverse pregnancy
outcomes16 such as the widespread endothelial dysfunction that is characteristic of PE. As

2
reviewed by Demir et al, PlGF and VEGF regulate the growth and differentiation of trophoblasts,
promote angiogenesis, and remodeling of the spiral arteries during normal placental
development.17 The release of excess sFLT-1 can be attributed to placental oxidative stress, thus
preventing the angiogenic factors, VEGF and PlGF, from binding to their receptors and initiating
angiogenesis.18
Polymorphisms within the sFLT-1 gene have been associated with a variety of human
health disorders. sFLT-1 single nucleotide polymorphisms (SNPs) have been found to be
associated with severity of rheumatoid arthritis,19 development of myocardial dysfunction,20 risk
of colorectal cancer,21 and survival rates of hepatocellular carcinoma.28 Genetic association
studies have also revealed relationships between some sFLT-1 SNPs and risk for PE,23,24 though
conflicting results have been observed in different populations.25,26
The primary aim of this study is to evaluate whether four currently unexamined
polymorphisms and haplotypes within the sFLT-1 gene are associated with pregnancies
complicated by HDP and severe PE/HELLP syndrome in mother-baby dyads and mother-fatherbaby triads, respectively. We also examine the presence of any parent-of-origin effects.

3
CHAPTER TWO: METHODS
Subjects.
HDP: This study population consisted of mother-baby dyads of cases of HDP (n = 143)
and healthy controls (n = 169) retrospectively recruited from Los Angeles County (LAC) +
University of Southern California (USC) Women’s and Children’s Hospital (WCH), identified
through delivery logs in 1999-2006 and during postpartum hospital stays in 2007-2008. Cases
recruited from WCH were women diagnosed with PE, eclampsia, gestational hypertension (GH),
or HELLP syndrome, identified by the attending physician and confirmed via chart review.
Controls from this same population were women with an absence of HDP clinical diagnosis in
pregnancy.
Severe PE/HELLP: Mother-father-baby triads (n = 130) were included in this study
population. Participants were recruited online through two HELLP syndrome-centered research
websites (www.hellpsyndromesociety.org or https://www.facebook.com/pages/Hellp-SyndromeResearch-at-USC/163745723652843). Cases (n = 99 triads) were women with self-identified
HELLP syndrome, verified through medical record abstraction whenever possible (92.9%).
Controls (n = 31 triads) were friends of cases who delivered a baby within 5 years of the index
pregnancy and self-reported that they did not experience HDP during their pregnancy.
Case Definition.
HDP: Cases were defined as PE if they had a systolic blood pressure ≥140 and/or
diastolic BP ≥ 90 on two occasions at least 6 hours apart and proteinuria, as demonstrated by ≥+1
on a dipstick or ≥300 mg/dL/24 hours. Participants with hypertension but no proteinuria were

4
defined as gestational hypertensives. Since we found no differences between these groups, they
were combined for analysis.
Severe PE/HELLP: Cases were verified to be HELLP syndrome if they met the following
criteria: (1) Hemolysis, as evidenced by peripheral blood smear indicating abnormal red blood
cells or by LDH ≥ 600, (2) AST or ALT ≥ 70, and (3) Platelets <100K with or without
hypertension and proteinuria. Women meeting 2 of 3 criteria were classified as severe PE, as all
presented with significant hypertension (BP ≥ 160/110 mmHg on two separate occasions, at least
6 hours apart) and proteinuria (500 mg/dL/24 hours or +3 dipstick on two occasions at least 6
hours apart). Cases for whom records could not be obtained were classified as severe PE (n = 6,
6.1%), as all study participants reviewed met at least these criteria.
Questionnaire.
Participant data was obtained through a standardized risk questionnaire in English or
Spanish to suit the Los Angeles Hispanic community (HDP population) based on the original
developed at the University of Pittsburgh (R. Ness, personal communication). The same
questionnaire, in English, was also used for the severe PE/HELLP population. Details regarding
family history, medical history, reproductive and sexual history, and the affected pregnancy were
collected via chart abstraction.
Chart Abstraction.
Medical records were requested from the hospital of delivery for all cases as well as
controls for the HDP population only. In the severe PE/HELLP population, obstetric and hospital
records were requested from the treating obstetrician and delivery hospital. To verify diagnosis,

5
records were reviewed by one of the investigators (MLW). A standardized data abstraction form,
with information regarding prenatal visits, delivery, obstetric history, and comorbidities, were
used to abstract record data.
Selection of Polymorphisms.
Four SNPs were selected for analysis within the sFLT-1 gene, intended to capture the
majority of the variation in the gene: rs7993594, rs3751395, rs7983774, and rs664393. Each
SNP was selected if it met at least one of the following criteria: 1) associated with health
outcomes in one or more peer-reviewed literature, 2) known to be a functional polymorphism
based on existing publications, 3) located in a coding region, resulting in a non-synonymous
amino acid substitution, 4) located in a regulatory or non-coding region, or 5) located in an
intronic region of the gene. Details on the selected SNPs are displayed in Tables 1a and 1b.
Table 1a. sFLT-1 single nucleotide polymorphisms
SNP (rs#) Variant
type Position Consequence Allele Reference
Allele
Alternate
Allele Associations
rs7993594 SNV chr13:28497814
(GRCh38.p14)
None C>T C=0.89 T=0.11 None
rs3751395 SNV chr13:28384818
(GRCh38.p14)
FLT1: Intron
Variant
C>A C=0.28 A=0.72 None
rs7983774 SNV chr13:28390188
(GRCh38.p14)
FLT1: Intron
Variant
G>A G=0.89 A=0.11 TP-53 mutated rectal
tumors [21]
rs664393 SNV chr13:28496864
(GRCh38.p14)
FLT1: 5’ UTR T>C T=0.10 C=0.90 Hepatocellular
carcinoma (HCC) [28]
Source: NCBI dbSNP41
Table 1b. Pairwise linkage disequilibrium in sFLT-1 single nucleotide polymorphisms*
Pairwise SNP (rs#)
Pairwise linkage
disequilibrium
(r2, d)

6
rs7993594-rs3751395 (0.035, 0.394)
rs7993594-rs7983774 (0.128, 0.383)
rs7993594-rs664393 (0.041, 1)
rs3751395-rs7983774 (0.151, 0.771)
rs3751395-rs664393 (0.051, 0.775)
rs7983774-rs664393 (0.13, 0.625)
*Calculated using LDlinkR Haplin package42
Sample Collection for Analytic Population.
DNA samples for the HDP population were obtained via saliva in mouthwash (73% of
samples) or buccal swabs for mothers and infants. For the severe PE/HELLP syndrome
population, DNA samples (n = 367) were collected via buccal swabs (n = 96) or saliva samples
(n = 271) (DNA Genotek, Ottawa, Canada). The DNA sampling method did not affect
genotyping failure rates. Buccal swab samples were extracted using QIAmp DNA mini kits,
according to the manufacturer's protocol (Qiagen, Valencia, CA). Samples obtained from saliva
were extracted using ethanol precipitation and following manufacturer protocol for those
collected via Oragene saliva kits (DNA Genotek, Ottawa, Canada).
Statistical Analyses.
Maternal demographic and clinical characteristics are presented as frequencies and
percentages for categorical variables or means ± standard deviations as well as median
(interquartile range) for continuous variables, stratified by case-control status for each patient
cohort (Table 2). The Haplin package (Version 7.3.0) implemented in the R statistical
programming language was used to analyze data from mother-baby dyads in the HDP population

7
and mother-father-baby triads in the HELLP syndrome population (R Foundation for Statistical
Programming, Vienna, Austria). Haplin is a flexible and robust software used to perform genetic
association analyses of case-parent triad data using a log-linear method, estimating single- and
double-dose relative risks (RR) and 95% confidence intervals for each genotype and haplotype.27
The most frequent alleles and haplotypes are used as reference. Haplin evaluates free response
models, parent-of-origin effects, and derives likelihood estimation
2
tests of association.
Unknown phases of haplotypes or missing genotypic data (father or child) were imputed using
Haplin’s Expectation-Maximization (EM) algorithm.27
Estimates of single-dose and double-dose effects in mothers and babies were analyzed.
We also evaluated free response models and parent-of-origin effects. A two-sided significance
level of α = 0.05 was used. Rare haplotypes (<4% frequency) were excluded due to wide
confidence intervals, thus resulting in a comparison of four haplotypes in the HDP population
and five haplotypes in the severe PE/HELLP syndrome population. All analyses were performed
using R statistical software (Version 4.2.3).

8
CHAPTER THREE: RESULTS
Participant Flow.
HDP: Data on 854 mothers and babies were collected at baseline. A total of 230
individuals that had not been genotyped were excluded from the final analysis. Select dyads were
only missing maternal genotypes (n = 3) or only missing baby genotypes (n = 6) due to failed
genotyping. In this case, genotypes were imputed using Haplin’s EM algorithm. 624 mothers and
babies were included in the final analytic dataset. Participant flow is illustrated in Figure 1.
Figure 1. Participant flow in HDP population
Severe PE/HELLP: Data was collected from 1187 mothers, fathers, babies, maternal
grandmothers, maternal grandfathers, sisters, or other extended family members at baseline.
Exclusion criteria were: triads missing biospecimen sample (n = 164), triads that had not been
Mother and baby cases and controls recruited
from WCH
(n = 854 individuals)
Excluded from dataset (n = 230):
- Both members of dyad not genotyped
Analytic population
(n = 624 individuals, 312 dyads)
Cases
(n = 286 individuals, 143 dyads)
Controls
(n = 338 individuals, 169 dyads)
- Imputed maternal genotypes (n = 3)
- Imputed baby genotypes (n = 6)

9
genotyped (n = 368), other family members who were not mother, father, or baby (n = 244), or
babies who were not the index child (n = 31). In the latter case, only 1 affected baby was
randomly chosen to be kept per family via an online randomizer tool. Information on maternal
grandmothers, maternal grandfathers, and sisters (n = 244) were collected in this cohort, but
ultimately excluded as these family members were not a part of the mother-father-baby triad. A
total of 807 individuals were excluded from the final analysis. The analytic population consisted
of 380 individuals (130 triads). Figure 2 depicts the flow of subjects within this cohort.
Figure 2. Participant flow in Severe PE/HELLP syndrome population
Maternal Demographics.
Medical records were reviewed for all cases in the HDP population and 92.9% of cases (n
= 92) in the severe PE/HELLP syndrome population. In the severe PE/HELLP population,
Participants with self-reported HELLP syndrome recruited
from HELLP syndrome research websites
(n = 1187 individuals)
Excluded from dataset (n = 807):
- Missing biospecimen data (n = 164)
- Not genotyped (n = 368)
- Not a member of the mom-dad-baby triad (n = 244)
- Multiple babies per triad (n = 31)
Cases
(n = 293 individuals, 99 triads)
Controls
(n = 87 individuals, 31 triads)
Analytic population
(n = 380 individuals, 130 triads)
Imputed baby genotypes
- Cases (n = 7)
- Controls (n = 1)

10
56.6% of subjects were classified as severe PE (n = 56) and 43.4% were classified as HELLP
syndrome (n = 43). Maternal characteristics are presented in Table 2.
Table 2: Maternal demographics and clinical characteristics stratified by case-control status
HDP SEVERE PE/HELLP SYNDROME
Variable N
Cases
(n = 143) N
Controls
(n = 169) N
Cases
(n = 99) N
Controls
(n = 31)
Age 142 27.9 ± 7.4 169 26.8 ± 7.0 98 31.0 ± 4.1 27 32.1 ± 4.0
Hispanic race
(%) 142 97.2 169 97.0 - NA - NA
White race (%) - NA - NA 98 97 (99.0) 28 28 (100.0)
Gestational age at
delivery (weeks) 142 36.8 ± 3.3 168 38.7 ± 2.0 96 33.1 ± 4.1 20 39.6 ± 1.8
Pre-pregnancy
weight (lbs) 143 151.9 ± 36.0 169 140.0 ± 27.1 81 147.5 ± 32.0 - NA
Max systolic
blood pressure
(mmHg)
134 162.9 ± 15.7 159 117.9 ± 10.9 92 159.6 ± 22.0 - NA
Max diastolic
blood pressure
(mmHg)
134 97.4 ± 9.9 159 68.9 ± 9.0 92 97.6 ± 13.4 - NA
Nulliparity (%) 142 168 96 23
Nulliparous 61 (43.0) 52 (31.0) 83 (86.5) 12 (52.2)
Parous 81 (57.0) 116 (69.0) 13 (13.4) 11 (47.8)
Parity 140 169 91 21
0 61 (43.6) 52 (30.8) 80 (87.9) 10 (47.6)
1 33 (23.6) 60 (35.5) 6 (6.6) 8 (38.1)
2 or more 46 (32.9) 57 (33.7) 5 (5.5) 3 (14.3)
Gravidity 142 169 92 21
1 50 (35.2) 43 (25.4) 68 (73.9) 10 (47.6)
2 34 (23.9) 48 (29.0) 16 (17.4) 6 (28.6)
3 20 (14.1) 30 (17.8) 5 (5.4) 3 (14.3)
4 or more 38 (26.8) 47 (27.8) 3 (3.3) 2 (9.5)
Status 99 -
Severe PE - NA - NA 56 (56.6) NA
HELLP - NA - NA 43 (43.4) NA
Lactate
dehydrogenase,
U/L
- NA - NA 52 601.5
(334, 1170) - NA

11
Bilirubin, mg/dL - NA - NA 67 1
(0.55, 2.1) - NA
Aspartate
aminotransferase,
U/L
- NA - NA 88 282
(129, 468) - NA
Alanine
aminotransferase,
U/L
- NA - NA 84 231
(137, 382) - NA
Creatinine
(mg/dL) - NA - NA 77 0.8
(0.7, 1) - NA
Platelet count,
10^9/L - NA - NA 90 58.5
(37.2, 89.6) - NA
Birthweight,
grams
127 3060
(2400, 3462) 159 3295
(3025, 3600) 83 1955
(1238, 2728) - NA
Fetal growth
restriction (%) 135 16 (11.9) 169 10 (5.9) 89 10 (11.2) - NA
Gestational
diabetes (%) 141 70 (49.6) 163 66 (40.5) 90 7 (7.8) - NA
HDP: The average maternal age was 27.9 ± 7.4 and 26.8 ± 7.0 among cases and controls,
respectively. A majority of subjects were Hispanic (97.2% of cases, 97% of controls). A larger
proportion of the cases presented as nulliparous (43%) as compared to controls (31%).
Severe PE/HELLP: Among cases and controls, the average maternal age was 31.0 ± 4.1
and 32.1 ± 4.0 respectively. Nearly all subjects were white (99% of cases, 100% of controls).
Similarly, a larger proportion of the cases were nulliparous (86.5%) as compared to controls
(52.2%).
Individual SNP Analysis.
HDP: Data from 312 mother-baby dyads (143 cases, 169 controls) were retained for
analysis. Missing genotypes were imputed for mothers (n = 3) and babies (n = 6) using Haplin’s
EM algorithm. We observed a statistically significant increased risk for HDP in mothers
possessing a double-dose carriage of the A allele in the SNP rs7993594 [RR = 3.52 (95% CI

12
1.08, 11.20), p = 0.04]. No other sFLT-1 SNP analyzed in mother and baby exhibited significant
associations with HDP (Table 3a).
Table 3a: Maternal and child carriage of sFLT-1 polymorphisms and risk of HDP
SNP Allele
Allele
frequency
(%)
Maternal Child
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
rs7993594 A 9.5
0.82
(0.46,
1.45)
0.50
3.52
(1.08,
11.20)
0.04
0.98
(0.57,
1.73)
0.96
0.77
(0.10,
6.45)
0.81
rs3751395 G 24.1
1.05
(0.71,
1.58)
0.81
1.06
(0.45,
2.46)
0.89
1.29
(0.85,
1.95)
0.23
1.33
(0.58,
3.14)
0.50
rs7983774 A 16.9
1.08
(0.70,
1.69)
0.72
1.30
(0.42,
3.97)
0.65
0.76
(0.48,
1.23)
0.26
0.66
(0.19,
2.26)
0.50
rs664393 A 9.9
0.66
(0.38,
1.17)
0.15 - -
0.76
(0.44,
1.34)
0.344
0.95
(0.12,
7.48)
0.95
-: RR not estimable due to small sample size
Severe PE/HELLP: 130 mother-father-baby triad (99 cases, 31 controls) data were
included in the analysis. A marginal significant protective effect was found in the child with a
single-dose carriage of the A allele in SNP rs7983774 [RR = 0.59 (95% CI 0.36, 0.98), p = 0.05].
Other sFLT-1 SNPs examined in mother or child were not significantly associated with severe
PE/HELLP syndrome risk (Table 3b).
Table 3b: Maternal and child carriage of sFLT-1 polymorphisms and risk of severe PE/HELLP
syndrome
SNP Allele
Allele
frequency
(%)
Maternal Child
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value

13
rs7993594 A 23.8
0.88
(0.54,
1.44)
0.60
0.46
(0.13,
1.69)
0.24
0.72
(0.44,
1.20)
0.21
0.38
(0.11,
1.41)
0.14
rs3751395 T 45.3
0.83
(0.49,
1.42)
0.49
1.22
(0.61,
2.49)
0.58
1.16
(0.65,
2.04)
0.61
1.35
(0.63,
2.99)
0.45
rs7983774 A 26.8
0.72
(0.44,
1.17)
0.18
0.50
(0.18,
1.45)
0.20
0.59
(0.36,
0.98)
0.05
0.50
(0.18,
1.42)
0.19
rs664393 A 11.3
0.87
(0.47,
1.64)
0.68
1.28
(0.27,
6.23)
0.75
0.98
(0.49,
1.89)
0.93
1.52
(0.32,
7.54)
0.59
Combined: RR ratios were similar among both the HDP and HELLP syndrome
populations, thus a combined analysis was performed (Table 3c). A total of 442 triads (242
cases, 200 controls) were included in the analysis. There was a marginally significant protective
effect found in a single-dose carriage of the A allele in the SNP rs7983774 in the child [RR =
0.72 (95% CI 0.51, 1.01), p = 0.05]. No other sFLT-1 SNPs analyzed in mother and child had
statistically significant associations with risk of HDP or severe PE/HELLP syndrome.
Table 3c: Combined analysis of maternal and child carriage of sFLT-1 polymorphisms and risk
of HDP and severe PE/HELLP syndrome
SNP Allele
Allele
frequency
(%)
Maternal Child
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
rs7993594 A 14.8
0.91
(0.64,
1.32)
0.64
1.44
(0.61,
3.43)
0.41
0.89
(0.60,
1.27)
0.51 0.68
(0.24, 2) 0.50
rs3751395 G 34.4
0.85
(0.62,
1.17)
0.31
1.27
(0.79,
2.07)
0.33
1.07
(0.77,
1.50)
0.68
1.37
(0.82,
2.31)
0.23
rs7983774 A 25.6
0.94
(0.68,
1.29)
0.69
0.93
(0.44,
2.02)
0.85
0.72
(0.51,
1.01)
0.05
0.71
(0.32,
1.54)
0.39

14
rs664393 A 10.4
0.75
(0.50,
1.13)
0.18
0.62
(0.14,
2.77)
0.52
0.85
(0.55,
1.30)
0.45
1.23
(0.36,
4.24)
0.74
Haplotype Analysis.
HDP: 95 dyads were removed in the haplotype analysis due to low frequencies. In the
remaining 217 dyads, no significant associations with maternal disease were found in mother or
child haplotypes (Table 4a).
Table 4a: Maternal and child sFLT-1 haplotypes and risk of HDP
rs7993594 rs3751395 rs7983774 rs664393 (n = 217)
Haplotype Frequency
(%)
Maternal Child
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
G-g-a-a 7.0
0.96
(0.25,
3.66)
0.94 - -
0.29
(0.04
2.30)
0.24 0.88
(0.04, 17) 0.93
a-g-a-G 4.3
1.35
(0.35,
5.42)
0.66
6.50
(0.50,
86.90)
0.16
0.31
(0.04,
2.51)
0.28 - -
G-g-G-G 6.6
1.02
(0.27,
3.90)
0.97 - -
0.59
(0.08,
4.79)
0.62
1.53
(0.12,
21.40)
0.74
G-T-G-G 81.8 REF REF
0.93
(0.24,
3.63)
0.92 REF REF
0.33
(0.04,
2.74)
0.32
-: RR not estimable due to small sample size
Severe PE/HELLP: A total of 58 triads were removed from analysis due to low
frequencies. An analysis of the 72 remaining triads revealed a significant increased risk in severe
PE/HELLP in mothers with double-dose carriage of the G-t-G-G haplotype [RR = 4.13 (CI 1.22,
13.80), p = 0.02] (Table 4b).

15
Table 4b: Maternal and child sFLT-1 haplotypes and risk of severe PE/HELLP syndrome
rs7993594 rs3751395 rs7983774 rs664393 (n = 72)
Haplotype Frequency
(%)
Maternal Child
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
G-G-a-a 9.9
1.60
(0.53,
4.75)
0.40 4.04
(0.32, 47) 0.27
1.30
(0.40,
4.29)
0.66
2.52
(0.19,
34.90)
0.48
a-G-a-G 19.7
1.68
(0.63,
4.51)
0.29 - -
0.64
(0.21, 2) 0.44
0.79
(0.07,
9.07)
0.85
G-G-G-G 23.1
2.01
(0.75,
5.46)
0.17
3.15
(0.58,
17.60)
0.19
1.16
(0.38,
3.51)
0.80
2.02
(0.35,
11.80)
0.42
a-t-G-G 6.0
1.06
(0.25,
4.39)
0.94
10.50
(0.72,
163)
0.09
1.10
(0.26,
4.42)
0.89
7.54
(0.46,
125)
0.16
G-t-G-G 40.3 REF REF
4.13
(1.22,
13.80)
0.02 REF REF
1.38
(0.38,
4.85)
0.63
-: RR not estimable due to small sample size
Combined: At a 4% threshold, 168 dyads or triads were excluded due to low haplotype
frequencies. Table 4c illustrates results from the combined population. We found a significant
increased risk for HDP/HELLP with double-dose carriage of the G-g-G-G haplotype in the child
[RR = 4.68 (CI 1.18, 18.20), p = 0.03] as well as double-dose G-T-G-G haplotype in mothers
[RR = 2.42 (CI 1.06, 5.47), p = 0.03]. A marginally significant increased risk was observed in
mothers with single-dose carriage of the a-g-a-G haplotype [RR = 2.13 (CI 0.98, 4.61), p = 0.06].
Table 4c: Combined analysis of maternal and child sFLT-1 haplotypes and risk of HDP and
severe PE/HELLP syndrome
rs7993594 rs3751395 rs7983774 rs664393 (n = 274)
Haplotype Frequency Maternal Child

16
(%) Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
Single
dose RR
(95% CI)
P-value
Double
dose RR
(95% CI)
P-value
G-g-a-a 7.9
1.82
(0.81,
4.02)
0.15 - -
1.04
(0.39,
2.78)
0.93
3.44
(0.54,
21.20)
0.19
a-g-a-G 8.0
2.13
(0.98,
4.61)
0.06 3.08
(0.33, 29) 0.32
0.93
(0.35,
2.53)
0.88
1.17
(0.12,
11.70)
0.89
G-g-G-G 11.0
2.03
(0.94,
4.42)
0.07
2.92
(0.64,
13.30)
0.17
1.30
(0.49,
3.44)
0.59
4.68
(1.18,
18.20)
0.03
G-T-G-G 73.0 REF REF
2.42
(1.06,
5.47)
0.03 REF REF
1.17
(0.43,
3.18)
0.76
-: RR not estimable due to small sample size
Parent-of-Origin Analysis.
No parent-of-origin effects were observed in individual alleles or haplotypes in mothers
or infants in the HDP or severe PE/HELLP populations separately. The combined analysis
showed a borderline significant parent-of-origin effect in rs3751395 [RRR = 0.46, 95% CI (0.21,
1.07), p = 0.07] associated with the maternal allele.

17
CHAPTER FOUR: DISCUSSION
Our study evaluated maternal and child genotypes and haplotypes to test for association
with development of maternal disease. We found evidence of significant increased risk of HDP
in mothers with the SNP rs7993594 as well as an increased risk for severe PE/HELLP syndrome
in the G-t-G-G haplotype. The combined analysis showed a significantly increased risk of HDP
and severe PE/HELLP syndrome in mothers with the G-T-G-G haplotype and infants with the Gg-G-G haplotype. No parent-of-origin effects were observed in the HDP and severe PE/HELLP
populations separately, however, a borderline significant result was found in the combined
analysis in rs3751395.
This study is the first to examine the four SNPs (rs7993594, rs3751395, rs7983774,
rs664393) in association with risk of HDP or HELLP syndrome in parent case-triads. Current
literature has examined the role of other sFLT-1 polymorphisms on PE susceptibility. A study by
McGinnis et al had observed a significant increased risk with PE in the SNP rs4769613, also
located on Chromosome 13, in the fetal genome in a genome-wide association study with
preferential inheritance of the C allele in a European population.23 An association signal
remained after conditioning out the effects of rs4769613, thus the investigators concluded that
other variants within the fetal FLT-1 genome may likely also be associated with PE susceptibility
independent of rs4769613. A similar study performed by Kikas et al also showed significance in
rs4769613 when stratified by placental sFLT-1 genotypes in Estonian cohorts.24 Placental FLT-1
gene expression and maternal serum sFLT-1 showed significantly higher transcript and
biomarker levels in PE cases. Contrary to the results from McGinnis and Kikas, studies by
Ohwaki et al and Macías-Salas et al did not find significant association in rs4769613 with
predisposition to PE in non-European populations.25,26 However, both of these studies had small

18
sample sizes which could have explained the non-significant results influenced by decreased
power to detect a significant genetic effect size.
Increased sFLT-1 gene expression has been observed in preeclamptic placentae in
addition to sFLT-1 overproduction.29,30 Upregulated sFLT-1 levels in PE cases have been found
in many similar studies.
16,30-33 sFLT-1 is released from the placenta into maternal circulation;
high concentrations of sFLT-1 have been identified in both early and late-onset PE, in
conjunction with diminished PlGF levels.34,35 This angiogenic imbalance in maternal serum has
been significantly associated with placental sFLT-1 levels,36 increased sFLT-1 mRNA
expression,37 and severity of preterm PE.33 A placentally derived sFLT-1 splice variant, sFLT-1
e15a protein, is expressed in the syncytiotrophoblast and found to have a ten-fold increase in
serum levels in PE cases.38 The same study by Palmer et al discovered that sFLT-1 e15a’s
antiangiogenic properties leads to endothelial dysfunction characterized by the inhibition of
endothelial cell tube formation and decreased endothelial cell migration and invasion.38
Angiogenic imbalance by excess sFLT-1 expression and its association with PE has been well
established by existing literature, however, there are no published studies on whether FLT-1
genetic variants confer higher sFLT-1 expression in PE cases. Our study adds to the existing
literature by introducing a genetic association within select sFLT-1 polymorphisms.
Of note, our study had observed a borderline significant parent-of-origin effect in
rs3751395 within the combined HDP and severe PE/HELLP population. A parent-of-origin
effect is statistically defined as the interaction effect of RRR = RRM,j / RRF,j, a measure of risk
associated with an allele Aj when inherited maternally versus paternally.39 Genomic imprinting,
an epigenetic phenomenon where either a maternal or paternal gene is expressed whereas the
other is silenced, can explain the presence of parent-of-origin effects.40 However, sFLT-1 is not

19
currently known to be an imprinted gene which is why our result is surprising. It is possible that
this may be a spurious finding.
This study has several limitations. First, one of four SNPs (rs7993594) showed deviation
from Hardy-Weinberg equilibrium (HWE). In the combined analysis, three of the four SNPs
(rs7993594, rs3751395, rs7983774) were not in HWE. This can occur for a variety of reasons
including, but not limited to: genotyping error, deletion polymorphisms, or parental
consanguinity.28 Another explanation could be the presence of maternal-fetal interactions.
Secondly, the severe PE/HELLP syndrome population relied on self-report of HELLP syndrome
diagnosis and only 92.9% of medical records were verified, though all cases reviewed were
confirmed severe PE cases as all at least met this criteria. There may have been some
misclassified cases in the severe PE/HELLP population, however, since we combined both
diagnoses into the case group, this should not affect our analysis. Additionally, charts were not
abstracted for the self-reported controls. If women with HDP were inadvertently included in the
control group, this could have led to attenuated RR estimates toward the null. Third, our results
may have been impacted by low sample size which reduces statistical power to detect the
presence of true associations, especially in the severe PE/HELLP syndrome population. Lastly,
participants in the HDP population were largely Hispanic and the severe PE/HELLP syndrome
population consisted of nearly all Caucasians. Due to the homogeneity of race/ethnicity within
each cohort, our results may not be generalizable to a larger, more diverse population.
Our study also has several strengths. This was the first study to examine the four SNPs
(rs7993594, rs3751395, rs7983774, rs664393) in association with HDP as well as severe
PE/HELLP syndrome in parent case-dyad/triads. Additionally, the inclusion of parent data in
mother-baby dyads and mother-father-baby triads allowed for the estimation of parent-of-origin

20
effects as well as the examination of individual genetic influences within each family member.
Lastly, all cases were verified PE diagnoses in the HDP population, and a majority (92.9%) of
cases were verified to be diagnosed as either severe PE or HELLP syndrome through medical
record abstraction in the severe PE/HELLP syndrome population.

21
CHAPTER FIVE: CONCLUSION
We conclude that one sFLT-1 polymorphism (rs7993594), expressed maternally, is
associated with increased risk of HDP and the G-t-G-G haplotype (rs7993594, rs3751395,
rs7983774, rs664393) is associated with severe-spectrum PE/HELLP syndrome. Future studies
should examine associations utilizing a larger sample size, within a more ethnically diverse
population, and with verification of diagnosis of all case participants.

22
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Abstract (if available)

Abstract Objective: Soluble fms-like tyrosine kinase-1 (sFLT-1) is a splice variant of VEGF receptor-1 (Flt-1) implicated in the pathogenesis of hypertensive disorders of pregnancy (HDP) such as preeclampsia (PE). Our study seeks to examine the role of sFLT-1 gene polymorphisms and its association with HDP and severe PE or hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome in parent-case dyads and triads.

Methods: Two patient cohorts (HDP and Severe PE/HELLP) were examined in this study. In the HDP population, cases (n = 143) and controls (n = 169) of mother-baby dyads were recruited from their postpartum hospital stay at the Los Angeles County Women’s and Children’s Hospital (WCH). Cases (n = 99) and controls (n = 31) of mother-father-baby triads in the severe PE/HELLP syndrome population were recruited through online HELLP syndrome research websites. Case diagnosis was verified by medical chart abstraction. Four sFLT-1 SNPs (rs7993594, rs3751395, rs7983774, and rs664393) were genotyped from buccal swab or saliva samples. Genetic association analyses were performed using a log-linear regression model in the Haplin package in R.

Results: In the HDP population, significant associations were found with double-dose maternal A allele in the SNP rs7993594 [RR = 3.52 (95% CI 1.08, 11.20), p = 0.04]. The severe PE/HELLP syndrome population revealed a significant protective effect in infants with single-dose carriage of the A allele in SNP rs7983774 [RR = 0.59 (95% CI 0.36, 0.98), p = 0.05]. Mothers with double-dose carriage of the G-t-G-G haplotype were also found to have significantly increased risk of severe PE/HELLP syndrome [RR = 4.13 (95% CI 1.22, 13.80), p = 0.02]. No parent-of-origin effects were observed.

Conclusion: rs7993594 polymorphism within the sFLT-1 gene is associated with increased risk of HDP in a primarily Hispanic population. The G-t-G-G haplotype is associated with risk of severe PE/HELLP syndrome in a Caucasian population.

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Asset Metadata

Creator Chen, Tracy (author)

Core Title sFLT-1 gene polymorphisms and risk of severe-spectrum hypertensive disorders of pregnancy

Contributor Electronically uploaded by the author (provenance)

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Degree Conferral Date 2024-05

Publication Date 04/05/2024

Defense Date 04/04/2024

Publisher Los Angeles, California (original), University of Southern California (original), University of Southern California. Libraries (digital)

Tag Gene,HELLP syndrome,OAI-PMH Harvest,polymorphisms,preeclampsia,sFLT-1

Format theses (aat)

Language English

Advisor Wilson, Melissa Lee (committee chair), Baldauf, Claire (committee member), Pickering, Trevor (committee member)

Creator Email tchen877@usc.edu,tracychen98@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC113871200

Unique identifier UC113871200

Identifier etd-ChenTracy-12765.pdf (filename)

Legacy Identifier etd-ChenTracy-12765

Document Type Thesis

Format theses (aat)

Rights Chen, Tracy

Internet Media Type application/pdf

Type texts

Source 20240408-usctheses-batch-1136 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA

Repository Email cisadmin@lib.usc.edu